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'all of us' research project diversifies the storehouse of genetic knowledge.

Results from a DNA sequencer used in the Human Genome Project. National Human Genome Research Institute hide caption

Results from a DNA sequencer used in the Human Genome Project.

A big federal research project aimed at reducing racial disparities in genetic research has unveiled the program's first major trove of results.

"This is a huge deal," says Dr. Joshua Denny , who runs the All of Us program at the National Institutes of Health. "The sheer quantify of genetic data in a really diverse population for the first time creates a powerful foundation for researchers to make discoveries that will be relevant to everyone."

The goal of the $3.1 billion program is to solve a long-standing problem in genetic research: Most of the people who donate their DNA to help find better genetic tests and precision drugs are white.

"Most research has not been representative of our country or the world," Denny says. "Most research has focused on people of European genetic ancestry or would be self-identified as white. And that means there's a real inequity in past research."

For example, researchers "don't understand how drugs work well in certain populations. We don't understand the causes of disease for many people," Denny says. "Our project is to really correct some of those past inequities so we can really understand how we can improve health for everyone."

But the project has also stirred up debate about whether the program is perpetuating misconceptions about the importance of genetics in health and the validity of race as a biological category.

New genetic variations discovered

Ultimately, the project aims to collect detailed health information from more than 1 million people in the U.S., including samples of their DNA.

In a series of papers published in February in the journals Nature , Nature Medicine , and Communications Biology , the program released the genetic sequences from 245,000 volunteers and some analysis of those data.

"What's really exciting about this is that nearly half of those participants are of diverse race or ethnicity," Denny says, adding that researchers found a wealth of genetic diversity.

"We found more than a billion genetic points of variation in those genomes; 275 million variants that we found have never been seen before," Denny says.

"Most of that variation won't have an impact on health. But some of it will. And we will have the power to start uncovering those differences about health that will be relevant really maybe for the first time to all populations," he says, including new genetic variations that play a role in the risk for diabetes .

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Researchers gather health data for 'all of us'.

But one concern is that this kind of research may contribute to a misleading idea that genetics is a major factor — maybe even the most important factor — in health, critics say.

"Any effort to combat inequality and health disparities in society, I think, is a good one," says James Tabery , a bioethicist at the University of Utah. "But when we're talking about health disparities — whether it's black babies at two or more times the risk of infant mortality than white babies, or sky-high rates of diabetes in indigenous communities, higher rates of asthma in Hispanic communities — we know where the causes of those problem are. And those are in our environment, not in our genomes."

Race is a social construct, not a genetic one

Some also worry that instead of helping alleviate racial and ethnic disparities, the project could backfire — by inadvertently reinforcing the false idea that racial differences are based on genetics. In fact, race is a social category, not a biological one.

"If you put forward the idea that different racial groups need their own genetics projects in order to understand their biology you've basically accepted one of the tenants of scientific racism — that races are sufficiently genetically distinct from each other as to be distinct biological entities," says Michael Eisen , a professor of molecular and cell biology at the University of California, Berkeley. "The project itself is, I think, unintentionally but nonetheless really bolstering one of the false tenants of scientific racism."

While Nathaniel Comfort, a medical historian at Johns Hopkins, supports the All of Us program, he also worries it could give misconceptions about genetic differences between races "the cultural authority of science."

Denny disputes those criticisms. He notes the program is collecting detailed non-genetic data too.

"It really is about lifestyle, the environment, and behaviors, as well as genetics," Denny says. "It's about ZIP code and genetic code — and all the factors that go in between."

And while genes don't explain all health problems, genetic variations associated with a person's race can play an important role worth exploring equally, he says.

"Having diverse population is really important because genetic variations do differ by population," Denny says. "If we don't look at everyone, we won't understand how to treat well any individual in front of us."

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As a leading authority in the field of genomics, the National Human Genome Research Institute (NHGRI) strives to accelerate scientific and medical breakthroughs that improve human health. NHGRI drives cutting-edge research, developing new technologies, and studying the impact of genomics on society. The Institute collaborates with the scientific and medical communities to enhance genomic technologies that accelerate breakthroughs and improve lives.

NHGRI was established originally as the National Center for Human Genome Research in 1989 to lead the International Human Genome Project. NHGRI is part of the National Institutes of Health (NIH), the nation’s medical research agency. The Human Genome Project, which had as its primary goal the sequencing of the 3 billion DNA letters that make up the human genetic instruction book, was successfully completed in April 2003.

Since completion of the Human Genome Project, NHGRI has funded and conducted research to uncover the role that the genome plays in human health and disease. (A genome is an organism's complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism.) This research occurs across a spectrum: basic research to shed light on the structure and function of the genome; translational research to decipher the molecular bases of human diseases; and clinical research to establish how to use genomic information to advance medical care.

NHGRI also supports exploration of the complex ethical, legal, and social implications of genomics, and is committed to ensuring that the knowledge and benefits generated from genomics research are disseminated widely, both to fuel current and future researchers and to benefit the general public and promote genomic literacy.

External research guidance and advice related to NHGRI grants comes from the National Advisory Council for Human Genome Research, which meets three times a year in Rockville, Maryland. Members include representatives from health and science disciplines, public health, social sciences, and the general public. Portions of the council meetings are open to the public and webcast on GenomeTVLive . In addition, the Division of Intramural Research Board of Scientific Counselors reviews and evaluates NHGRI’s intramural program and the work of individual investigators within the Division.

Important Events in NHGRI history

1988 — Program advisory committee on the human genome is established to advise NIH on all aspects of research in the area of genomic analysis.

1988 — The Office for Human Genome Research is created within the NIH Office of the Director. Also, NIH and the Department of Energy (DOE) sign a memorandum of understanding, outlining plans for cooperation on genome research.

1988 — NIH Director James Wyngaarden, M.D., assembles scientists, administrators, and science policy experts in Reston, Virginia, to lay out an NIH plan for the Human Genome Project.

1989 — The program advisory committee on the human genome holds its first meeting in Bethesda, Maryland.

1989 — The NIH-DOE Ethical, Legal and Social Implications (ELSI) working group is created to explore and propose options for the development of the ELSI component of the Human Genome Project.

1989 — The National Center for Human Genome Research (NCHGR) is established to carry out the NIH's component of the Human Genome Project. James Watson, Ph.D., co-discoverer of the structure of DNA, is appointed as NCHGR’s first director.

1990 — The first five-year plan with specific goals for the Human Genome Project is published.

1990 — The National Advisory Council for Human Genome Research (NACHGR) is established.

1990 — The Human Genome Project officially begins.

1991 — NACHGR meets for the first time in Bethesda, Maryland.

1992 — James Watson resigns as first director of NCHGR. Michael Gottesman, M.D., is appointed acting center director.

1993 — The center's Division of Intramural Research is established.

1993 — Francis S. Collins, M.D., Ph.D., is appointed NCHGR director.

1993 — The Human Genome Project revises its five-year goals and extends them to September 1998.

1994 — The first genetic linkage map of the human genome is achieved one year ahead of schedule. Such maps consist of DNA patterns, called markers, positioned on chromosomes, and help researchers search for disease-related genes.

1995 — Task Force on Genetic Testing is established as a subgroup of the NIH-DOE Ethical, Legal, and Social Implications (ELSI) working group.

1996 — Human DNA sequencing begins with pilot studies at six U.S. universities.

1996 — An international team completes the DNA sequence of the first eukaryotic genome , Saccharomyces cerevisiae , or common brewer's yeast. (A eukaryote is any organism whose cells contain a nucleus and other organelles enclosed within membranes.)

1996 — The Center for Inherited Disease Research, a project co-funded by eight NIH institutes and centers to study the genetic components of complex disorders, is established on the Johns Hopkins Bayview Medical Center campus in Baltimore, Maryland.

1996 — Scientists from government, university, and commercial laboratories around the world reveal a map that pinpoints the locations of more than 16,000 genes in human DNA.

1996 — NCHGR and other researchers identify the location of the first gene associated with Parkinson's disease.

1996 — NCHGR and other researchers identify the location of the first major gene that predisposes men to prostate cancer.

1997 — Department of Health and Human Services Secretary Donna E. Shalala signs documents elevating NCHGR to an NIH institute, the National Human Genome Research Institute.

1997 — A federal government-citizen group – the NIH-DOE ELSI Working Group and the National Action Plan on Breast Cancer (NAPBC) – suggests policies to limit genetic discrimination in the workplace.

1997 — NHGRI and other scientists show that three specific alterations in the breast cancer genes BRCA1 and BRCA2 are associated with an increased risk of breast, ovarian and prostate cancers.

1997 — A map of human chromosome 7 is completed. Changes in the number or structure of chromosome 7 occur frequently in human cancers.

1997 — NHGRI and other researchers identify an altered gene that causes Pendred syndrome, a genetic disorder that causes early hearing loss in children.

1998 — Vice President Al Gore announces that the Clinton administration is calling for legislation to bar employers from discriminating against workers in hiring or promotion because of their genetic makeup.

1998 — At a meeting of the Human Genome Project’s main advisory body, project planners present a new five-year plan to produce a “finished” version of the DNA sequence of the human genome by the end of year 2003, two years ahead of its original schedule. The Human Genome Project plans to generate a “working draft” that, together with the finished sequence, will cover at least 90 percent of the genome in 2001. The “working draft” will be immediately valuable to researchers and form the basis for a high-quality, “finished” genome sequence.

1998 — A major international collaborative research study finds the site of a gene for susceptibility to prostate cancer on the X chromosome. This is the first time a gene for a common type of cancer is mapped to the X chromosome.

1998 — NHGRI and other Human Genome Project-funded scientists sequence the genome of the tiny roundworm Caenorhabditis elegans . It marks the first time scientists have spelled out the instructions for a complete animal that, like humans, has a nervous system, digests food and has sex.

1999 — The pilot phase of the Human Genome Project is completed. A large-scale effort to sequence the human genome begins.

1999 — NHGRI, DOE, and the Wellcome Trust, a global charity based in London, hold a celebration of the completion and deposition of 1 billion base pairs of the human genome DNA sequence into GenBank (http://www.ncbi.nlm.nih.gov/genbank/). GenBank is the NIH genetic sequence database, an annotated collection of all publicly available DNA sequences.

1999 — For the first time, NHGRI and other Human Genome Project-funded scientists unravel the genetic code of an entire human chromosome (chromosome 22). The findings are reported in Nature .

2000 — President Clinton signs an Executive Order to prevent genetic discrimination in the federal workplace. NHGRI programs on the ethical, legal and social implications of the Human Genome Project played a role in the development of policy principles on this issue.

2000 — Public consortium of scientists and a private companyelease a substantially complete genome sequence of the fruit fly, Drosophila melanogaster . Science publishes the findings.

2000 — Scientists in Japan and Germany report that they have unraveled the genetic code of human chromosome 21, known to be involved with Down syndrome, Alzheimer's disease, Usher syndrome, and amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. Nature publishes these findings.

2000 — President Bill Clinton, NHGRI Director Francis Collins, British Prime Minister Tony Blair (via satellite), and Craig Venter, president, Celera Genomics Corp., announce the completion of the first survey of the human genome in a White House ceremony.

2000 — An international team led by NHGRI scientists discover a genetic “signature” that may help explain how malignant melanoma, a deadly form of skin cancer, can spread to other parts of the body. The findings are reported in Nature .

2000 — The NIH, the Wellcome Trust, and three private companies collaborate to form the Mouse Sequencing Consortium to accelerate the sequencing of the mouse genome.

2001 — The ELSI Research Programs of NHGRI and DOE cosponsor a conference to celebrate a decade of research and consider the impact of the new science on genetic research, health and policy.

2001 — The Human Genome Project publishes the first analysis of the human genome sequence, describing how it is organized and how it evolved. The analysis, published in the journal Nature , reveals that the human genome only contains 30,000 to 40,000 genes, far fewer than the 100,000 previously estimated.

2001 — NHGRI and Human Genome Project-funded scientists find a new tumor suppressor gene on human chromosome 7 that is involved in breast, prostate and other cancers. A single post-doctoral researcher, using the “working draft” data, pins down the gene in weeks. In the past, the same work would have taken several years and contributions from many scientists.

2001 — Researchers from NHGRI and Sweden's Lund University develop a method of accurately diagnosing four complex, hard-to-distinguish childhood cancers using DNA microarray technology and artificial neural networks. Nature Medicine publishes the results.

2001 — NHGRI creates the Centers for Excellence in Genomic Sciences (CEGS) program, which supports interdisciplinary research teams that use data sets and technologies developed by the Human Genome Project. The initial CEGS grants for innovative genomic research projects are awarded to the University of Washington and Yale University.

2002 — NHGRI scientists and collaborators at Johns Hopkins Medical Institution in Baltimore and The Cleveland Clinic identify a gene on chromosome 1 that is associated with an inherited form of prostate cancer in some families. Nature Genetics publishes the findings.

2002 — NHGRI and the NIH Office of Rare Diseases launch a new information center – the Genetic and Rare Diseases Information Center (GARD) — to provide accurate, reliable information about genetic and rare diseases to patients and their families.

2002 — NHGRI launches a redesigned Web site, www.genome.gov , which provides improved usability and easy access to new content for a wide range of users.

2002 — NHGRI launches the International HapMap Project, a $100 million, public-private effort to create a new type of genome map that will chart genetic variation among human populations. The HapMap serves as a tool to speed the search for the genes involved in common disorders such as asthma, diabetes, heart disease and cancer. The SNP Consortium, a collaborative effort among industry, academic centers and the Wellcome Trust, helps provide an instrumental public catalog of genetic variation.

2002 — NHGRI names Alan E. Guttmacher, M.D., as its new deputy director. It selects Eric D. Green, M.D., Ph.D., as its new scientific director, and William A. Gahl, M.D., Ph.D., as its new intramural clinical director.

2003 — NHGRI launches the ENCyclopedia of DNA Elements (ENCODE) pilot project to identify all functional elements in human DNA.

2003 — NHGRI celebrates the successful completion of the Human Genome Project — two years ahead of schedule and under budget. The event coincides with the 50th anniversary of the description of DNA’s double helix and the 2003 publication of the vision document for the future of genomics research.

2003 — NHGRI researchers identify the gene that causes the premature aging disorder progeria. Nature publishes the findings .

2003 — A detailed analysis of the sequence of the human Y chromosome is published in the journal Nature .

2003 — A detailed analysis of the sequence of chromosome 7 uncovers structural features that appear to promote genetic changes that can cause disease. The findings by a multinational team of scientists are reported in the journal Nature .

2003 — A team of researchers, led by NHGRI, compares the genomes of 13 vertebrate animals. The results, published in Nature , suggest that comparing a wide variety of species' genomes will illuminate genomic evolution and help identify functional elements in the human genome.

2003 — NHGRI establishes the Education and Community Involvement Branch to engage the public in understanding genomics and accompanying ethical, legal and social issues.

2003 — NHGRI announces the first grants in a three-year, $36 million scientific program called ENCyclopedia Of DNA Elements (ENCODE) , aimed at discovering all parts of the human genome that are crucial to biological function.

2003 — NHGRI selects five centers to carry out a new generation of large-scale genome sequencing projects to realize the promise of the Human Genome Project and expand understanding of human health and disease.

2003 — NHGRI announces formation of the Social and Behavioral Research Branch within its Division of Intramural Research .

2003 — NHGRI announces the first draft version of the chimpanzee genome sequence and its alignment with the human genome.

2004 — NHGRI announces that the first draft version of the honey bee genome sequence has been deposited into free public databases.

2004 — The Genetic and Rare Disease Information Center announces efforts to enable healthcare workers, patients and families who speak Spanish to take advantage of its free services.

2004 — NHGRI's Large-Scale Sequencing Research Network announces it will begin genome sequencing of the first marsupial, the gray short-tailed South American opossum, and more than a dozen other model organisms to further understanding of the human genome.

2004 — NHGRI announces that the first draft version of the chicken genome sequence has been deposited into free public databases.

2004 — The International Rat Genome Sequencing Project Consortium announces the publication of a high-quality draft sequence of the rat genome. The publication is important because of the rat’s ubiquitous use as a disease research model.

2004 — NHGRI announces that the first draft version of the dog genome sequence has been deposited into free public databases.

2004 — NHGRI launches the NHGRI Policy and Legislative Database, an online resource to enable researchers, health professionals, and the public to locate information on laws and policies related to genetic discrimination and other genomic issues .

2004 — NHGRI's Large-Scale Sequencing Research Network announces a comprehensive strategic plan to sequence 18 additional organisms, including the African savannah elephant, the domestic cat, and the orangutan to help interpret the human genome.

2004 — NHGRI launches four interdisciplinary Centers for Excellence in Ethical, Legal and Social Implications Research to address some of the most pressing societal questions raised by recent advances in genetic and genomic research .

2004 — NHGRI announces that the first draft version of the cow genome sequence has been deposited into free public databases.

2004 — NHGRI awards more than $38 million in grants to develop new genome sequencing technologies to accomplish the near-term goal of sequencing a mammalian-sized genome for $100,000, and the longer-term challenge of sequencing an individual human genome for $1,000 or less. These are the first grants from the Advanced Sequencing Technology Program .

2004 — The International Human Genome Sequencing Consortium, led in the United States by NHGRI and the Department of Energy, publishes its scientific description of the finished human genome sequence. The analysis, published in Nature, reduces the estimated number of human protein-coding genes from 35,000 to only 20,000-25,000, a surprisingly low number for our species.

2004 — The ENCODE Consortium publishes a paper in Science that sets forth the scientific rationale and strategy behind its quest to produce a comprehensive catalog of all parts of the human genome crucial to biological function.

2005 — NIH hails the first comprehensive analysis of the sequence of the human X chromosome. The work, some of which was carried out as part of the Human Genome Project, is published in Nature. It provides sweeping new insights into the evolution of sex chromosomes and the biological differences between males and females.

2005 — The International HapMap Consortium publishes a comprehensive catalog of human genetic variation. This landmark achievement published in Nature , will serve to accelerate the search for genes involved in common diseases, such as asthma, diabetes, cancer, and heart disease.

2005 — NHGRI and the National Cancer Institute (NCI) launch The Cancer Genome Atlas (TCGA), a comprehensive effort to accelerate understanding of the molecular basis of cancer through the application of genome analysis technologies .

2006 — The Genetic Association Information Network (GAIN), a public-private partnership led by NHGRI, is established to help find the genetic causes of common diseases by conducting large-scale genomic studies and making their results broadly available to researchers worldwide.

2006 — NIH launches the Genes, Environment and Health Initiative (GEI) to understand the interactions of genetics and environment in common conditions and disease. It is managed by NHGRI and the National Institute of Environmental Health Sciences.

2007 — The Electronic Medical Records and Genomics (eMERGE) Network is announced in September 2007 . Researchers use DNA biorepositories and electronic medical records in large-scale studies to better understand the underlying genomics of disease .

2007 — In a White House Ceremony, NHGRI Director Francis S. Collins is awarded the Presidential Medal of Freedom by President George W. Bush for his leadership of and contributions to the Human Genome Project.

2007 — To better understand the role that bacteria, fungi, and other microbes play in human health, NIH launches the Human Microbiome Project. The human microbiome is all microorganisms present in or on the human body. NHGRI, the National Institute of Allergy and Infectious Diseases, and the National Institute of Dental and Craniofacial Research lead the project on behalf of NIH.

2008 — The NIH Genome-Wide Association Studies (GWAS) data sharing policy goes into effect to promote access to genomics research data while ensuring research participant protections.

2008 — An international research consortium announces the establishment of the 1000 Genomes Project. This effort will involve sequencing the genomes of at least 1000 people from around the world to create the most detailed and medically useful picture to date of human genetic variation. NHGRI is a major funder of the 1000 Genomes Project .

2008 — NHGRI and the National Institute of Environmental Health Sciences collaborate with the U.S. Environmental Protection Agency to begin testing the safety of chemicals, ranging from pesticides to household cleaners . The initiative uses the NIH Chemical Genomics Center's high-speed, automated screening robots to test suspected toxic compounds using cells and isolated molecular targets instead of laboratory animals.

2008 — President George W. Bush signs into law the Genetic Information Nondiscrimination Act (GINA) that will protect Americans against discrimination based on their genetic information when it comes to health insurance and employment. The bill passed the Senate unanimously and the House by a vote of 414 to 1.

2008 — Francis S. Collins steps down as NHGRI director. Alan E. Guttmacher is named acting director of NHGRI.

2008 — The TCGA Research Network reports the first results of its large-scale, comprehensive study of the most common form of brain cancer, glioblastoma. In a paper published in Nature , the TCGA team describes the discovery of new genetic mutations and other types of DNA alterations with potential implications for the diagnosis and treatment of glioblastoma.

2008 — The NIH Human Microbiome Project, collaborating with scientists around the globe, announces they will form the International Human Microbiome Consortium, an effort that will enable researchers to characterize the relationship of the human microbiome in the maintenance of health and in disease.

2008 — An international consortium including NHGRI researchers, in search of the genetic risk factors for obesity, identifies six new genetic variants associated with BMI, or body mass index, a measurement that compares height to weight. The results, funded in part by NIH, are published online in the journal Nature Genetics .

2009 — A team led by NHGRI scientists identifies a gene that suppresses tumor growth in melanoma, the deadliest form of skin cancer. The finding is reported in the journal Nature Genetics as part of a systematic genetic analysis of a group of enzymes implicated in skin cancer and many other types of cancer.

2009 — NHGRI announces the release of the first version of PhenX, a free online toolkit aimed at standardizing measurements of research subjects' physical characteristics and environmental exposures. The tools give researchers more power to compare data from multiple studies, accelerating efforts to understand the complex genetic and environmental factors that cause cancer, heart disease, depression and other common diseases.

2009 — The U.S. Department of Agriculture and NIH announce that an international consortium of researchers has completed an analysis of the genome of domestic cattle, the first livestock mammal to have its genetic blueprint sequenced and analyzed. The landmark research, which received major support from NHGRI, bolsters efforts to produce better beef and dairy products and will lead to a better understanding of the human genome.

2009 — NIH launches the first integrated drug development pipeline to produce new treatments for rare and neglected diseases. The $24 million program, whose laboratory operations are managed by NHGRI at the NIH Chemical Genomics Center, jumpstarts a trans-NIH initiative called the Therapeutics for Rare and Neglected Diseases program.

2009 — NHGRI researchers studying the skin's microbiome publish an analysis in Science revealing that our skin is home to a much wider array of bacteria than previously thought. The study, done in collaboration with other NIH researchers, also shows the bacteria that live under your arms are likely to be more similar to those under another person's arm than they are to the bacteria that live on your forearm.

2009 — An NIH research team led by NHGRI researchers finds that a single evolutionary event appears to explain the short, curved legs that characterize all of today's dachshunds, corgis, basset hounds and at least 16 other breeds of dogs. The unexpected discovery provides new clues about how physical differences may arise within species and suggests new approaches to understanding a form of human dwarfism. The results are reported in Science .

2009 — NIH researchers report in the online issue of PLoS Genetics the discovery of five genetic variants related to blood pressure in African Americans, findings that may provide new clues to treating and preventing hypertension. This effort, which includes NHGRI researchers, marks the first time that a relatively new research approach, called a genome-wide association study, has focused on blood pressure and hypertension in an African-American population.

2009 — Researchers, supported in part by NHGRI, generate massive amounts of DNA sequencing data of the complete set of exons, or “exomes,” from the genomes of 12 people. The findings, which demonstrate the feasibility of this strategy to find rare genetic variants that may cause or contribute to disease, are published online in Nature.

2009 — NHGRI researchers lead a study that identifies a new group of genetic mutations involved in melanoma, the deadliest form of skin cancer. This discovery, published in Nature Genetics , is particularly encouraging because some of the mutations, which were found in nearly one-fifth of melanoma cases, reside in a gene already targeted by a drug approved for certain types of breast cancer.

2009 — NHGRI launches the next generation of its online Talking Glossary of Genetic Terms. The glossary contains several new features, including more than 100 colorful illustrations and more than two dozen 3-D animations that allow the user to dive in and see genetic concepts in action at the cellular level.

2009 — An NHGRI-led research team finds that carriers of a rare, genetic condition called Gaucher disease face a risk of developing Parkinson's disease more than five times greater than the general public. The findings are published in the New England Journal of Medicine .

2009 — NIH director Francis S. Collins, M.D., Ph.D., announces the appointment of Eric D. Green, M.D., Ph.D., to be director of NHGRI. It is the first time an institute director has risen to lead the entire NIH and subsequently picked his own successor.

2010 — NHGRI launches the Genetics/Genomics Competency Center (G2C2) , an online tool to help educators teach the next generation of health professionals about genetics and genomics.

2010 — An international research team, including researchers from NHGRI, produce the first whole genome sequence of the 3 billion letters in the Neanderthal genome.

2010 — NIH and the Wellcome Trust, a global charity based in London, announce a partnership called the Human Heredity and Health in Africa project (H3Africa) to support population-based genetic studies in Africa by Africa. NHGRI helps administer H3Africa .

2010 — Daniel L. Kastner, M.D., Ph.D., is appointed scientific director of the NHGRI.

2011 — NHGRI's new strategic plan, Charting a course for genomic medicine, from base pairs to bedside , for the future of human genome research is published in the February 10, 2011, issue of Nature .

2011 — A research team from the NIH Undiagnosed Diseases Program, which is co-led by NHGRI, reports in the New England Journal of Medicine the first genetic finding of a rare, adult-onset vascular disorder associated with progressive and painful arterial calcification.

2011 — The Partnership for Public Service selects NHGRI Clinical Director William A. Gahl, M.D., Ph.D., to receive its Science and Environmental Medal (one of nine annual Service to America Awards, or Sammies).

2011 — P. Paul Liu, M.D., Ph.D., a world expert in the onset, development and progression of leukemia, is named NHGRI's deputy scientific director.

2011 — Mark S. Guyer, Ph.D., is named NHGRI deputy director.

2011 — NHGRI announces funding for its five Clinical Sequencing Exploratory Research projects aimed at studying ways that healthcare professionals can use genome sequencing information in the clinic.

2012 — For the first time, researchers in the NIH Human Microbiome Project (HMP) Consortium – including NHGRI investigators — map the normal microbial make-up of healthy humans. They report their findings in a series of coordinated papers in Nature and other journals.

2012 — ENCODE researchers produce a more dynamic picture of the human genome that gives the first holistic view of how the human genome actually does its job. The findings are reported in two papers appearing in Nature .

2012 — NHGRI reorganizes the institute's Extramural Research Program into four new divisions and promotes to division status the office overseeing policy, communications, and education, and the office overseeing administration and management. The divisions and their inaugural directors include: Division of Genome Sciences, Jeffery Schloss, Ph.D.; Division of Genomic Medicine, Teri Manolio, M.D., Ph.D.; Division of Extramural Operations, Bettie Graham, Ph.D.; Division of Genomics and Society, (acting director) Mark Guyer, Ph.D.; Division of policy, communications, and education, Laura Lyman Rodriguez, Ph.D.; and Division of Management, Janis Mullaney, M.B.A.

2012 — NHGRI Director, Dr. Eric Green, creates the The History of Genomics Program within the Office of the Director.

2013 — A special symposium, The Genomics Landscape: A Decade After the Human Genome Project, marks the 10th anniversary of the completion of the Human Genome Project.

2013 — The Smithsonian Institution in Washington, D.C. opens a high-tech, high-intensity exhibition Genome: Unlocking Life's Code to celebrate the 10th anniversary of researchers producing the first complete human genome sequence. The exhibition is a collaboration between the Smithsonian Institution’s National Museum of Natural History and NHGRI. The exhibition will travel across North America following its time at the Smithsonian.

2013 — NHGRI and the Eunice Kennedy Shriver National Institute of Child Health and Human Development announce awards for pilot projects to explore the use of genomic sequencing in newborn healthcare.

2013 — NHGRI selects Lawrence C. Brody, Ph.D., to be the first director of the Division of Genomics and Society, established through the October 2012 reorganization.

2014 — NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., implements a reorganization of NHGRI's 45 intramural investigators and associated research programs into nine branches.

2014 — NHGRI Deputy Director Mark Guyer, who played a critical role in the Human Genome Project and countless other genomics programs, retires from federal service.

2014 — NIH issues the NIH Genomic Data Sharing policy to promote data sharing as a way to speed the translation of data into knowledge, products and procedures that improve health while protecting the privacy of research participants. The final policy will be effective for all NIH-supported research beginning in January 2015.

2014 — Scientists looking across human, fly, and worm genomes find that these species have shared biology. The findings, appearing in the journal Nature , offer insights into embryonic development, gene regulation and other biological processes vital to understanding human biology and disease.

2014 — An international team including researchers from NIH completes the first comprehensive characterization of genomic diversity across sub-Saharan Africa. The study provides clues to medical conditions in people of sub-Saharan African ancestry, and indicates that the migration from Africa in the early days of the human race was followed by a migration back into the continent.

2014 — Investigators with The Cancer Genome Atlas (TCGA) Research Network identify new potential therapeutic targets for a major form of bladder cancer.

2014 — Ellen Rolfes, M.A., is appointed the NHGRI executive officer and director of the NHGRI Division of Management.

2015 — NHGRI celebrates the 25th anniversary of the launch of the Human Genome Project (HGP). To commemorate this anniversary, NHGRI’s History of Genomics Program hosts a seminar series titled, “A Quarter Century after the Human Genome Project: Lessons Beyond Base Pairs,” featuring HGP participants sharing their perspectives about the project and its impact on their careers.

2015 — The Undiagnosed Diseases Network (UDN) opens an online patient application, the UDN Gateway, to streamline the patient application process across its individual clinical sites.

2015 — An international team of scientists from the 1000 Genomes Project Consortium creates the world’s largest catalog of genomic differences among humans, providing researchers with powerful clues to help them establish why some people are susceptible to various diseases.

2015 — NHGRI awards grants of more than $28 million aimed at deciphering the language of how and when genes are turned on and off. The awards emanate from NHGRI’s Genomics of Gene Regulation (GGR) program.

2015 — Shawn Burgess, Ph.D., and colleagues develop transgenic zebrafish as a live animal model of metastasis, offering cancer researchers a new, potentially more accurate way to screen for drugs and to identify new targets against disease.

2015 — Experts from academic and non-profit institutions across the United States join NHGRI and NIH staff at a roundtable meeting to discuss opportunities and challenges associated with the inclusion and engagement of underrepresented populations in genomics research.

2015 — Research funded by NHGRI’s Centers for Excellence in Genome Sciences and published in Nature Genetics provides new insights into the effects and roles of genetic variation and parental influence on gene activity in mice and humans.

2015 — NIH researchers discover the genomic switches of a blood cell are key to regulating the human immune system. The findings, published in Nature , open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders.

2016 — NHGRI launches the Centers for Common Disease Genomics, which will use genome sequencing to explore the genomic contributions to common diseases such as heart disease, diabetes, stroke and autism.

2016 — NHGRI awards approximately $11.1 million to support research aimed at identifying differences - called genetic variants - in the less-studied regions of the genome that are responsible for regulating gene activity.

2016 — NHGRI funds researchers at its Centers of Excellence in Ethical, Legal and Social Implications Research program to examine the use of genomic information in the prevention and treatment of infectious diseases; genomic information privacy; communication about prenatal and newborn genomic testing results; and the impact of genomics in American Indian and Alaskan Native communities.

2016 — NIH scientists identify a genetic mutation responsible for a rare form of inherited hives induced by vibration, also known as vibratory urticarial.

2016 — NHGRI Senior Investigator Dr. Francis Collins and an international team of more than 300 scientists conduct a comprehensive investigation of the underlying genetic architecture of type 2 diabetes. Their findings suggest that most of the genetic risk for type 2 diabetes can be attributed to common shared genomic variants.

2016 — The Policy and Program Analysis Branch held a public workshop, “Investigational Device Exemptions and Genomics,” to help investigators and institutional review board members learn more about Food and Drug Administration regulations and their application to genomics research.

2017 — NHGRI celebrates 20 years as an NIH Institute. The milestone highlights the transition from the center known as the National Center for Human Genome Research, to our current status as a full-fledged NIH institute. Those 20 years encompassed a host of research accomplishments, from the completion of The Human Genome Project, to DNA sequencing technology development, to bringing genomic medicine to the clinic.

2017 — NHGRI releases a collection of oral history videos featuring candid conversations with pioneering genomics researchers and an interactive discussion with the institute's three directors to date. NHGRI plans to release approximately 25 videos over the next year and additional videos in the future.

2017 — Laura Koehly, Ph.D., is named chief of NHGRI's Social and Behavioral Research Branch (SBRB) , which conducts research that will potentially transform healthcare through the integration of genomic medicine into the clinic.

2018 — NHGRI launches a new round of strategic planning that will establish a 2020 vision for genomics research aimed at accelerating scientific and medical breakthroughs.

2018 — NIH and INOVA Health System launch The Genomic Ascertainment Cohort (TGAC) , a two-year pilot project that will allow them to recall genotyped people and examine the genes and gene variants' influence on their phenotypes, an individual's observable traits, such as height, eye color or blood type.

2018 — Rep. Louise M. Slaughter (D-N.Y.), lead author of the Genetic Information Nondiscrimination Act of 2008 (GINA), passes away at the age of 88 .

2018 — The Cancer Genome Atlas publishes the PanCancer Atlas , a detailed genomic analysis on a data set of molecular and clinical information from over 10,000 tumors representing 33 types of cancer.

2019 — NHGRI researchers discover a new autoinflammatory disease called CRIA syndrome .

2019 — NHGRI appoints Dr. Benjamin Solomon as clinical director.

2020 — NHGRI appoints Chris Gunter, Ph.D. , as a senior advisor to the director for genomics engagement.

2020 — NHGRI establishes new intramural precision health research program .

2020 — NHGRI commemorates 20th anniversary of White House event announcing draft human genome sequence.

2020 — NIH announces the provision of $75 million in funding over five years for the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network.

2020 — NHGRI researchers reframe dog-to-human aging comparisons .

2020 — NHGRI researchers generate the complete human X chromosome sequence .

2020 — Scientists use genomics to discover ancient dog species that may teach us about human vocalization .

2020 — NHGRI celebrates the 30th Anniversary of the commencement of The Human Genome Project

2020 — NHGRI researchers work with patients, families and the scientific community to improve the informed consent process .

2021 — NHGRI proposes an action agenda for building a diverse genomics workforce .

2021 — Dr. Neil Hanchard joins NHGRI as a clinical investigator.

2021 — NHGRI appoints Oleg Shchelochkov as intramural training program director .

2021 — NIH researchers develop guidelines for reporting polygenic risk scores .

2021 — NIH scientists develop breath test for methylmalonic acidemia .

2021 — NHGRI director appoints Vence Bonham as acting deputy director .

2021 — NIH expands existing gene expression resources to include developmental tissues .

2021 — Charles Rotimi selected as next scientific director .

2021 — NHGRI creates Office of Training, Diversity and Health Equity .

2021 — NHGRI researchers narrow down the number of genomic variants that are strongly associated with blood lipid levels and generated a polygenic risk score to predict elevated low-density lipoprotein cholesterol levels, a major risk factor for heart disease.

2021 — NHGRI selects Valentina Di Francesco as chief data science strategist.

2021 — NHGRI creates the Office of Genomic Data Science .

2021 — NIH researchers find thousands of new microorganisms living on human skin.

2022 — NIH-funded small businesses contributed to the completion of the human genome sequence .

2022 — Researchers generate the first complete, gapless sequence of a human genome .

2022 — NHGRI History of Genomics Program celebrates it's 10th anniversary .

2022 — NHGRI selects Charles P. Venditti as new chief of the Metabolic Medicine Branch .

2023 — NHGRI hosts a roundtable on potential concerns of social and behavioral genomics .

Biographical Sketch of NHGRI Director, Eric D. Green, M.D., Ph.D.

Eric D. Green, M.D., Ph.D., is the director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH), a position he has held since late 2009. Previously, he served as the NHGRI scientific director (2002-2009), chief of the NHGRI Genome Technology Branch (1996-2009), and director of the NIH Intramural Sequencing Center (1997-2009).

Dr. Green received his B.S. degree in bacteriology from the University of Wisconsin-Madison in 1981, and his M.D. and Ph.D. from Washington University, St. Louis, in 1987. During residency training in clinical pathology (laboratory medicine), he worked in the laboratory of Dr. Maynard Olson. In 1992, he was appointed assistant professor of pathology and genetics and co-investigator in the Human Genome Center at Washington University. In 1994, he joined the newly established Intramural Research Program of the National Center for Human Genome Research, later renamed the National Human Genome Research Institute.

Honors given to Dr. Green include a Helen Hay Whitney Postdoctoral Research Fellowship (1989-1990), a Lucille P. Markey Scholar Award in Biomedical Science (1990-1994), induction into the American Society for Clinical Investigation (2002), an Alumni Achievement Award from Washington University School of Medicine (2005), induction into the Association of American Physicians (2007), a Distinguished Alumni Award from Washington University (2010), the Cotlove Lectureship Award from the Academy of Clinical Laboratory Physicians and Scientists (2011), a Ladue Horton Watkins High School Distinguished Alumni Award (2012), and the Wallace H. Coulter Lectureship Award from the American Association for Clinical Chemistry (2012). He is a founding editor of the journal Genome Research (1995-present) and a series editor for Genome Analysis: A Laboratory Manual (1994-1998), both published by Cold Spring Harbor Laboratory Press. He is also co-editor of the Annual Review of Genomics and Human Genetics (since 2005). Dr. Green has authored or co-authored over 340 scientific publications.

While directing an independent research program for almost two decades, Dr. Green was at the forefront of efforts to map, sequence, and understand eukaryotic genomes. (A eukaryote is any organism whose cells contain a nucleus and other organelles enclosed within membranes.) His work included significant involvement in the Human Genome Project. These efforts eventually blossomed into a highly productive program in comparative genomics that provided important insights about genome structure, function and evolution. His laboratory also identified and characterized several human disease genes, including those implicated in certain forms of hereditary deafness, vascular disease and inherited peripheral neuropathy.

As NHGRI director, Dr. Green leads the Institute's research programs and other initiatives. Under his guidance, the Institute has completed two major cycles of strategic planning to ensure that its research investments in genomics effectively advance human health. The first effort yielded the highly cited 2011 NHGRI strategic vision, “ Charting a course for genomic medicine from base pairs to bedside ” ( Nature 470:204-213, 2011); the second yielded the 2020 paper ” Strategic vision for improving human health at The Forefront of Genomics ” ( Nature 586:683-692, 2020).

These two strategic planning processes have guided a major expansion of NHGRI’s research portfolio, highlights of which include the design and launch of major new programs to unravel the functional complexities of the human genome, to catalyze the growth of genomic data science, to accelerate the application of genomics to medical care and to enhance the building of a robust and diverse genomics workforce of the future.

Dr. Green has also played an instrumental leadership role in developing many high-profile efforts relevant to genomics. These efforts include multiple NIH Common Fund Programs — such as the Undiagnosed Diseases Network, Human Heredity and Health in Africa (H3Africa), and the Human Microbiome Project — the Smithsonian-NHGRI exhibition Genome: Unlocking Life's Code , several trans-NIH data science initiatives, the NIH Genomic Data Sharing Policy and the NIH All of Us Research Program.

Beyond NHGRI-specific programs, Dr. Green has also played an instrumental leadership role in the development of a number of high-profile efforts relevant to genomics, including the Smithsonian-NHGRI exhibition Genome: Unlocking Life's Code , the NIH Big Data to Knowledge (BD2K) program, the NIH Genomic Data Sharing Policy, and the U.S. Precision Medicine Initiative.

NHGRI Directors

Office of the Director

The Office of the Director oversees general operations, administration and communications for the National Human Genome Research Institute (NHGRI). It provides overall leadership; sets policies; develops scientific, fiscal and management strategies; assists in governing the ethical behavior of its employees, and coordinates genomic research for the National Institutes of Health with other federal, private and international programs.

There are three offices housed within the Office of the Director. The Office of Communications (OC), which leads corporate communications about the research and programs supported by the National Human Genome Research Institute (NHGRI), the Office of Genomic Data Science (OGDS), which provides leadership, strategic guidance and coordination for NHGRI activities, programs and policies in genomic data science, and the Training, Diversity and Health Equity Office (TiDHE), which develops and supports initiatives that expand opportunities for genomics education and careers; cultivates genomics training programs and workforce development initiatives for individuals underrepresented in biomedical research; and promotes genomics research to improve minority health, reduce health disparities and foster health equity.

Extramural Research Program

NHGRI's Extramural Research Program (ERP) helps provide intellectual vision to the field of genomics. It also manages the meetings of NHGRI's National Advisory Council for Human Genome Research. In consultation with the broader genomics community, the ERP supports grants for research and training and career development at sites across the country.

The ERP is composed of four divisions:

• The Division of Genome Sciences oversees basic genomic research and technology development, as well as major activities such as large-scale genome sequencing. It plans, directs, and facilitates multi-disciplinary research to understand the structure and function of genomes in health and disease. The division develops and funds research projects, and supports research training grants, research center grants, and contracts.
• The Division of Genomic Medicine leads the institute's efforts to move genomic technologies and approaches into clinical applications and care. It develops and supports research to identify and advance approaches for the use of genomic data to improve diagnosis, treatment, and prevention of disease through grants, training, and contracts.
• The Division of Genomics and Society carries out research related to the many societal issues relevant to genomics research, and includes the institute's Ethical, Legal and Social Implications (ELSI) program.
• The Division of Extramural Operations manages ERP’s operational aspects, including conducting the review of grant applications and grants management.

Division of Intramural Research

The National Human Genome Research Institute's (NHGRI) Division of Intramural Research (DIR) plans and conducts laboratory and clinical research to enable greater understanding of human disease and develop better methods for detection, prevention and treatment of heritable and genetic disorders.

The DIR is one of the premier research programs working to unravel the genetic basis of human disease. In its short existence, the division has made many seminal contributions to the fields of genetics and genomics.

Highlights of NHGRI investigators' accomplishments in recent years include the identification of the genes responsible for numerous human genetic diseases; development of new paradigms for mapping, sequencing, and interpreting the human and other vertebrate genomes; Development and application of DNA microarray technologies for large-scale analyses of gene expression; creation of innovative computational tools for analyzing large quantities of genomic data; generation of animal models critical to the study of human inherited disorders; and design of novel approaches for diagnosing and treating genetic disease.

NHGRI investigators, along with their collaborators at other NIH Institutes and various research institutions worldwide, have embarked on a number of high-risk efforts to unearth clues about the complex genetic pathways involved in human diseases. These efforts have used genomic sequence data from humans and other species to pinpoint hundreds of potential disease genes, including those implicated in cancer, diabetes, premature aging, hereditary deafness, various neurological, developmental, metabolic, and immunological disorders, and others. These studies have brought together NHGRI basic scientists and clinicians in collaborations aimed at developing better approaches for detecting, diagnosing, and managing these often-debilitating genetic disorders.

Division of Management

The Division of Managementplans and directs administrative management functions at the National Human Genome Research Institute, including administrative management, management analysis and evaluation, financial management, information technology, ethics and human resources. It advises senior leadership on developments in administrative management and their implications and effects on program management, and coordinates administrative management activities in support of their programs.

This page last reviewed on December 19, 2023

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Genomics research to elucidate the genetics of rare diseases.

The GREGoR Consortium (Genomics Research to Elucidate the Genetics of Rare diseases) seeks to develop and apply approaches to discover the cause of currently unexplained rare genetic disorders.

Linking diseases to their genetic cause allows for improved genetic testing and a shortened diagnostic odyssey for families affected by rare disease, and can:

• improve care and expand treatment options
• facilitate connections with others affected by the same condition
• aid in medical care and family planning for related individuals
• help researchers understand the function of these genes in everyone

Whole-exome sequencing has helped researchers identify about 300 Mendelian disease genes each year, but this technique has not been successful in identifying the genes responsible for many Mendelian diseases. New approaches are needed and thus Consortium investigators will:

• engage in enhanced data sharing and collaboration
• apply new technologies, genome sequencing strategies, and analytical approaches

The Consortium will bring together communities affected by rare disease.  We will:

• help researchers leverage new technologies to advance gene discovery
• assist clinicians in connecting patients and families to Consortium Research Centers
• partner with advocacy groups both to spread awareness of our work and to improve understanding of barriers to research participation - especially amongst those who have been under-represented

News  &  Publications

The American Society of Human Genetics (ASHG) announced their professional award recipients for 2024, including 2 of our GREGoR Consortium members. James R. Lupski, MD, PhD, DSc has been recognized with the prestigious ASHG Lifetime Achievement Award, while Gail Jarvik, MD, PhD, has received the ASHG Mentorship Award.

Research Topics

The Center for Genetic Medicine’s faculty members represent 33 departments or programs across three Northwestern University schools and three Feinberg-affiliated healthcare institutions. Faculty use genetics and molecular genetic approaches to understand biological processes for a diverse range of practical and clinical applications.

Select a topic below to learn more and see a list of faculty associated with that type of research. For a full list of Center for Genetic Medicine members, visit our Members section .

  Animal Models of Human Disease

Using genetic approaches with model organisms to investigate cellular and physiological processes can lead to improved approaches for detection, prevention and treatment of human diseases.

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  Bioinformatics & Statistics

Bioinformatics, a discipline that unites biology, computer science, statistical methods, and information technology, helps researchers understand how genes or parts of genes relate to other genes, and how genes interact to form networks. These studies provide insight to normal cellular functions and how these functions are disturbed by disease. Statistics is central to genetic approaches, providing quantitative support for biological observations, and statistical genetics is heavily used by laboratories performing gene and trait mapping, sequencing and genotyping, epidemiology, population genetics and risk analysis.

  Cancer Genetics and Genomics

Cancer begins with genetic changes, or mutations, that disrupt normal regulation of cell proliferation, survival and death. Inherited genetic changes contribute to the most common cancers, like breast and colon cancer, and genetic testing can help identify risks for disease. Tumors also develop additional genetic changes, or somatic mutations, that promote cancer growth and tumor metastases. These genetic changes can be readily defined through DNA and RNA sequencing. Genetic changes within a tumor can be used to develop and guide treatment options.

  Cardiovascular Genetics

Cardiovascular disease is one of the leading causes of death in the US, and the risk of  cardiovascular disease is highly dependent inherited genetic changes. The most common forms of heart disease including heart failure, arrhythmias, and vascular disease are under heritable genetic changes. We work to identify and understand the functions of genes that affect the risk of developing cardiovascular disease, as well as to understand the function of genes involved in the normal and pathological development of the heart.

  Clinical and Therapeutics

Using genetic data identifies pathways for developing new therapies and applying existing therapies. DNA sequencing and epigenetic profiling of tumors helps define the precise defects responsible for cancer progression. We use genetic signals to validate pathways for therapy development.  We are using gene editing methods to correct genetic defects. These novel strategies are used to treat patients at Northwestern Memorial Hospital and the Ann & Robert H. Lurie Children's Hospital of Chicago.

  Development

The genomic blueprint of a single fertilized egg directs the formation of the entire organism. To understand the cellular processes that allow cells to create organs and whole animals from this blueprint, we use genetic approaches to investigate the development of model organisms and humans. Induced pluripotent stem cells can be readily generated from skin, blood or urine cells and used to mirror human developmental processes. These studies help us define how genes coordinate normal human development and the changes that occur in diseases, with the goal of improving detection, prevention and treatment of human disease.

  Epigenetics/Chromatin Structure/Gene Expression

Abnormal gene expression underlies many diseases, including cancer and cardiovascular diseases. We investigate how gene expression is regulated by chromatin structure and other regulators to understand abnormal gene expression in disease, and to learn how to manipulate gene expression for therapeutic purposes.

  Gene Editing/Gene Therapy

Gene editing tools like CRISPR/Cas can be used to directly alter the DNA code. This tool is being used to generate cell and animal models of human diseases and disease processes. Gene therapy is being used to treat human disease conditions.

  Genetic Counseling

As part of training in genetic counseling, each student completes a thesis project. These projects examine all aspects of genetic counseling ranging from family-based studies to mechanisms of genetic action. With the expansion of genetic testing, genetic counselors are now conducting research on outcomes, cost effectiveness, and quality improvement.

  Genetic Determinants of Cellular Biology

Genetic mutations ultimately change the functionality of the cells in which they are found. Mutations in genes encoding nuclear, cytoplasmic and extracellular matrix protein lead to many different human diseases, ranging from neurological and developmental disorders to cancer and heart disease. Using induced pluripotent stem cell and gene-editing technologies, it is now possible to generate and study nearly every human genetic disorder. Having cellular models of disease is necessary to develop new treatments.

  Immunology

Many immunological diseases, such as Rheumatoid arthritis, Lupus, scleroderma, and others have a genetic basis. We work to understand how genetic changes and misregulation contribute to immunological diseases, and use genetic approaches to investigate how the immune system functions.

  Infectious Disease/Microbiome

The susceptibility and/or pathological consequences of many infectious diseases have a genetic basis. We investigate how human genes interact with infectious diseases, and use genetic approaches to determine the interactions between pathogens and the host. Genetic tools, including deep sequencing, are most commonly used to define the microbiome as it undergoes adaptation and maladaptation to its host environment.

  Neuroscience

We work to understand how genes contribute to neurological diseases, and use genetic approaches to investigate how the nervous system functions. Epilepsy, movement disorders, and dementia are heritable and under genetic influence. Neuromuscular diseases including muscular dystrophies and myopathies arise from primary mutations and research in genetic correction is moving into human trials and drug approvals.

  Population Genetics/Epidemiology

Genetic data is increasingly available from large human populations and is advancing the population-level understanding of genetic risk. Northwestern participates in All-Of-US, which aims to build a cohort of one million citizens to expand genetic knowledge of human diseases. Race and ancestry have genetic determinants and genetic polymorphisms can help mark disease risks better than other markers of race/ancestry. We use epidemiology and population genetics to investigate the genetic basis of disease, and to assess how genetic diseases affect subgroups within broader populations.

  Reproduction

Research is examining how germ cells are specified. We study the broad range of biology required to transmit genetic information from one generation to another, and how to facilitate the process of reproduction when difficulties arise or to avoid passing on mutant genes.

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• Published: 14 October 2020

Evidence for 28 genetic disorders discovered by combining healthcare and research data

• Joanna Kaplanis 1   na1 ,
• Kaitlin E. Samocha   ORCID: orcid.org/0000-0002-1704-3352 1   na1 ,
• Laurens Wiel   ORCID: orcid.org/0000-0003-3410-760X 2 , 3   na1 ,
• Zhancheng Zhang 4   na1 ,
• Kevin J. Arvai   ORCID: orcid.org/0000-0001-8751-8918 4 ,
• Ruth Y. Eberhardt   ORCID: orcid.org/0000-0001-6152-1369 1 ,
• Giuseppe Gallone 1 ,
• Stefan H. Lelieveld 2 ,
• Hilary C. Martin 1 ,
• Jeremy F. McRae   ORCID: orcid.org/0000-0003-3411-9248 1 ,
• Patrick J. Short 1 ,
• Rebecca I. Torene 4 ,
• Elke de Boer   ORCID: orcid.org/0000-0002-7022-577X 5 ,
• Petr Danecek 1 ,
• Eugene J. Gardner   ORCID: orcid.org/0000-0001-9671-1533 1 ,
• Ni Huang 1 ,
• Jenny Lord   ORCID: orcid.org/0000-0002-0539-9343 1 , 6 ,
• Iñigo Martincorena 1 ,
• Rolph Pfundt 5 ,
• Margot R. F. Reijnders 2 , 7 ,
• Alison Yeung 8 , 9 ,
• Helger G. Yntema 5 ,
• Deciphering Developmental Disorders Study ,
• Lisenka E. L. M. Vissers 5 ,
• Jane Juusola 4 ,
• Caroline F. Wright 10 ,
• Han G. Brunner 5 , 7 , 11 , 12 ,
• Helen V. Firth 1 , 13 ,
• David R. FitzPatrick 14 ,
• Jeffrey C. Barrett 1 ,
• Matthew E. Hurles   ORCID: orcid.org/0000-0002-2333-7015 1   na2 ,
• Christian Gilissen   ORCID: orcid.org/0000-0003-1693-9699 2   na2 &
• Kyle Retterer 4   na2  

Nature volume  586 ,  pages 757–762 ( 2020 ) Cite this article

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• Clinical genetics
• Genetics research
• Neurodevelopmental disorders
• Statistical methods

De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1 . However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1 , 2 . Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

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Combining exome/genome sequencing with data repository analysis reveals novel gene–disease associations for a wide range of genetic disorders

Hypothesis-free phenotype prediction within a genetics-first framework

Evaluating variants classified as pathogenic in ClinVar in the DDD Study

Data availability.

Sequence and variant-level data and phenotypic data for the DDD study data are available from the European Genome-phenome Archive (EGA; https://www.ebi.ac.uk/ega/ ) with study ID EGAS00001000775. The RadboudUMC sequence and variant-level data cannot be made available through the EGA owing to the nature of consent for clinical testing. To access the data, please contact C.G. ([email protected]) with a request. Data sharing will be dependent on patient consent, diagnostic status of the patient, the type of request and the potential benefit to the patient. GeneDx data cannot be made available through the EGA owing to the nature of consent for clinical testing. GeneDx-referred patients are consented for aggregate, deidentified research and subject to US HIPAA privacy protection. As such, we are not able to share patient-level BAM or VCF data, which are potentially identifiable without a HIPAA Business Associate Agreement. Access to the deidentified aggregate data used in this analysis is available upon request to GeneDx. GeneDx has contributed deidentified data to this study to improve clinical interpretation of genomic data, in accordance with patient consent and in conformance with the ACMG position statement on genomic data sharing (details are provided in the  Supplementary Note ). Clinically interpreted variants and associated phenotypes from the DDD study are available through DECIPHER ( https://decipher.sanger.ac.uk ). Clinically interpreted variants from RUMC are available from the Dutch national initiative for sharing variant classifications ( https://www.vkgl.nl/nl/diagnostiek/vkgl-datashare-database ) as well as LOVD ( https://databases.lovd.nl/shared/variants ), where they are listed with ‘VKGL-NL_Nijmegen’ as the owner. Clinically interpreted variants from GeneDx are deposited in ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar ) under accession number 26957 ( https://www.ncbi.nlm.nih.gov/clinvar/submitters/26957/ ). Previously described datasets were from the Genome Aggregation Database (gnomAD v2.1.1; https://gnomad.broadinstitute.org/ ), The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov ) and the Developmental Disorders Genotype-Phenotype Database (DDG2P; https://www.ebi.ac.uk/gene2phenotype/downloads ).

Code availability

The DeNovoWEST method is available on GitHub ( https://github.com/queenjobo/DeNovoWEST ) along with code to recreate all of the figures in the manuscript ( https://doi.org/10.5281/zenodo.3909398 ). Code to run the Phenopy method is also available on GitHub ( https://github.com/GeneDx/phenopy ).

Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542 , 433–438 (2017).

Article   Google Scholar  

Martin, H. C. et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science 362 , 1161–1164 (2018).

Article   ADS   CAS   Google Scholar  

Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet . 46 , 310–315 (2014).

Article   CAS   Google Scholar  

Samocha, K. E. et al. Regional missense constraint improves variant deleteriousness prediction. Preprint at https://doi.org/10.1101/148353 (2017).

Kosmicki, J. A. et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat. Genet . 49 , 504–510 (2017).

Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581 , 434–443 (2020).

Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536 , 285–291 (2016).

Cooper, G. M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet . 43 , 838–846 (2011).

Coe, B. P. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet . 46 , 1063–1071 (2014).

Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol . 29 , 24–26 (2011).

Villegas, F. et al. Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3. Cell Stem Cell 24 , 257–270 (2019).

Diaz, J., Berger, S. & Leon, E. TFE3-associated neurodevelopmental disorder: a distinct recognizable syndrome. Am. J. Med. Genet. A 182 , 584–590 (2020).

Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell 176 , 535–548 (2019).

Yilmaz, R. et al. A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing. Am. J. Med. Genet. A 167 , 3006–3010 (2015).

Wu, X., Pang, E., Lin, K. & Pei, Z.-M. Improving the measurement of semantic similarity between gene ontology terms and gene products: insights from an edge- and IC-based hybrid method. PLoS ONE 8 , e66745 (2013).

Catterall, W. A., Dib-Hajj, S., Meisler, M. H. & Pietrobon, D. Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J. Neurosci . 28 , 11768–11777 (2008).

Lasser, M., Tiber, J. & Lowery, L. A. The role of the microtubule cytoskeleton in neurodevelopmental disorders. Front. Cell. Neurosci . 12 , 165 (2018).

Hamilton, M. J. et al. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J. Med. Genet . 55 , 28–38 (2018).

Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171 , 1029–1041 (2017).

Qi, H., Dong, C., Chung, W. K., Wang, K. & Shen, Y. Deep genetic connection between cancer and developmental disorders. Hum. Mutat . 37 , 1042–1050 (2016).

Ronan, J. L., Wu, W. & Crabtree, G. R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet . 14 , 347–359 (2013).

Cancer Genome Atlas Research Network et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet . 45 , 1113–1120 (2013).

Goriely, A. & Wilkie, A. O. M. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet . 90 , 175–200 (2012).

Duncan, B. K. & Miller, J. H. Mutagenic deamination of cytosine residues in DNA. Nature 287 , 560–561 (1980).

Maher, G. J. et al. Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes. Proc. Natl Acad. Sci. USA 113 , 2454–2459 (2016).

Maher, G. J. et al. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Res . 28 , 1779–1790 (2018).

Young, L. C. et al. SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proc. Natl Acad. Sci. USA 115 , E10576–E10585 (2018).

Coe, B. P. et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet . 51 , 106–116 (2019).

Lord, J. et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393 , 747–757 (2019).

Cassa, C. A. et al. Estimating the selective effects of heterozygous protein-truncating variants from human exome data. Nat. Genet . 49 , 806–810 (2017).

Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519 , 223–228 (2015).

Article   ADS   Google Scholar  

Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180 , 568–584 (2020).

Deelen, P. et al. Improving the diagnostic yield of exome-sequencing by predicting gene–phenotype associations using large-scale gene expression analysis. Nat. Commun . 10 , 2837 (2019).

He, X. et al. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet . 9 , e1003671 (2013).

Download references

Acknowledgements

We thank the families and their clinicians for their participation and engagement, and our colleagues who assisted in the generation and processing of data. Inclusion of RadboudUMC data was in part supported by the Solve-RD project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 779257. This work was in part financially supported by grants from the Netherlands Organization for Scientific Research (917-17-353 to C.G.). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER, which is funded by the Wellcome Trust. The full acknowledgements can be found at www.ddduk.org/access.html. The DDD study authors acknowledges the work of R. Kelsell. Finally, we acknowledge the contribution of an esteemed DDD clinical collaborator, M. Bitner-Glindicz, who died during the course of the study.

Author information

These authors contributed equally: Joanna Kaplanis, Kaitlin E. Samocha, Laurens Wiel, Zhancheng Zhang

These authors jointly supervised this work: Matthew E. Hurles, Christian Gilissen, Kyle Retterer

Authors and Affiliations

Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

Joanna Kaplanis, Kaitlin E. Samocha, Ruth Y. Eberhardt, Giuseppe Gallone, Hilary C. Martin, Jeremy F. McRae, Patrick J. Short, Petr Danecek, Eugene J. Gardner, Ni Huang, Jenny Lord, Iñigo Martincorena, Helen V. Firth, Jeffrey C. Barrett & Matthew E. Hurles

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

Laurens Wiel, Stefan H. Lelieveld, Margot R. F. Reijnders & Christian Gilissen

Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

Laurens Wiel

GeneDx, Gaithersburg, MD, USA

Zhancheng Zhang, Kevin J. Arvai, Rebecca I. Torene, Jane Juusola & Kyle Retterer

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

Elke de Boer, Rolph Pfundt, Helger G. Yntema, Lisenka E. L. M. Vissers & Han G. Brunner

Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands

Margot R. F. Reijnders & Han G. Brunner

Victorian Clinical Genetics Services, Melbourne, Victoria, Australia

Alison Yeung

Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK

Caroline F. Wright

GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands

Han G. Brunner

MHENS School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands

East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Steve Abbs, Ruth Armstrong, Carolyn Dunn, Simon Holden, Soo-Mi Park, Joan Paterson, Lucy Raymond, Evan Reid, Richard Sandford, Ingrid Simonic, Marc Tischkowitz, Geoff Woods & Helen V. Firth

MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK

Tara Azam, Elaine Cleary, Andrew Jackson, Wayne Lam, Anne Lampe, David Moore, Mary Porteous & David R. FitzPatrick

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Silvia Borras, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross & Stephen Tennant

Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK

Tabib Dabir, Deirdre Donnelly, Mervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J. Morrison, Gillian Rea & Fiona Stewart

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Trevor Cole, Nicola Cooper, Lisa Cooper-Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O’Driscoll, Kai-Ren Ong, Deborah Osio, Nicola Ragge, Sarah Turton, Julie Vogt & Denise Williams

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Lisa Bradley, Joanne Comerford, Andrew Green, Sally Lynch, Shirley McQuaid & Brendan Mullaney

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Ana Beleza, Charu Deshpande, Frances Flinter, Muriel Holder, Melita Irving, Louise Izatt, Dragana Josifova, Shehla Mohammed, Aneta Molenda, Leema Robert, Wendy Roworth, Deborah Ruddy, Mina Ryten & Shu Yau

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Christopher Bennett, Moira Blyth, Jennifer Campbell, Andrea Coates, Angus Dobbie, Sarah Hewitt, Emma Hobson, Eilidh Jackson, Rosalyn Jewell, Alison Kraus, Katrina Prescott, Eamonn Sheridan & Jenny Thomson

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Kirsty Bradshaw, Abhijit Dixit, Jacqueline Eason, Rebecca Haines, Rachel Harrison, Stacey Mutch, Ajoy Sarkar, Claire Searle, Nora Shannon, Abid Sharif & Mohnish Suri

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Pradeep Vasudevan

Merseyside and Cheshire Genetics Service, Liverpool Women’s NHS Foundation Trust, Royal Liverpool Children’s Hospital Alder Hey, Liverpool, UK

Natalie Canham, Ian Ellis, Lynn Greenhalgh, Emma Howard, Victoria Stinton, Andrew Swale & Astrid Weber

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Siddharth Banka, Catherine Breen, Tracy Briggs, Emma Burkitt-Wright, Kate Chandler, Jill Clayton-Smith, Dian Donnai, Sofia Douzgou, Lorraine Gaunt, Elizabeth Jones, Bronwyn Kerr, Claire Langley, Kay Metcalfe, Audrey Smith & Ronnie Wright

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David Bourn, John Burn, Richard Fisher, Steve Hellens, Alex Henderson, Tara Montgomery, Miranda Splitt, Volker Straub, Michael Wright & Simon Zwolinski

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Zoe Allen, Birgitta Bernhard, Angela Brady, Claire Brooks, Louise Busby, Virginia Clowes, Neeti Ghali, Susan Holder, Rita Ibitoye & Emma Wakeling

Oxford Regional Genetics Service, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK

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Shadi Albaba, Duncan Baker, Meena Balasubramanian, Diana Johnson, Michael Parker, Oliver Quarrell, Alison Stewart & Josh Willoughby

South West Thames Regional Genetics Centre, St George’s Healthcare NHS Trust, St George’s, University of London, London, UK

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Rachel Butler, Angus Clarke, Sian Corrin, Andrew Fry, Arveen Kamath, Emma McCann, Hood Mugalaasi, Caroline Pottinger, Annie Procter, Julian Sampson, Francis Sansbury & Vinod Varghese

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Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK

Faculty of Medicine, University of Southampton, Southampton, UK

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Contributions

J.K., K.E.S., L.W., K.J.A., M.E.H., C.G. and K.R. contributed to the generation of figures and writing of the manuscript. J.K., K.E.S., L.W., Z.Z., K.J.A., R.Y.E., G.G., S.H.L., H.C.M., J.F.M., E.d.B., R.P., M.R.F.R. and H.G.Y. contributed to the generation and quality control of data. J.K., K.E.S., L.W., Z.Z., K.J.A., R.I.T., J.F.M., P.J.S., P.D., E.J.G., N.H., J.L., I.M., A.Y. and K.R. developed methods, contributed data or performed analyses. H.C.M., L.E.L.M.V., J.J., C.F.W., H.G.B., H.V.F., D.R.F., J.C.B., M.E.H., C.G. and K.R. provided experimental and analytical supervision. M.E.H., C.G. and K.R. provided project supervision.

Corresponding author

Correspondence to Matthew E. Hurles .

Ethics declarations

Competing interests.

Z.Z., K.J.A., R.I.T., J.J. and K.R. are employees of GeneDx. J.J. and K.R. are shareholders of OPKO. M.E.H. is a co-founder of, consultant to and holds shares in Congenica, a genetics diagnostic company.

Additional information

Peer review information Nature thanks Ipsita Agarwal, James Lupski, Shamil Sunyaev and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended data fig. 1 exploring the remaining number of dd genes..

a , Number of significant genes after downsampling the full cohort and running the enrichment test of DeNovoWEST. b , The likelihood of the observed distribution of de novo PTV mutations was modelled. This model varies the numbers of remaining haploinsufficient (HI) DD genes and PTV enrichment in those remaining genes. The 50% credible interval is shown in red and the 90% credible interval is shown in orange. Note that the median PTV enrichment in genes that are significant and known to operate through a loss-of-function mechanism (as indicated by an arrow) is 39.7.

Supplementary information

Supplementary information.

This file contains Supplementary Methods and descriptions of Supplementary Analyses, Supplementary Figures 1-14, descriptions of Supplementary Tables 1-3, Supplementary Tables 4-9 and Supplementary References. It also contains Supplementary notes detailing the DDD consortia members.

Reporting Summary

41586_2020_2832_moesm3_esm.txt.

Supplementary Table 1 De novo mutations from 31,058 individuals with developmental disorders . For every de novo mutation, we provide: proband ID (‘id’), chromosome (‘chrom’), position in GRCh37 (‘pos’), the reference allele (‘ref’), the alternative allele (‘alt’), the VEP consequence of the mutation (‘consequence’), the HGNC symbol (‘symbol’), the centre which sequence the proband (‘study’), the fraction of reads that are from the alternative allele (‘altprop_child’), and the HGNC ID (‘hgnc_id’).

41586_2020_2832_MOESM4_ESM.xlsx

Supplementary Table 2 Results of DeNovoWEST . Results from analysis on the full cohort and on the undiagnosed subset, along with gene-level DNM counts per consequence. Column headers are described within the file.

41586_2020_2832_MOESM5_ESM.xlsx

Supplementary Table 3 Novel genes . For each of the 28 novel genes in this analysis, we determined if it had an associated phenotype in OMIM, any publications about an association between mutations in that gene and developmental disorders, and whether it was significant in a study of inherited and de novo mutations in autism spectrum disorders21 (“sig_ASD”) or a metaanalysis of de novo mutations in individuals with neurodevelopmental disorders22 (“sig_meta”).

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Kaplanis, J., Samocha, K.E., Wiel, L. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586 , 757–762 (2020). https://doi.org/10.1038/s41586-020-2832-5

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DOI : https://doi.org/10.1038/s41586-020-2832-5

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Project GIVE: using a virtual genetics service platform to reduce health inequities and improve access to genomic care in an underserved region of Texas

• Blake Vuocolo 1 ,
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The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of improving pediatric health outcomes. We describe our experience of establishing a virtual pediatric genomic service in this region to expeditiously identify, recruit, and evaluate pediatric patients with undiagnosed diseases.

We have utilized an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform called Consultagene to receive referrals from healthcare providers in the RGV. Using this portal, genetic services, including virtual evaluation and genome sequencing (GS), are being delivered to children with rare diseases. The study has also integrated effective methods to involve and educate community providers through in-person meetings and Continuing Professional Education (CPE) events.

The recruitment efforts have proven highly successful with the utilization of Consultagene in this medically underserved region. The project’s ongoing engagement efforts with local healthcare providers have resulted in progressively more referrals to the study over time, thus improving inclusion and access to genomic care in the RGV. Additionally, the curated CPE content has been well received by healthcare providers in the region.

Conclusions

Project GIVE study has allowed advanced genetic evaluation and delivery of GS through the virtual Consultagene portal, effectively circumventing the recognized socioeconomic and logistical barriers to accessing genetic services within this border community.

Rare genetic diseases are known to disproportionately affect children, causing early childhood death or chronic physical and/or neurodevelopmental challenges. Diagnosing children in a timely manner is crucial for providing appropriate disease-specific intervention, counseling families about recurrence risks, and addressing the psychosocial and financial challenges that are known to be associated with diagnostic odysseys [ 1 ]. However, within the United States healthcare system, low-income communities and ethnic minorities often do not have equitable access to genetic services [ 2 , 3 ]. Multiple studies have shown that Hispanic/Latino individuals living in the United States are less likely to get genetic testing compared to non-Hispanic/Latino groups [ 4 , 5 , 6 ].

There currently exists a substantial gap in the access to genomic healthcare for the community along the southernmost tip of the Texas-Mexico border called the Rio Grande Valley (RGV), which has a population of about 1.4 million residents [ 7 ]. Over 94% of the population in the RGV identifies as Hispanic/Latino; approximately 30% of individuals under the age of 65 years are uninsured; and 30-40% of children live in poverty [ 8 , 9 ]. The RGV has four counties (Starr, Cameron, Hidalgo and Willacy), three of which are amongst the Texas counties with the highest concentrations of colonias, defined as residential areas that lack basic living necessities such as potable water and sanitation infrastructure [ 10 ]. All four counties in the RGV are designated medically underserved areas by the Health Resources and Service Administration (HRSA), indicating an inadequate amount of primary care services to address the health needs of the population [ 11 , 12 ].

Access to genomic care is not only restricted by low socioeconomic status of the residents, but also by limited familiarity of the local healthcare professionals with genetic disorders. Previous studies have indicated that primary care providers in a Federally Qualified Health Center generally found clinical advantages in providing genetic testing to their patients. However, a significant number of them lacked training in genetics and did not integrate genetic service into their practices [ 13 ]. Even when children with rare diseases are eventually identified for assessment, the limited availability of highly trained and board-certified full-time pediatric geneticists in this region necessitates families to travel significant distances to large pediatric centers for comprehensive genomic care. Families facing financial, logistical, or social challenges are unable to make the journey, resulting in inability to access these vital services and receive timely genetic diagnoses. The interwoven socioeconomic and healthcare system barriers in this region result in prolonged diagnostic odysseys, which in turn can lead to preventable health declines, missed opportunities for participation in clinical trials, and recurrence of frequently devastating diseases within families. There is an urgent need to implement alternate modes of delivery of care that could be readily integrated into the workflow of healthcare providers in the RGV to improve the lives of children with genetic disorders.

Project GIVE ( G enetic I nclusion by V irtual E valuation), an NIH-funded research study, has been designed to provide state-of-the art virtual genetic evaluation and whole genome sequencing (GS) for children with rare diseases in the RGV using Consultagene, an academically-developed virtual genetics service platform, with the goal of reducing their time to diagnosis (TTD). Furthermore, efforts are aimed at improving the genomic competency of local healthcare providers through educational events to expedite genetics referrals for children with suspected genetic diseases. The trial is registered in Clinicaltrials.gov (Identifier NCT05318222). The study is conducted at the University of Texas Rio Grande Valley (UTRGV) and Baylor College of Medicine (BCM). Here, we describe the processes and insights gained from the study design and our engagement with the healthcare providers in the RGV to advance pediatric genomic care. We also outline our experience of using a virtual genomics evaluation platform to deliver both remote evaluation and GS for children with rare diseases living in this region.

Utilization of a telehealth platform

Between 2016 and 2018, a HIPAA-compliant EHR-agnostic genetics tele-engagement platform called Consultagene was developed at BCM to improve access to genomic care and education for individuals with limited access to a genetics specialist [ 14 ]. This virtual platform offers comprehensive services, including patient scheduling, medical document sharing, interpretation of genetic test results, tele-genetic counseling, and educational videos for patients and healthcare providers, which are available in multiple languages including Spanish. The platform’s features are modular, which allows it to adapt to the unique needs of both clinical and research settings. Healthcare providers and patients themselves can submit a referral request through Consultagene for a patient to be scheduled and seen by one of BCM’s clinical genetic counselors via video conference. Referrers are also able to submit a request for a “peer-to-peer” consultation, whereby they can consult with a BCM provider through the platform and obtain genetics advice on any given case. Since 2019, Consultagene has clinically engaged patients requiring counseling for prenatal testing, preconception, and in vitro fertilization considerations, as well as specialized consultations related to cancer genetics and neurodegenerative diseases such as Huntington’s disease and Alzheimer’s disease. Project GIVE presents a novel use of this technology in a research setting that caters to the pediatric rare disease population coupled with the delivery of GS.

Inclusion and exclusion criteria

Children who are 0–18 years of age are eligible to participate in Project GIVE if they reside in the RGV and have a suspected underlying genetic etiology for their medical presentation. Families must primarily speak English or Spanish to participate. Participants are not eligible if they already have a genetic diagnosis that explains their symptoms. In this phase of the study, Project GIVE assesses children within an outpatient setting. Neonates with suspected genetic disorders are directed to Consultagene for evaluation following their discharge from the hospital.

Selection of study site, participant recruitment, and application review

In collaboration with UTRGV, the UT Health RGV Pediatric Specialty Clinic in Edinburg, Texas was strategically selected as the primary study site because of its ease of access for families. Additionally, there is a diverse range of pediatric subspecialists in this single facility, including a neurologist, a developmental pediatrician, and a pulmonologist, which presented adequate opportunities for patient referrals. The Consultagene kiosk was set up in this clinic for families to engage with the Project GIVE genetics team located in Houston.

Project GIVE has been designed to recruit approximately 100 pediatric participants from the RGV between February 2022-January 2024 (Fig.  1 ) for genetic evaluation and GS. Prioritizing inclusion and access to care, the referrer base for this study has been extended to a wider network of healthcare professionals in this region, including physicians, nurses, nurse practitioners, medical assistants, early childhood intervention (ECI) specialists, as well as physical, occupational, and speech therapists taking care of children with complex medical needs in rehabilitation centers. The UTRGV pediatricians, along with the project’s local research coordinator (R.S.), who has a background in social work and prior experience at a local geneticist’s office, work together to identify community healthcare professionals who could potentially refer study participants. The bilingual research coordinator regularly visits clinics to proactively distribute study flyers and discuss the benefits of the study for children with complex medical conditions. Additionally, the team of clinical geneticists and the genetic counselor based in Houston conduct multiple visits to this region to engage in face-to-face meetings with local clinicians.

Study timeline. a Pre-enrollment preparation included development of the IRB protocol, identification of study site at the UTRGV pediatric multi-specialty clinic in Edinburg, TX and installation of the Consultagene kiosk. b Personnel includes research coordinator and UTRGV pediatricians who participate in Project GIVE clinical meetings. We began enrolling patients shortly after receiving our first referrals. Return of genomic results appointments were scheduled once results were returned from the lab. Outreach to community providers (including genetics providers visits to the RGV and visits to clinics by our research coordinator) has been ongoing throughout the study period

The healthcare providers send in a referral through Consultagene requesting “Peer-to-Peer consultation”. After accessing the portal, the referrers are prompted to upload pertinent clinical information including available electronic health records for their patients. The Project GIVE clinical team, consisting of geneticists and a genetic counselor at BCM, the research coordinator, and the UTRGV pediatricians, convenes remotely on a weekly basis to review the referrals and ascertain those most likely to benefit from genetic evaluation.

Additionally, the study team has established a collaborative partnership with the Texas Department of State Health Services’ Texas Birth Defects Registry (TBDR), which plays a pivotal role in identifying pregnancies and infants with birth defects in Texas [ 15 ]. The registry team conducts routine visits to pediatric hospitals, birthing centers, and midwife facilities throughout Texas to identify affected individuals. The TBDR team conducts systematic reviews of medical records, and both the International Classification of Diseases (ICD) codes for birth defects and text descriptions are detailed for each patient. Information for patients diagnosed with birth defects between 2015 and 2020 in the RGV is accessible to the Project GIVE study team as approved by the Institutional Review Board of the Texas Department of State Health Services. Utilizing our established provider engagement process, our team facilitates a Consultagene referral for the patient through the patient’s pediatrician.

Delivering virtual genetic evaluation with GS and longitudinal follow-up via Consultagene

Figure  2 illustrates a participant’s journey from referral to the final study visit. Upon acceptance into the study, participating families undergo a structured three-visit protocol over one year. At the initial encounter, “Visit 1”, the research coordinator meets with the pediatric participant and their family at the study site for the informed consent process. After being consented into the study, families then access two educational videos in their preferred language that are integrated in the Consultagene platform: (1) Basics of Genetics , and (2) What to Expect at a Genetics Clinic Visit. Due to the lower genetic health literacy levels of many of the study participants and their limited exposure to genetics, these videos provide relevant context to the patients regarding the research study. Families complete a five-question survey, including three 5-point Likert scale questions about their perspectives on the eduational videos and two knowledge questions related to the content covered in the videos. Following this, the clinical geneticists and genetic counselor, located in Houston, conduct an in-depth remote evaluation and physical exam of the pediatric participant through Consultagene’s videoconferencing platform. The virtual assessment is facilitated by the research coordinator present at the study site. Anthropometric measurements, including weight, height, and head circumference, are gathered for all participants by a medical assistant at the study site.

Project GIVE evaluation process. Participants participate in 3 study visits over one year. KFM = known familial mutation. * indicates timepoints in which survey data is collected from families (including demographic information, perceptions of genetics, and experiences receiving genetic test results). a KFM of affected/unaffected siblings or family members or other genetic testing (ex. RNA sequencing) may be recommended by the study team to help resolve a VUS

The research coordinator is also responsible for collection of buccal samples for proband, duo, or trio GS and coordinating transfer to Baylor Genetics, a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory in Houston, TX, where a clinical GS report is generated. Families can opt-in to receiving the ACMG medically actionable secondary findings during the consenting process [ 16 ]. The genetics evaluation and GS studies are both carried out as part of the research study and are not billed through families’ insurance.

When the clinical team receives the GS results in ∼  4–8 weeks, a videoconference return of results (ROR) call is scheduled with the families for “Visit 2”. Positive cases undergo an in-depth review of the diagnosis and medical management, with accompanying informational letters crafted for both providers and patients, in their preferred language. The Project GIVE’s clinical team facilitates follow up appointment referrals in the RGV whenever possible. In cases where it is clinically necessary, patients are directed to specialty clinics at Texas Children’s Hospital (TCH) in Houston, which is approximately 350 miles away from the study site. When a variant of uncertain significance is ascertained, familial testing is undertaken to interpret the genomic results. In the event of a negative GS result, further exploration of any research findings detailed on the GS report takes place, including clinical labs/imaging, and/or GeneMatcher submissions. Additionally, selected patients are referred to additional research studies like the Undiagnosed Diseases Network.

“Visit 3”, occurring approximately 6 months post-disclosure, serves as a follow-up to collect additional medical information about the child and review the GS results again. A detailed summary of each visit is meticulously documented and promptly shared with the referring providers through the Consultagene portal to facilitate effective communication.

Enhancing genomic competency of healthcare professionals

A critical component of Project GIVE involves training and educating referrers to ensure expeditious patient referrals to genetic services. In 2023, we developed and delivered two Continuing Professional Education (CPE) seminars designed to cater to the unique needs of non-genetics providers in this region. The content for both events focused on the importance of genetic testing and recognition of rare diseases in pediatric patients. When designing the curriculum for these events, our goal was to help local healthcare professionals develop greater confidence in referring patients to genetics, understanding different genetic testing methodologies, and interpreting genomic results at some level to address families’ basic inquiries. Additionally, we introduced conference attendees to Face2Gene [ 17 ], a machine-assisted technology for identifying patients eligible for genetics referral. Attendees also received updates on the regional impact of Project GIVE. At the September 2023 CPE event, attendees completed a pre-CPE survey that collected provider and clinic information and asked questions about how comfortable providers were with ordering, interpreting, and explaining different genetic tests. They also completed a post-CPE survey that allowed them to answer the same questions about comfortability with genetic tests. Responses for the pre- and post-CPE surveys were linked using a study ID that was randomly assigned to the attendees. Survey data were analyzed using descriptive statistics, and responses for the comfortability questions were paired to assess whether there were changes in responses at the two time points.

Expected study outcomes

The primary outcome measure of Project GIVE is TTD of rare diseases, with the starting point designated as the date when a healthcare provider initially referred the patient to Consultagene. Patients are longitudinally followed for a duration of up to one year post-referral. Event time is computed in months as the time from referral to the date of ROR.

Additionally, we have incorporated harmonized surveys developed by the Clincial Sequencing Evidence-Generating Research (CSER) consortium that were designed to study the effectiveness of integrating genomic sequencing into the clinical care of ethnically diverse and medically underserved individuals [ 18 , 19 , 20 , 21 ]. These measures are suitable for participants with low literacy levels and are fully translated into the Spanish language. Survey data are collected to characterize sociodemographic variables, literacy, understanding, perceived utility of sequencing, and satisfaction with the ROR process. Surveys are administered to families at each of the three study visits. As the study design of Project GIVE is the specific emphasis of this paper, the TTD analysis and the survey data regarding participants’ experiences will be explored in a forthcoming publication.

Referrals and evaluations

Between February 2022 and January 2024, 196 pediatric patients (ages 0–18 years) with suspected undiagnosed rare diseases were referred through the Consultagene portal by healthcare professionals in the RGV. Notably, 18 referrals (9.2%) were from private-practice community pediatricians and 39 referrals (19.8%) were from developmental and rehabilitation therapists. The bulk of referrals came from pediatricians, endocrinologists, developmental pediatricians, pulmonologists, neonatologists, oncologists, and audiologists in the region (Fig.  3 ). Approximately 80% of the accepted study participants predominantly presented with a neurodevelopmental phenotype – including intellectual disability, seizures, developmental delay, autism spectrum disorder, behavioral/mental health concerns, and neuromuscular disease – often with other organ systems affected as well.

Referrals to Consultagene by healthcare provider designation ( n  = 196). Specialists include pulmonologists, psychiatrists, developmental pediatricians, endocrinologists, oncologists, and audiologists

Participant surveys

About 98% of enrolled families identified as Hispanic/Latino, and 40% of participants preferred communicating in Spanish with their healthcare providers. About half of enrolled families reported an annual household income of <$20,000 in the last year. The 5-question survey regarding the Consultagene video content was completed by 9/60 enrolled families. Results from this survey data suggest that families are overall satisfied with these educational videos (Supplemental Fig.  1 ).

Clinician engagement and CPE events

We strengthened collaborations with community healthcare providers in the RGV by engaging in multiple in-person meetings with local pediatricians and subspecialists. These in-person engagements have cultivated strong connections with healthcare providers in the region, leading to a surge of Consultagene referrals around times of our visits, as well as an overall incremental increase in referrals to our study over time (Fig.  4 ).

Number of referrals to Consultagene by month ( n  = 196). Arrows indicate months in which Houston Project GIVE team traveled to the RGV for in-person engagement with healthcare providers. CPE events (green arrows) were held on 4/15/23 and 9/23/23. Collaborator visits (yellow arrows) included presentations to local pediatricians, specialty groups, and hospital departments

Additionally, two CPE seminars were held on April 15th, 2023, and September 23rd, 2023. In total, 32 pediatricians, specialists, developmental therapists, and social workers attended these meetings (19 attendees at the April 2023 event; 13 attendees at the September 2023 event). Data collected at the September 2023 CPE event indicated growing confidence of the healthcare professionals in approaching children with genetic disorders after attending the CPE event (Supplemental Fig.  2 ). We continue to actively engage with attendees of the meetings and seek their input in selecting future curricula, fostering a collaborative approach.

Evolution of the study protocol

Project GIVE was originally designed as a peer-to-peer study, and we envisioned participation of the referrers for all three study visits throughout the Project GIVE journey. However, once we began recruiting, we recognized that there were several logistical barriers to scheduling patients around the busy providers’ schedules. We subsequently transitioned to a more traditional telemedicine set-up whereby the study geneticist, genetic counselor, and research coordinator met with the families independently of the referring providers.

At the outset, our team planned to establish a framework for assessing referrals, expecting each submission to contain detailed medical records and previous genetic evaluations. Over time, it became increasingly apparent that accessing comprehensive medical records for referred participants was challenging. These children routinely receive care from multiple specialists across different hospital systems that employ various EHR systems. Frequently, supporting ancillary investigations, such as brain MRIs, EEG records, X-rays, echocardiograms, and any previously-completed genetic tests, are inaccessible to our team. In a significant number of referrals, only a concise clinical note regarding the medical concerns is submitted via the Consultagene portal. To address potential barriers posed by limited available medical records for these families, our clinical team has revised the acceptance criteria to cater to the majority of referrals. Through our experience, we have learned that even a concise narrative, when combined with information about the involvement of multiple specialists in the patient’s care, is often adequate for identifying those who would benefit from GS. We have found it necessary to amend our original study framework and prioritize a genotype-driven approach to expedite diagnoses in this frequently under-phenotyped population.

While our efforts have aimed to maximize enrollment opportunities, approximately 20% of referred patients have not been accepted. In some cases, we discovered that the child already had a genetic diagnosis that the clinical team/family were unaware of, and in other cases, the clinical indication did not warrant a comprehensive sequencing work-up; for example, the child may have exhibited a milder phenotype, or the phenotype may have suggested a genetic diagnosis that could be identified through more targeted testing. We have made continued efforts to provide quality care for all patients who have been referred to Project GIVE, regardless of their acceptance into the study. For individuals referred who had a previously identified diagnosis, we provide a detailed letter to both the provider and the family that explains the diagnosis, inheritance pattern, and necessary follow-up care. For patients who would benefit from alternative genetic testing options, we work with the referring providers to facilitate the ordering of the most suitable test. Consequently, most patients referred to us will undergo an appropriate genetics workup.

The integration of genomic information to enhance health outcomes is becoming more prevalent in clinical practice across the country. Nevertheless, disparities in accessing genetic services among ethnic minorities and individuals with low socioeconomic status have resulted in the marginalization of the most vulnerable populations. Consultagene has emerged as a transformative solution, positioned to contribute significantly towards reducing TTD in underserved communities with limited resources. Given the scarcity of local access to clinical geneticists in the region, this advanced referral tool has played a pivotal role in streamlining patient pathways and enabling genetic evaluation of children with rare diseases. It represents one of the first systematic initiatives to integrate virtual health delivery with GS, particularly focused on a medically underserved pediatric population.

A previous study from a Hidalgo county specialty clinic in the RGV during COVID-19 found that only 15.6% of their patients opted to be seen via telemedicine rather than in-person, and while 92.4% of the community identified as Hispanic/Latino, only 69% of individuals who opted to use telemedicine were Hispanic/Latino. The authors speculated that this difference could be attributed to limited access to technology, technological literacy, or cultural perceptions of telemedicine [ 22 ]. Our decision to integrate Consultagene into a local RGV clinic allowed us to circumvent some of these proposed challenges.

Within our research team, we are fortunate to have a bilingual study coordinator native to the RGV who has an intimate understanding of the region’s culture and challenges. She has emerged as a trusted member of our group, fostering strong connections with both providers and participants, especially those who prefer communication in Spanish. With training in social work, she assists families in accessing additional support beyond the study’s genetic services, such as identifying school and mental health resources, housing assistance programs, and local specialists. In essence, her role has evolved into a patient navigator role commonly implemented in cancer settings to reduce barriers to care for patients from underserved backgrounds [ 23 , 24 ]. Her comprehensive care plays a crucial role in the success of our virtual tele-genetics program. As such, we advocate for the integration of a patient navigator into similar virtual genetics programs in other underserved regions.

A recognized challenge in initiating a genomic study in an underrepresented region involves establishing trust among medical providers and community members. The UTRGV clinicians, who are already trusted medical professionals in the community, have continually utilized their networks in the region to help ascertain children most likely to most benefit from Project GIVE. Furthermore, our efforts to establish a wide referrer base – including physicians, nurse practitioners, medical assistants, and ECI specialists – has significantly expedited the referral of patients requiring urgent evaluation to Project GIVE. This strategic inclusion has enhanced the accessibility and efficiency of our services.

Virtual evaluation limitations

While the virtual setup of our study has expanded access to genomic care, conducting a remote physical examination comes with its limitations. The information gathered may often be insufficient, potentially leading to the oversight of pertinent features crucial for phenotyping and informing GS. To address the constraints of telemedicine examinations, our research coordinator collects photographs after informed consent and electronically transfers the images to the study team for detailed assessment. We emphasize the importance of having an in-person coordinator to help facilitate the genetics evaluation.

Future directions

In the months ahead, we will continue to recruit pediatric patients with undiagnosed diseases living in the RGV. Concurrently, we are committed to analyzing the CSER survey data to gain a deeper understanding of parental experiences with and perceptions of genetic testing. Furthermore, we are in the process of concluding a qualitative study that explores the barriers and facilitators to accessing comprehensive medical care and social/educational services for children in the RGV with rare diseases. The combination of quantitative and qualitative data from our cohort will highlight the experiences of families in the RGV with children facing complex, undiagnosed diseases and will provide insight into the longitudinal experiences that families may face after receiving a diagnosis. This information is crucial for informing best practices to improve genomic health equity along the Texas-Mexico border.

When considering the sustainability of these genetics services in the region beyond Project GIVE, it is important to consider whether a true peer-to-peer consultation model would increase access to care for children with undiagnosed diseases in this region while still providing patients with quality genetics services. Considering that GS is currently fully funded by our study’s grant, it’s imperative to acknowledge the potential impact of insurance status on families’ future access to testing.

In summary, Project GIVE has successfully increased access to genomic care in a medically underserved, predominantly Hispanic/Latino population by implementing a virtual telehealth platform and offering GS to pediatric patients with rare diseases. We strongly believe that these initiatives are readily applicable and replicable in other regions with limited healthcare resources.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Continuous Professional Education

Clinical Sequencing Evidence-Generating Research

Early Childhood Intervention

Whole Genome sequencing

Genetic Inclusion by Virtual Evaluation

Rio Grande Valley

Return of results

Texas Birth Defects Registry

Time to Diagnosis

University of Texas Rio Grande Valley

Fraiman YS, Wojcik MH. The influence of social determinants of health on the genetic diagnostic odyssey: who remains undiagnosed, why, and to what effect? Pediatr Res. 2021;89(2):295–300. https://doi.org/10.1038/s41390-020-01151-5

Article   PubMed   Google Scholar  

Aldrighetti CM, Niemierko A, Van Allen E, Willers H, Kamran SC. Racial and ethnic disparities among participants in precision oncology clinical studies. JAMA Netw Open. 2021;4(11):e2133205. https://doi.org/10.1001/jamanetworkopen.2021.33205

Article   PubMed   PubMed Central   Google Scholar  

Glenn BA, Chawla N, Bastani R. Barriers to genetic testing for breast cancer risk among ethnic minority women: an exploratory study. Ethn Dis. 2012;22(3):267–73.

PubMed   Google Scholar  

Cragun D, Weidner A, Lewis C, et al. Racial disparities in BRCA testing and cancer risk management across a population-based sample of young breast cancer survivors. Cancer. 2017;123(13):2497–505. https://doi.org/10.1002/cncr.30621

Article   CAS   PubMed   Google Scholar  

George S, Duran N, Norris K. A systematic review of barriers and facilitators to minority research participation among African Americans, latinos, Asian Americans, and Pacific islanders. Am J Public Health. 2014;104(2):e16–31. https://doi.org/10.2105/AJPH.2013.301706

Hann KEJ, Freeman M, Fraser L, et al. Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review. BMC Public Health. 2017;17(1):503. https://doi.org/10.1186/s12889-017-4375-8

2023 Demographics Summary Data for Region: Rio Grande Valley. RGV health connect. March 2023. Accessed June 9. 2023. https://www.rgvhealthconnect.org/demographicdata

The South Texas Region. Texas Comptroller of Public Accounts. 2022. Accessed June 8, 2023. https://comptroller.texas.gov/economy/economic-data/regions/2022/south.php#:~:text=According to the 2020 Census,to 15.9 percent growth statewide

Small Area Income and Poverty Estimates. United States Census Bureau. Accessed June 9. 2023. https://www.census.gov/data-tools/demo/saipe/#/?s_state=48&s_county=48061&s_district=&s_geography=county&s_measures=u18

Federal Reserve Bank of Dallas. Las Colonias in the 21st century - progress along the Texas-Mexico Border. April 2015. Accessed February 1. 2024. https://www.dallasfed.org/~/media/microsites/cd/colonias/index.html

MUA Find. Health Resources & Services Administration. Accessed June 9. 2023. https://data.hrsa.gov/tools/shortage-area/mua-find

What Is Shortage Designation? Bureau of Health Workforce. Accessed June 8. 2023. https://bhw.hrsa.gov/workforce-shortage-areas/shortage-designation#mups

Sharma Y, Cox L, Kruger L, Channamsetty V, Haga SB. Evaluating primary care providers’ readiness for delivering genetic and genomic services to underserved populations. Public Health Genomics September. 2021;7:1–10. https://doi.org/10.1159/000518415

Article   Google Scholar  

Consultagene. Accessed June 27, 2023. https://consultagene.org/

Miller E. Evaluation of the Texas birth defects registry: an active surveillance system. Birth Defects Res Part Clin Mol Teratol. 2006;76(11):787–92. https://doi.org/10.1002/bdra.20331

Article   CAS   Google Scholar  

Miller DT, Lee K, Abul-Husn NS, et al. ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24(7):1407–14. https://doi.org/10.1016/j.gim.2022.04.006

Face2Gene. Accessed February 28. 2024. https://www.face2gene.com

Suckiel SA, O’Daniel JM, Donohue KE, et al. Genomic sequencing results disclosure in diverse and medically underserved populations: themes, challenges, and strategies from the CSER Consortium. J Pers Med. 2021;11(3). https://doi.org/10.3390/jpm11030202

Robinson JO, Wynn J, Biesecker B, et al. Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven clinical sequencing exploratory research (CSER) Consortium studies. Genet Med. 2019;21(12):2781–90. https://doi.org/10.1038/s41436-019-0565-3

Goddard KAB, Angelo FAN, Ackerman SL, et al. Lessons learned about harmonizing survey measures for the CSER consortium. J Clin Transl Sci. 2020;4(6):537–46. https://doi.org/10.1017/cts.2020.41

CSER Resources. AnVIL. Accessed February 18. 2024. https://anvilproject.org/consortia/cser/resources

Ramirez AV, Ojeaga M, Espinoza V, Hensler B, Honrubia V. Telemedicine in minority and socioeconomically disadvantaged communities amidst COVID-19 pandemic. Otolaryngol Head Neck Surg. 2021;164(1):91–2. https://doi.org/10.1177/0194599820947667

Freeman HP, Rodriguez RL. History and principles of patient navigation. Cancer. 2011;117(15 Suppl):3539–42. https://doi.org/10.1002/cncr.26262

Genoff MC, Zaballa A, Gany F, et al. Navigating language barriers: a systematic review of patient navigators’ impact on cancer screening for limited English proficient patients. J Gen Intern Med. 2016;31(4):426–34. https://doi.org/10.1007/s11606-015-3572-3

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Acknowledgements

We are grateful to the families for participating in Project GIVE. We sincerely thank Dr. Philip Lupo for assisting with patient recruitment through the TBDR. We are also grateful to the leadership of Easterseals RGV and Milestones Therapeutics for serving as exceptional community partners. We thank Lisa Trevino from DHR Health for assisting with patient recruitment. We are grateful to Dr. Lizardo and Dr. Wiernik, the community pediatricians for referring patients.

This study was funded by the National Center for Advancing Translational Sciences, 5UG3TR004047. This work was supported in part by funding of the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from the Eunice Kennedy Shriver NICHD. The contents of this publication do not necessarily reflect the views or policies of the NIH. The mention of trade names, commercial products, or organizations do not imply endorsement by the US Government.

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Blake Vuocolo, Roberta Sierra, Daniel Brooks, Christopher Holder, Lauren Urbanski, Hongzheng Dai, Claudia Soler-Alfonso, Brendan Lee & Seema R. Lalani

Primary and Community Care, University of Texas Rio Grande Valley, Harlingen, TX, 78550, USA

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Rio Grande Valley, Easterseals, TX, 78505, USA

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Baylor Genetics Laboratories, Houston, TX, 77030, USA

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Contributions

SRL and BL conceptualized and designed the study. KR, JDG, SNM, LB, AA, HH, SR, SM, LM, KC referred patients for evaluation. RN and JG made the study visits possible. RS, DB, CSA, SRL, BV were involved in all patient evaluations. HD carried out the GS results. CH and LU were involved in Consultagene development and administration. SRL and BV conducted the write-up. All authors approved the final manuscript.

Corresponding author

Correspondence to Seema R. Lalani .

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Approved by the IRB of Baylor College of Medicine. Informed consent was signed by all study participants.

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The authors declare that they have no competing interests.

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Supplementary Material 1: Supplemental Figure 1

| Participant responses on the Consultagene post-video survey ( n  = 9). A five-question survey was administered to participants after they watched the Basics of Genetics and What to Expect at a Genetics Clinic Visit videos in the Consultagene portal. Three questions (A, B, C) assessed participants’ perceptions of the videos, and two true/false questions (D, E) assessed participants’ understanding of the material covered in the videos. Only six participants completed the final question (E)

Supplementary Material 2: Supplemental Figure 2

| RGV providers’ pre- and post-CME survey responses ( n  = 10, paired). Attendees of the CPE events were asked to complete questions pertaining to their comfortability with different aspects of genetics before (left column graphs) and after (right column graphs) the CPE content was presented

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Vuocolo, B., Sierra, R., Brooks, D. et al. Project GIVE: using a virtual genetics service platform to reduce health inequities and improve access to genomic care in an underserved region of Texas. J Neurodevelop Disord 16 , 52 (2024). https://doi.org/10.1186/s11689-024-09560-x

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• Saori Mizuno-Iijima 1 ,
• Shoko Kawamoto   ORCID: orcid.org/0000-0002-6404-3443 2 ,
• Masahide Asano   ORCID: orcid.org/0000-0002-9087-6481 3 ,
• Tomoji Mashimo   ORCID: orcid.org/0000-0001-7543-7301 4 ,
• Shigeharu Wakana   ORCID: orcid.org/0000-0002-7037-8354 5 ,
• Katsuki Nakamura   ORCID: orcid.org/0000-0002-2376-8755 6 ,
• Ken-ichi Nishijima   ORCID: orcid.org/0000-0002-7189-465X 7 ,
• Hitoshi Okamoto   ORCID: orcid.org/0000-0002-7512-8549 8 ,
• Kuniaki Saito   ORCID: orcid.org/0000-0001-8233-9283 9 ,
• Sawako Yoshina 10 ,
• Yoshihiro Miwa   ORCID: orcid.org/0000-0003-4827-5022 11 ,
• Yukio Nakamura 12 ,
• Moriya Ohkuma 13 &
• Atsushi Yoshiki   ORCID: orcid.org/0000-0002-9450-5151 1  

Mammalian genome research has conventionally involved mice and rats as model organisms for humans. Given the recent advances in life science research, to understand complex and higher-order biological phenomena and to elucidate pathologies and develop therapies to promote human health and overcome diseases, it is necessary to utilize not only mice and rats but also other bioresources such as standardized genetic materials and appropriate cell lines in order to gain deeper molecular and cellular insights. The Japanese bioresource infrastructure program called the National BioResource Project (NBRP) systematically collects, preserves, controls the quality, and provides bioresources for use in life science research worldwide. In this review, based on information from a database of papers related to NBRP bioresources, we present the bioresources that have proved useful for mammalian genome research, including mice, rats, other animal resources; DNA-related materials; and human/animal cells and microbes.

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Meeting report: 31st international mammalian genome conference, mammalian genetics and genomics: from molecular mechanisms to translational applications.

Establishment and application of information resource of mutant mice in RIKEN BioResource Research Center

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Introduction

Bioresources represent a fundamental component of the research infrastructure that supports the life sciences. The development of bioresources is a lengthy and meticulous process, and they serve as the foundation for discoveries and future research endeavors. The sharing of these resources among researchers is crucial for the advancement of research and development. In response to this need, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) established the National BioResource Project (NBRP) in FY2002. This initiative aims to create a systematic framework for the collection, preservation, and distribution of bioresources, with a particular emphasis on those requiring strategic development at the national level. This review synthesizes information on bioresources that have proven valuable for mammalian genome research. These resources include mice, rats, other animal resources, DNA-related materials, and human/animal cells and microbes. This review draws upon data extracted from a comprehensive database of publications related to NBRP bioresources, offering insights into the current landscape and potential future directions of bioresource utilization in genomic research.

The Core Center of NBRP-Mice is the Experimental Animal Division of the RIKEN BioResource Research Center (RIKEN BRC) (Mizuno-Iijima et al. 2022 ), which has collected mouse strains developed mainly in Japan that have been reported in academic publications (Fig.  1 ) in order to preserve unique and cutting-edge mouse models (Table  1 ). NBRP-Mice performs rigorous quality control, including microbial and genetic testing to ensure the reproducibility of animal experiments. As one of the international hubs for mouse resources, we continuously participate in global mouse resource networks such as International Mouse Strain Resource (IMSR), International Mouse Phenotyping Consortium (IMPC), Asian Mouse Mutagenesis & Resource Association (AMMRA) and Asian Network of Research Resource Centers (ANRRC). NBRP-Mice has archived approximately 10,000 mouse strains, most of which are genetically modified mice, as tools for gene functional analysis tools, including Cre/Flp drivers, fluorescent and luminescent reporters, and human disease models such as the third-generation Alzheimer’s disease model with genetic mutations of Alzheimer’s disease patients (Sasaguri et al. 2018 ; Sato et al. 2021 ) as well as a novel Down syndrome mouse model using a mouse artificial chromosome-based chromosome engineering technique (Kazuki et al. 2020 ). Information on the available mouse strains is disseminated through the NBRP-Mice website ( https://mus.brc.riken.jp/ ) and the IMSR ( https://www.findmice.org/ ), an all-encompassing database of the major international mouse repositories. NBRP-Mice receives requests from research communities worldwide (Fig.  2 ) and distributes live mice, frozen embryos/sperm, recovered litters from frozen embryos/sperm, and organ/tissue/genomic DNA. To date, NBRP-Mice has distributed mouse resources to researchers at 712 domestic and 1003 overseas academic and industry organizations in 44 countries. Outstanding research results from studies using NBRP-Mice have been published in 1300 papers so far (Fig.  3 ) and registered in our database.

Breakdown of collected mouse strains in NBRP-Mice (FY2017-FY2023)

Breakdown of distributed mouse strains from NBRP-Mice (FY2017-FY2023)

Number of publications using NBRP-Mice mouse resources

In addition to genetically modified strains, NBRP-Mice also preserves wild-derived inbred strains such as the Japanese subspecies MSM/MsRbrc (MSM, RBRC00209) and JF1/MsRbrc (JF1, RBRC00639). The enormous number of genomic polymorphisms present between these subspecies and classical inbred strains is useful for understanding the genomic function and diverse biological phenotypes in mice and other mammals including humans as well. MoG + ( https://molossinus.brc.riken.jp/mogplus/ ) (Takada et al. 2022 ) is a mouse genome database designed to support research using Mus musculus subspecies, with a focus on comparisons between mouse subspecies and classical inbred strains. MoG + provides access to more than 40 million polymorphisms found by comparative genomic analysis of 10 Asian wild-derived strains, including Mus musculus molossinus -derived MSM and JF1; Mus musculus musculus -derived KJR/Ms (RBRC00655), SWN/Ms (RBRC00654), CHD/Ms (RBRC00738), NJL/Ms (RBRC00207), and BLG2/Ms (RBRC00653); Mus musculus domesticus -derived BFM/2Ms (RBRC00659) and PGN2/Ms (RBRC00667); and Mus musculus castaneus -derived HMI/Ms (RBRC00657), all of which are available from NBRP-Mice, while linking to mouse resource catalog information, human genome variations, and so on. In addition, public genome polymorphism information on 36 classical inbred strains is stored. MoG + has been utilized for disease and phenotypic analysis (Takeishi et al. 2022 ; Yasuda et al. 2020 ). Reproductive engineering techniques are being developed to support research involving subspecies mouse strains (Hasegawa et al. 2021 ; Hirose et al. 2017 ; Mochida et al. 2014 ). An example of the use of subspecies strains is gene expression analysis based on single nucleotide polymorphisms (SNPs) in F1 hybrid mice (Saito et al. 2024 ; Yagi et al. 2017 , 2020 ). Genomic DNA derived from these multiple subspecies strains has also been used (Bamunusinghe et al. 2013 , 2016 , 2018 ).

The Core Center of NBRP-Rats is the Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University. Scientists conducting research involving rats have conventionally accumulated physiological and pharmacological data. Compared with mice, rats have typically been used for experiments involving drug administration and surgery because of their larger body size and for behavioral studies because of their higher intelligence. NBRP-Rats collects rat strains that have been maintained by individual scientists or laboratories in Japan and overseas, making over 800 strains available, including inbred and genetically modified strains, and has provided about 1500 strains so far (Table  2 ). NBRP-Rats has common inbred strains, spontaneous mutants, congenic strains, recombinant inbred strains, transgenic and newly genetically modified strains, and so on. Recently, genome-edited rats have also been collected. Available strains can be accessed via the NBRP-Rats website ( https://www.anim.med.kyoto-u.ac.jp/nbr/Default.aspx ). NBRP-Rats provides reference information for strain selection, including the results of approximately 200 strains on 109 phenotypic measurements for physiological and behavioral parameters such as body weight at various ages, blood pressure, spontaneous locomotor activity, and the passive avoidance test ( https://www.anim.med.kyoto-u.ac.jp/nbr/phenome.aspx ); the phylogenetic tree of 132 rat strains based on genomic profile data ( https://www.anim.med.kyoto-u.ac.jp/nbr/phylo.aspx ); and a pedigree-like charting tool showing 357 simple sequence length polymorphism (SSLP) marker differences for 179 genotyped rat strains ( https://www.anim.med.kyoto-u.ac.jp/nbr/pedigree/sb.aspx ). NBRP-Rats has also worked to develop reproductive technology and has established optimal freezing and thawing methods for sperm, stable in vitro fertilization (IVF) technology (Honda et al. 2019 ; Mochida et al. 2024 ; Morita et al. 2023 ) and is making progress in the cryopreservation of rat strains.

At the Institute of Medical Science, The University of Tokyo, which is an NBRP-Rats Sub-Core Center, the development of novel genome-edited rat models is underway. Three severely immunodeficient (SCID) rat strains generated using the CRISPR/Cas9 system [F344- Il2rg em1Iexas (NBRP Rat No: 0883), F344- Rag2 em1Iexas (NBRP Rat No: 0894), and F344- Il2rg/Rag2 em1Iexas (NBRP Rat No: 0895)] (Mashimo et al. 2010 ) have already been made available to researchers ( https://www.ims.u-tokyo.ac.jp/animal-genetics/scid/index_en.html ). SCID rats can be transplanted with human induced pluripotent stem cells (iPS cells), cancer cells, liver cells, and so on. Therefore, SCID rats are useful for analyzing human physiological functions in vivo (Eguchi et al. 2022 ; Lahr et al. 2021 ; Miyasaka et al. 2022 ). In fact, the demand from translational research and regenerative medicine is increasing every year. In addition, NBRP-Rats has been collecting and developing new Cre driver rats, and 22 Cre driver strains are available for conditional studies. In the near future, a database of Cre driver rats will be made available on the website, and the results of comprehensive expression analysis, local expression analysis using adeno-associated virus (AAV), behavioral analysis, and magnetic resonance imaging (MRI) analysis will be published as phenotype information.

The other animal resources

In addition to laboratory mice and rats, the NBRP provides Aged mice and Japanese macaques as mammalian resources for researchers in Japan. NBRP-Aged mice provides three standard mouse strains [C57BL/6J, C57BL/6N (B6N), BALB/cA] that are bred for about 2 years in a uniform environment under strict microbiological control. Aged mice are expected to be used for various aging research, such as elucidating the mechanisms of the aging process, aging control, and aging-related diseases. The Japanese macaque is a species of macaque monkey. Due to their close relationship with humans, Japanese macaques are used mainly in the field of neuroscience but also in the fields of infectious diseases, immunology, and regenerative medicine. Compared with other Southeast Asian macaque species such as rhesus and cynomolgus macaques, Japanese macaques have a curious and calm temperament as well as highly developed cognitive and learning abilities, making them suitable for research on higher brain functions and fine motor functions that require complex task acquisition (Kubota et al. 2024 ; Kumano and Uka 2024 ; Sasaki et al. 2024 ). In fact, Japanese macaques have contributed to the elucidation of the pathogenesis and pathology of neurological disorders such as dementia and Parkinson's disease as well as to the development of treatments to restore neurological functions (Chiken et al. 2021 ; Darbin et al. 2022 ; Oyama et al. 2023 ).

The NBRP supports life science research by providing a total of 12 animal bioresources for which whole-genome sequencing has been performed, which is necessary for analyzing orthologs of human genes (Table 3 ). For example, chickens and quails have been used in a variety of fields, particularly in embryology. In vitro culture of primordial germ cells (PGCs) is now possible in 20 chicken strains, and gene transfer and genome editing of chickens using such cells are under development. To meet the demand for fluorescent live imaging of developmental processes, NBRP-Chickens & Quails provides a transgenic chicken strain (pLSi/ΔAeGFP-TG) that expresses enhanced green fluorescent protein (eGFP) almost systemically under the control of the chicken β-actin promoter (Motono et al. 2010 ; Tsujino et al. 2019 ) and a PRDM14-eGFP knock-in chicken strain that express eGFP under the control of the chicken endogenous PRDM14 promoter (Hagihara et al. 2020 ). As a tool for generating new models, Cas9-T2A-mCherry transgenic chickens that expresses Cas9 under the control of the homeostatic human EF1α promoter are also available. NBRP-Chickens & Quails releases the results of quail genome analysis as the Quail Genome Browser ( http://viewer.shigen.info/uzura/index.php ). A PGK:H2B-chFP-TG quail strain that expresses mCherry throughout the body (Huss et al. 2015 ) is used for live imaging of developmental processes, with the advantage of easy microsurgery in embryos (Haneda et al. 2024 ; Yoshihi et al. 2020 ).

Zebrafish are transparent throughout embryogenesis, are easy to breed, have a short life cycle, and are amenable to mutation and genetic modification. NBRP-Zebrafish has about 400 mutant lines and about 1800 transgenic lines. The neuronal composition and neural mechanisms of the zebrafish brain are highly conserved with those of humans, making zebrafish particularly useful in the field of neuroscience. Tg(CM-isl1:GFP), which expresses green fluorescent protein (GFP) in hindbrain motor neurons (Higashijima et al. 2020 ), is useful for imaging neural circuit networks (Derrick et al. 2024 ; Zhao et al. 2024 ). Tg(vglut2a:loxP-DsRed-loxP-GFP), which expresses DsRed in glutamatergic neurons prior to Cre recombinase exposure and GFP in the Cre-recombined cells (Satou et al. 2012 ), has been used to elucidate the mechanisms of neural circuit construction processes (Itoh et al. 2024 ; Schmidt et al. 2024 ) and the relationship between behavior/movement and neuronal activity (Berg et al. 2023 ; Carbo-Tano et al. 2023 ).

Drosophila is used to study life phenomena and in disease research because of its many similarities to humans, including gene homology and basic biological mechanisms. The NBRP- Drosophila conserves many useful mutants for life science research, including about 14,000 RNAi strains and about 30 FlyCas9 strains. CAS-001 (Kondo and Ueda 2013 ), a transgenic line expressing the Cas9 protein, can be crossed with various guide RNA strains to generate gene knock-out mutant flies with high efficiency. The generation of mutant strains with CAS-001 is versatile and has been reported in the development of novel models for metabolic disease research (Martelli et al. 2024 ) and biochemical research (Banreti et al. 2022 ). GAL4 enhancer trap insertion strains (Hayashi et al. 2002 ) are useful for tissue-specific expression and knock-down using the GAL4/UAS system, and approximately 4200 such lines have been conserved. A traffic jam-GAL4 driver strain (DGRC#104055), which is expressed in all stages of ovarian follicle cells at every developmental stage, has been used by many scientists in various fields as well as for the elucidation of reproductive mechanisms (Mallart et al. 2024 ; Taniguchi and Igaki 2023 ).

Ca enorhabditis elegans is useful for understanding gene function because C.elegans has only about 1000 somatic cells, the cell lineage of which has been extensively described, and detailed descriptions of its morphology have been made through serial electron microscopy images. NBRP- C. elegans has about half the number of deletion mutants as there are genes in wild-type C. elegans. The drp-1 deletion mutant (tm1108), an ortholog of the human DMNL1 gene that functions in mitochondrial division, has been used to study mitochondria-related diseases (Chen et al. 2024 ) and aging (Sharifi et al. 2024 ). The brc-1 deletion mutant (tm1145), an ortholog of the human BRCA1 gene that is involved in DNA repair and has been reported to be associated with several diseases including cancer, is used to elucidate DNA repair mechanisms (Bujarrabal-Dueso et al. 2023 ; Wang et al. 2023 ).

DNA-related materials

The Gene Engineering Division, RIKEN BRC provides genetic materials such as plasmids, expression and reporter vectors, and comprehensive clone sets of cDNAs and genomic DNAs. To date, NBRP-DNA-related materials have conserved about 3.8 million resources including about 3400 research tools for imaging and genome editing, about 600,000 human cDNA/genomic DNA clones, about 350,000 mouse cDNA/genomic DNA clones, and 1.3 million animal cDNA/genomic DNA clones (Table  4 ). Mammalian expression vectors for protein production and gene expression, mouse and rat BAC clones, and fluorescent and luminescent protein expression vectors for imaging are used to generate genetically modified mice, rats, and mammalian cells. BAC clones can be searched with the BAC browser, using gene symbols as keywords, and the physical location of BAC clones on the genome can be confirmed. The BAC browsers for B6N and MSM mouse strains ( http://analysis2.nig.ac.jp/mouseBrowser/cgi-bin/index.cgi?org=mm ), for F344/Stm and LE/Stm rat strains ( http://analysis2.nig.ac.jp/ratBrowser/cgi-bin/index.cgi?org=rn ), and for Japanese macaque ( http://analysis2.nig.ac.jp/jmonkeyBrowser/cgi-bin/index.cgi?org=jm ) are published on the website. The B6N BAC library consists of 128,000 clones representing 90.2% of the actual coverage of the haploid genome. The MSM BAC library consists of 200,000 BAC clones.

NBRP-DNA-related materials collects useful tools that are expected to be requested by researchers in the future using artificial intelligence technology. Regarding genome-editing tools, Cas9-poly(A) expressing improved plasmid [T7-NLS hCas9-pA (RDB13130)] (Yoshimi et al. 2016 ) and the expression vector of sgRNA with hSpCas9-Cdt1(mouse) fusion protein [px330-mC (RDB14406)] (Mizuno-Iijima et al. 2021 ) are available. In addition to conventionally used fluorescent and luminescent proteins, NBRP-DNA-related materials also provides the highly photostable and bright GFP StayGold [e.g., (n1)StayGold/pRSET (RDB19605) (Hirano et al. 2022 ) and pRSETB/mStayGold (RDB20214) (Ando et al. 2023 )], and the novel yellow fluorescent protein Achilles [Achilles/pRSETB (RDB15982)] (Yoshioka-Kobayashi et al. 2020 ) to meet the needs of researchers. The highly luminescent luciferases Akaluc [pcDNA3 Venus-Akaluc (RDB15781)] (Iwano et al. 2018 ) and oFluc [pPmat Luc1 (RDB14359)] (Ogoh et al. 2020 ) are also provided. Reporter mice expressing Akaluc or oFluc are available from NBRP-Mice [C57BL/6J- Gt(ROSA)26Sor em13(CAG-luc)Rbrc /#77 (RBRC10451), C57BL/6J- Gt(ROSA)26Sor em14(CAG-Venus/Akaluc)Rbrc /#87 (RBRC10858), C57BL/6J- Gt(ROSA)26Sor em13.1(CAG-luc)Rbrc /#77 (RBRC10919), and C57BL/6J- Gt(ROSA)26Sor em17.1(CAG-Venus/Akaluc)Rbrc /#11 (RBRC10921)] (Nakashiba et al. 2023 ).

Human and animal cells

The Cell Engineering Division, RIKEN BRC has collected many cultured cell lines, including about 4600 human cell lines and about 3800 animal cell lines. Mouse embryonic stem (ES) cell lines with germline-transmission [e.g., B6J-S1 UTR (AES0140), B6NJ-22 UTR (AES0141) (Tanimoto et al. 2008 ), and EGR-G101 (AES0182) (Fujihara et al. 2013 )] are used to generate genetically engineered mice, using both conventional gene targeting and genome-editing technologies (Hasan et al. 2021 ; Noda et al. 2017 , 2019 ; Serizawa et al. 2019 ). As mentioned above, because SCID rat strains are transplantable with human cells, human iPS cells and cancer cells have been transplanted and used for in vivo functional analysis. Some users have reported research results in combination with human iPS cells derived from healthy volunteers provided by NBRP-Human and animal cells (Gima et al. 2024 ; Hayashi et al. 2024 ; Tada et al. 2022 ). NBRP-Human and animal cells also provides human iPS cell lines derived from patients with various diseases (Table  5 ). These disease-specific iPS cell lines are expected to be further used for research with a view toward clinical application.

NBRP-Human and animal cells performs genetic analysis of some disease-specific iPS cells to promote their use. For example, for iPS cells derived from amyotrophic lateral sclerosis, commonly referred to as ALS, the results of target sequence analysis for the casual genes ( SOD1 / TARDBP / ALS10 / TDP-43 genes) have been published on the RIKEN BRC website ( https://cell.brc.riken.jp/en/ga-als ). As for iPS cells derived from spinocerebellar degeneration, the results of the number of repeated sequences in related 8-gene regions have been published ( https://cell.brc.riken.jp/en/ga-scd ). In addition to the cell material itself, human iPS cell lines (disease-specific iPS cells and healthy human iPS cells) provide clinical information such as sex, age and the names of diseases, and researchers can use these data upon appropriate application and review.

The NBRP also manages general microbes (bacteria, archaea, yeast, and filamentous fungi), prokaryotes ( Escherichia coli and Bacillus subtilis ), pathogenic eukaryotic microbes, pathogenic bacteria, and human pathogenic viruses). The most popular paper among NBRP-Mice users’ results sorted by Citation Index is one that identified and isolated 11 gut bacterial strains that strongly induce IFNγ-producing CD8T cells and showed that administration of these strains inhibited infection and tumor growth in mouse strains (Tanoue et al. 2019 ). The influence of the gut microbiota and skin microbiota on phenotype is a topic of great interest, and more results are expected in the future.

Research Resource Circulation

All the article information discussed in this paper, which is based on studies using NBRP resources, is registered and accessible in the Research Resource Circulation (RRC) database ( https://rrc.nbrp.jp/ ) (Fig.  4 ). RRC is an integrated database that connects published research outcomes to the specific bioresources used in those studies. Its primary objective is to aggregate and organize information on published papers and patents that have utilized these resources and to make this information publicly available along with statistical data, thereby enhancing the information content of each resource and promoting their utilization.

Research Resource Circulation (RRC) Database: a system for tracking and analyzing the utilization of NBRP bioresources and research outcomes

A key feature of the RRC is assigning a unique RRC ID to each paper corresponding PubMed information, strain names, citation metrics, and other relevant data. Development of the RRC began in 2007, and it presently contains entries for approximately 55,000 papers and 1300 patents. Users can easily register papers using PubMed IDs or DOIs. Moreover, the RRC is linked with NCBI’s LinkOut service, enabling resource links to be added to corresponding papers in PubMed.

The NBRP provides useful biological resources, technologies, and information for mammalian genome research both in Japan and overseas, and many users’ research results have been reported. Not only the use of individual bioresources but also the combination of bioresources has been reported by many users. We encourage global scientists to conduct a comprehensive search with biological resources of high quality available from NBRP. In addition, we are constantly updating the information on each bioresource to meet the needs of increasingly sophisticated and complex research while reviewing the latest research trends and increasing the number of stored resources. We hope you will make effective use of the NBRP to advance mammalian genome research.

Data availability

No datasets were generated or analysed during the current study.

Ando R, Shimozono S, Ago H, Takagi M, Sugiyama M, Kurokawa H, Hirano M, Niino Y, Ueno G, Ishidate F, Fujiwara T, Okada Y, Yamamoto M, Miyawaki A (2023) StayGold variants for molecular fusion and membrane-targeting applications. Nat Methods 21(4):648–656. https://doi.org/10.1038/s41592-023-02085-6

Article   CAS   PubMed   PubMed Central   Google Scholar  

Bamunusinghe D, Liu Q, Lu X, Oler A, Kozak CA (2013) Endogenous gammaretrovirus acquisition in Mus musculus subspecies carrying functional variants of the XPR1 virus receptor. J Virol 87(17):9845–9855. https://doi.org/10.1128/jvi.01264-13

Bamunusinghe D, Naghashfar Z, Buckler-White A, Plishka R, Baliji S, Liu Q, Kassner J, Oler AJ, Hartley J, Kozak CA (2016) Sequence diversity, intersubgroup relationships, and origins of the mouse Leukemia gammaretroviruses of laboratory and wild mice. J Virol 90(23):10682–10692. https://doi.org/10.1128/jvi.03186-15

Article   Google Scholar  

Bamunusinghe D, Skorski M, Buckler-White A, Kozak CA (2018) Xenotropic mouse gammaretroviruses isolated from pre-leukemic tissues include a recombinant. Viruses 10(8):418. https://doi.org/10.3390/v10080418

Banreti A, Bhattacharya S, Wien F, Matsuo K, Réfrégiers M, Meinert C, Meierhenrich U, Hudry B, Thompson D, Noselli S (2022) Biological effects of the loss of homochirality in a multicellular organism. Nat Commun 13(1):7059. https://doi.org/10.1038/s41467-022-34516-x

Berg EM, Mrowka L, Bertuzzi M, Madrid D, Picton LD, El Manira A (2023) Brainstem circuits encoding start, speed, and duration of swimming in adult zebrafish. Neuron 111(3):372-386.e4. https://doi.org/10.1016/j.neuron.2022.10.034

Article   CAS   PubMed   Google Scholar  

Bujarrabal-Dueso A, Sendtner G, Meyer DH, Chatzinikolaou G, Stratigi K, Garinis GA, Schumacher B (2023) The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities. Nat Struct Mol Biol 30(4):475–488. https://doi.org/10.1038/s41594-023-00942-8

Carbo-Tano M, Lapoix M, Jia X, Thouvenin O, Pascucci M, Auclair F, Quan FB, Albadri S, Aguda V, Farouj Y, Hillman EMC, Portugues R, Del Bene F, Thiele TR, Dubuc R, Wyart C (2023) The mesencephalic locomotor region recruits V2a reticulospinal neurons to drive forward locomotion in larval zebrafish. Nat Neurosci. https://doi.org/10.1038/s41593-023-01418-0

Article   PubMed   PubMed Central   Google Scholar  

Chen TY, Wang FY, Lee PJ, Hsu AL, Ching TT (2024) Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans . Aging Cell 23(4):e14103. https://doi.org/10.1111/acel.14103

Chiken S, Takada M, Nambu A (2021) Altered dynamic information flow through the cortico-basal ganglia pathways mediates Parkinson’s disease symptoms. Cereb Cortex 31(12):5363–5380. https://doi.org/10.1093/cercor/bhab164

Darbin O, Hatanaka N, Takara S, Kaneko N, Chiken S, Naritoku D, Martino A, Nambu A (2022) Subthalamic nucleus deep brain stimulation driven by primary motor cortex γ2 activity in parkinsonian monkeys. Sci Rep 12(1):6493. https://doi.org/10.1038/s41598-022-10130-1

Derrick CJ, Szenker-Ravi E, Santos-Ledo A, Alqahtani A, Yusof A, Eley L, Coleman AHL, Tohari S, Ng AY, Venkatesh B, Alharby E, Mansard L, Bonnet-Dupeyron MN, Roux AF, Vaché C, Roume J, Bouvagnet P, Almontashiri NAM, Henderson DJ, Reversade B, Chaudhry B (2024) Functional analysis of germline VANGL2 variants using rescue assays of VANGL2 knockout zebrafish. Hum Mol Genet 33(2):150–169. https://doi.org/10.1093/hmg/ddad171

Article   PubMed   Google Scholar  

Eguchi S, Kimura K, Kageyama K, Tani N, Tanaka R, Nishio K, Shinkawa H, Ohira GO, Amano R, Tanaka S, Yamamoto A, Takemura S, Yashiro M, Kubo S (2022) Optimal organ for patient-derived Xenograft model in pancreatic cancer and microenvironment that contributes to success. Anticancer Res 42(5):2395–2404. https://doi.org/10.21873/anticanres.15718

Fujihara Y, Kaseda K, Inoue N, Ikawa M, Okabe M (2013) Production of mouse pups from germline transmission-failed knockout chimeras. Transgenic Res 22(1):195–200. https://doi.org/10.1007/s11248-012-9635-x

Gima S, Oe K, Nishimura K, Ohgita T, Ito H, Kimura H, Saito H, Takata K (2024) Host-to-graft propagation of inoculated α-synuclein into transplanted human induced pluripotent stem cell-derived midbrain dopaminergic neurons. Regen Ther 25:229–237. https://doi.org/10.1016/j.reth.2023.12.019

Hagihara Y, Okuzaki Y, Matsubayashi K, Kaneoka H, Suzuki T, Iijima S, Nishijima KI (2020) Primordial germ cell-specific expression of eGFP in transgenic chickens. Genesis 58(8):e23388. https://doi.org/10.1002/dvg.23388

Haneda Y, Miyagawa-Tomita S, Uchijima Y, Iwase A, Asai R, Kohro T, Wada Y, Kurihara H (2024) Diverse contribution of amniogenic somatopleural cells to cardiovascular development: with special reference to thyroid vasculature. Dev Dyn 253(1):59–77. https://doi.org/10.1002/dvdy.532

Hasan ASH, Dinh TTH, Le HT, Mizuno-Iijima S, Daitoku Y, Ishida M, Tanimoto Y, Kato K, Yoshiki A, Murata K, Mizuno S, Sugiyama F (2021) Characterization of a bicistronic knock-in reporter mouse model for investigating the role of CABLES2 in vivo. Exp Anim 70(1):22–30. https://doi.org/10.1538/expanim.20-0063

Hasegawa A, Mochida K, Matoba S, Inoue K, Hama D, Kadota M, Hiraiwa N, Yoshiki A, Ogura A (2021) Development of assisted reproductive technologies for Mus spretus . Biol Reprod 104(1):234–243. https://doi.org/10.1093/biolre/ioaa177

Hayashi S, Ito K, Sado Y, Taniguchi M, Akimoto A, Takeuchi H, Aigaki T, Matsuzaki F, Nakagoshi H, Tanimura T, Ueda R, Uemura T, Yoshihara M, Goto S (2002) GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps. Genesis 34(1–2):58–61. https://doi.org/10.1002/gene.10137

Hayashi Y, Ohnishi H, Kitano M, Kishimoto Y, Takezawa T, Okuyama H, Yoshimatsu M, Kuwata F, Tada T, Mizuno K, Omori K (2024) Comparative study of immunodeficient rat strains in engraftment of human-induced pluripotent stem cell-derived airway epithelia. Tissue Eng Part A 30(3–4):144–153. https://doi.org/10.1089/ten.tea.2023.0214

Higashijima S, Hotta Y, Okamoto H (2020) Visualization of cranial motor neurons in live transgenic zebrafish expressing green fluorescent protein under the control of the islet-1 promoter/enhancer. J Neurosci 20(1):206–218. https://doi.org/10.1523/jneurosci.20-01-00206.2000

Hirano M, Ando R, Shimozono S, Sugiyama M, Takeda N, Kurokawa H, Deguchi R, Endo K, Haga K, Takai-Todaka R, Inaura S, Matsumura Y, Hama H, Okada Y, Fujiwara T, Morimoto T, Katayama K, Miyawaki A (2022) A highly photostable and bright green fluorescent protein. Nat Biotechnol 40(7):1132–1142. https://doi.org/10.1038/s41587-022-01278-2

Hirose M, Hasegawa A, Mochida K, Matoba S, Hatanaka Y, Inoue K, Goto T, Kaneda H, Yamada I, Furuse T, Abe K, Uenoyama Y, Tsukamura H, Wakana S, Honda A, Ogura A (2017) CRISPR/Cas9-mediated genome editing in wild-derived mice: generation of tamed wild-derived strains by mutation of the a (nonagouti) gene. Sci Rep 14(7):42476. https://doi.org/10.1038/srep42476

Article   CAS   Google Scholar  

Honda A, Tachibana R, Hamada K, Morita K, Mizuno N, Morita K, Asano M (2019) Efficient derivation of knock-out and knock-in rats using embryos obtained by in vitro fertilization. Sci Rep 9(1):11571. https://doi.org/10.1038/s41598-019-47964-1

Huss D, Benazeraf B, Wallingford A, Filla M, Yang J, Fraser SE, Lansford R (2015) A transgenic quail model that enables dynamic imaging of amniote embryogenesis. Development 142(16):2850–2859. https://doi.org/10.1242/dev.121392

Itoh T, Uehara M, Yura S, Wang JC, Fujii Y, Nakanishi A, Shimizu T, Hibi M (2024) Foxp and Skor family proteins control differentiation of Purkinje cells from Ptf1a- and Neurog1-expressing progenitors in zebrafish. Development 151(7):202546. https://doi.org/10.1242/dev.202546

Iwano S, Sugiyama M, Hama H, Watakabe A, Hasegawa N, Kuchimaru T, Tanaka KZ, Takahashi M, Ishida Y, Hata J, Shimozono S, Namiki K, Fukano T, Kiyama M, Okano H, Kizaka-Kondoh S, McHugh TJ, Yamamori T, Hioki H, Maki S, Miyawaki A (2018) Single-cell bioluminescence imaging of deep tissue in freely moving animals. Science 359(6378):935–939. https://doi.org/10.1126/science.aaq1067

Kazuki Y, Gao FJ, Li Y, Moyer AJ, Devenney B, Hiramatsu K, Miyagawa-Tomita S, Abe S, Kazuki K, Kajitani N, Uno N, Takehara S, Takiguchi M, Yamakawa M, Hasegawa A, Shimizu R, Matsukura S, Noda N, Ogonuki N, Inoue K, Matoba S, Ogura A, Florea LD, Savonenko A, Xiao M, Wu D, Batista DA, Yang J, Qiu Z, Singh N, Richtsmeier JT, Takeuchi T, Oshimura M, Reeves RH (2020) A non-mosaic transchromosomic mouse model of down syndrome carrying the long arm of human chromosome 21. Elife 9:e56223. https://doi.org/10.7554/elife.56223

Kondo S, Ueda R (2013) Highly improved gene targeting by germline-specific Cas9 expression in Drosophila . Genetics 195(3):715–721. https://doi.org/10.1534/genetics.113.156737

Kubota S, Sasaki C, Kikuta S, Yoshida J, Ito S, Gomi H, Oya T, Seki K (2024) Modulation of somatosensory signal transmission in the primate cuneate nucleus during voluntary hand movement. Cell Rep 43(3):113884. https://doi.org/10.1016/j.celrep.2024.113884

Kumano H, Uka T (2024) Employment of time-varying sensory evidence to test the mechanisms underlying flexible decision-making. NeuroReport 35(2):107–114. https://doi.org/10.1097/wnr.0000000000001980

Lahr CA, Landgraf M, Wagner F, Cipitria A, Moreno-Jiménez I, Bas O, Schmutz B, Meinert C, Mashimo T, Miyasaka Y, Holzapfel BM, Shafiee A, McGovern JA, Hutmacher DW (2021) A humanised rat model reveals ultrastructural differences between bone and mineralised tumour tissue. Bone 158:116018. https://doi.org/10.1016/j.bone.2021.116018

Mallart C, Netter S, Chalvet F, Claret S, Guichet A, Montagne J, Pret AM, Malartre M (2024) JAK-STAT-dependent contact between follicle cells and the oocyte controls Drosophila anterior–posterior polarity and germline development. Nat Commun 15(1):1627. https://doi.org/10.1038/s41467-024-45963-z

Martelli F, Lin J, Mele S, Imlach W, Kanca O, Barlow CK, Paril J, Schittenhelm RB, Christodoulou J, Bellen HJ, Piper MDW, Johnson TK (2024) Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics. Cell Rep 43(3):113861. https://doi.org/10.1016/j.celrep.2024.113861

Mashimo T, Takizawa A, Voigt B, Yoshimi K, Hiai H, Kuramoto T, Serikawa T (2010) Generation of knockout rats with X-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases. PLoS ONE 5(1):e8870. https://doi.org/10.1371/journal.pone.0008870

Miyasaka Y, Wang J, Hattori K, Yamauchi Y, Hoshi M, Yoshimi K, Ishida S, Mashimo T (2022) A high-quality severe combined immunodeficiency (SCID) rat bioresource. PLoS ONE 17(8):e0272950. https://doi.org/10.1371/journal.pone.0272950

Mizuno-Iijima S, Ayabe S, Kato K, Matoba S, Ikeda Y, Dinh TTH, Le HT, Suzuki H, Nakashima K, Hasegawa Y, Hamada Y, Tanimoto Y, Daitoku Y, Iki N, Ishida M, Ibrahim EAE, Nakashiba T, Hamada M, Murata K, Miwa Y, Okada-Iwabu M, Iwabu M, Yagami KI, Ogura A, Obata Y, Takahashi S, Mizuno S, Yoshiki A, Sugiyama F (2021) Efficient production of large deletion and gene fragment knock-in mice mediated by genome editing with Cas9-mouse Cdt1 in mouse zygotes. Methods 191:23–31. https://doi.org/10.1016/j.ymeth.2020.04.007

Mizuno-Iijima S, Nakashiba T, Ayabe S, Nakata H, Ike F, Hiraiwa N, Mochida K, Ogura A, Masuya H, Kawamoto S, Tamura M, Obata Y, Shiroishi T, Yoshiki A (2022) Mouse resources at the RIKEN bioresource research center and the national bioresource project core facility in Japan. Mamm Genome 33(1):181–191. https://doi.org/10.1007/s00335-021-09916-x

Mochida K, Hasegawa A, Otaka N, Hama D, Furuya T, Yamaguchi M, Ichikawa E, Ijuin M, Taguma K, Hashimoto M, Takashima R, Kadota M, Hiraiwa N, Mekada K, Yoshiki A, Ogura A (2014) Devising assisted reproductive technologies for wild-derived strains of mice: 37 strains from five subspecies of Mus musculus . PLoS ONE 9(12):e114305. https://doi.org/10.1371/journal.pone.0114305

Mochida K, Morita K, Sasaoka Y, Morita K, Endo H, Hasegawa A, Asano M, Ogura A (2024) Superovulation with an anti-inhibin monoclonal antibody improves the reproductive performance of rat strains by increasing the pregnancy rate and the litter size. Sci Rep 14(1):8294. https://doi.org/10.1038/s41598-024-58611-9

Morita K, Honda A, Asano M (2023) A Simple and efficient method for generating KO rats using in vitro fertilized oocytes. Methods Mol Biol 2637:233–246. https://doi.org/10.1007/978-1-0716-3016-7_18

Motono M, Yamada Y, Hattori Y, Nakagawa R, Nishijima K, Iijima S (2010) Production of transgenic chickens from purified primordial germ cells infected with a lentiviral vector. J Biosci Bioeng 109(4):315–321. https://doi.org/10.1016/j.jbiosc.2009.10.007

Nakashiba T, Ogoh K, Iwano S, Sugiyama T, Mizuno-Iijima S, Nakashima K, Mizuno S, Sugiyama F, Yoshiki A, Miyawaki A, Abe K (2023) Development of two mouse strains conditionally expressing bright luciferases with distinct emission spectra as new tools for in vivo imaging. Lab Anim (NY) 52(10):247–257

Noda T, Oji A, Ikawa M (2017) Genome editing in mouse zygotes and embryonic stem cells by introducing SgRNA/Cas9 expressing plasmids. Methods Mol Biol 1630:67–80. https://doi.org/10.1007/978-1-4939-7128-2_6

Noda T, Fujihara Y, Matsumura T, Oura S, Kobayashi S, Ikawa M (2019) Seminal vesicle secretory protein 7, PATE4, is not required for sperm function but for copulatory plug formation to ensure fecundity. Biol Reprod 100(4):1035–1045. https://doi.org/10.1093/biolre/ioy247

Ogoh K, Akiyoshi R, Suzuki H (2020) Cloning and mutagenetic modification of the firefly luciferase gene and its use for bioluminescence microscopy of engrailed expression during Drosophila metamorphosis. Biochem Biophys Rep 23:100771. https://doi.org/10.1016/j.bbrep.2020.100771

Oyama K, Nagai Y, Minamimoto T (2023) Targeted delivery of chemogenetic adeno-associated viral vectors to cortical sulcus regions in macaque monkeys by handheld injections. Bio Protoc 13(23):e4897. https://doi.org/10.21769/bioprotoc.4897

Saito A, Tahara R, Hirose M, Kadota M, Hasegawa A, Kondo S, Kato H, Amano T, Yoshiki A, Ogura A, Kiyosawa H (2024) Inter-subspecies mouse F1 hybrid embryonic stem cell lines newly established for studies of allelic imbalance in gene expression. Exp Anim. https://doi.org/10.1538/expanim.24-0002

Sasaguri H, Nagata K, Sekiguchi M, Fujioka R, Matsuba Y, Hashimoto S, Sato K, Kurup D, Yokota T, Saido TC (2018) Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID. Nat Commun 9(1):2892. https://doi.org/10.1038/s41467-018-05262-w

Sasaki R, Ohta Y, Onoe H, Yamaguchi R, Miyamoto T, Tokuda T, Tamaki Y, Isa K, Takahashi J, Kobayashi K, Ohta J, Isa T (2024) Balancing risk-return decisions by manipulating the mesofrontal circuits in primates. Science 383(6678):55–61. https://doi.org/10.1126/science.adj6645

Sato K, Watamura N, Fujioka R, Mihira N, Sekiguchi M, Nagata K, Ohshima T, Saito T, Saido TC, Sasaguri H (2021) A third-generation mouse model of Alzheimer’s disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide. J Biol Chem 297(3):101004. https://doi.org/10.1016/j.jbc.2021.101004

Satou C, Kimura Y, Higashijima S (2012) Generation of multiple classes of V0 neurons in zebrafish spinal cord: progenitor heterogeneity and temporal control of neuronal diversity. J Neurosci 32(5):1771–1783. https://doi.org/10.1523/jneurosci.5500-11.2012

Schmidt AR, Placer HJ, Muhammad IM, Shephard R, Patrick RL, Saurborn T, Horstick EJ, Bergeron SA (2024) Transcriptional control of visual neural circuit development by GS homeobox 1. PLoS Genet 20(4):e1011139. https://doi.org/10.1371/journal.pgen.1011139

Serizawa T, Isotani A, Matsumura T, Nakanishi K, Nonaka S, Shibata S, Ikawa M, Okano H (2019) Developmental analyses of mouse embryos and adults using a non-overlapping tracing system for all three germ layers. Development 146(21):174938. https://doi.org/10.1242/dev.174938

Sharifi S, Chaudhari P, Martirosyan A, Eberhardt AO, Witt F, Gollowitzer A, Lange L, Woitzat Y, Okoli EM, Li H, Rahnis N, Kirkpatrick J, Werz O, Ori A, Koeberle A, Bierhoff H, Ermolaeva M (2024) Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans . Nat Commun 15(1):1702. https://doi.org/10.1038/s41467-024-46037-w

Tada T, Ohnishi H, Yamamoto N, Kuwata F, Hayashi Y, Okuyama H, Morino T, Kasai Y, Kojima H, Omori K (2022) Transplantation of a human induced pluripotent stem cell-derived airway epithelial cell sheet into the middle ear of rats. Regen Ther 19:77–87. https://doi.org/10.1016/j.reth.2022.01.001

Takada T, Fukuta K, Usuda D, Kushida T, Kondo S, Kawamoto S, Yoshiki A, Obata Y, Fujiyama A, Toyoda A, Noguchi H, Shiroishi T, Masuya H (2022) MoG+: a database of genomic variations across three mouse subspecies for biomedical research. Mamm Genome 33(1):31–43. https://doi.org/10.1007/s00335-021-09933-w

Takeishi T, Fujiwara K, Osada N, Mita A, Takada T, Shiroishi T, Suzuki H (2022) Phylogeographic study using nuclear genome sequences of Asip to infer the origins of ventral fur color variation in the house mouse Mus musculus . Genes Genet Syst 96(6):271–284. https://doi.org/10.1266/ggs.21-00075

Taniguchi K, Igaki T (2023) Sas-Ptp10D shapes germ-line stem cell niche by facilitating JNK-mediated apoptosis. PLoS Genet 19(3):e1010684. https://doi.org/10.1371/journal.pgen.1010684

Tanimoto Y, Iijima S, Hasegawa Y, Suzuki Y, Daitoku Y, Mizuno S, Ishige T, Kudo T, Takahashi S, Kunita S, Sugiyama F, Yagami K (2008) Embryonic stem cells derived from C57BL/6J and C57BL/6N mice. Comp Med 58(4):347–352

CAS   PubMed   PubMed Central   Google Scholar  

Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W, Sugiura Y, Narushima S, Vlamakis H, Motoo I, Sugita K, Shiota A, Takeshita K, Yasuma-Mitobe K, Riethmacher D, Kaisho T, Norman JM, Mucida D, Suematsu M, Yaguchi T, Bucci V, Inoue T, Kawakami Y, Olle B, Roberts B, Hattori M, Xavier RJ, Atarashi K, Honda K (2019) A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565(7741):600–605. https://doi.org/10.1038/s41586-019-0878-z

Tsujino K, Okuzaki Y, Hibino N, Kawamura K, Saito S, Ozaki Y, Ishishita S, Kuroiwa A, Iijima S, Matsuda Y, Nishijima K, Suzuki T (2019) Identification of transgene integration site and anatomical properties of fluorescence intensity in a EGFP transgenic chicken line. Dev Growth Diffe 61(7–8):393–401

Wang S, Meyer DH, Schumacher B (2023) Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature 613(7943):365–374. https://doi.org/10.1038/s41586-022-05544-w

Yagi M, Kishigami S, Tanaka A, Semi K, Mizutani E, Wakayama S, Wakayama T, Yamamoto T, Yamada Y (2017) Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation. Nature 548(7666):224–227. https://doi.org/10.1038/nature23286

Yagi M, Kabata M, Tanaka A, Ukai T, Ohta S, Nakabayashi K, Shimizu M, Hata K, Meissner A, Yamamoto T, Yamada Y (2020) Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development. Nat Commun 11(1):3199. https://doi.org/10.1038/s41467-020-16989-w

Yasuda SP, Miyasaka Y, Hou X, Obara Y, Shitara H, Seki Y, Matsuoka K, Takahashi A, Wakai E, Hibino H, Takada T, Shiroishi T, Kominami R, Kikkawa Y (2020) Two loci contribute to age-related hearing loss resistance in the Japanese wild-derived inbred MSM/Ms mice. Biomedicines 10(9):2221. https://doi.org/10.3390/biomedicines10092221

Yoshihi K, Kato K, Iida H, Teramoto M, Kawamura A, Watanabe Y, Nunome M, Nakano M, Matsuda Y, Sato Y, Mizuno H, Iwasato T, Ishii Y, Kondoh H (2020) Live imaging of avian epiblast and anterior mesendoderm grafting reveals the complexity of cell dynamics during early brain development. Development 149(6):199999. https://doi.org/10.1242/dev.199999

Yoshimi K, Kunihiro Y, Kaneko T, Nagahora H, Voigt B, Mashimo T (2016) ssODN-mediated knock-in with CRISPR-cas for large genomic regions in zygotes. Nat Commun 20(7):10431. https://doi.org/10.1038/ncomms10431

Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, Kori H, Miyawaki A, Kageyama R (2020) Coupling delay controls synchronized oscillation in the segmentation clock. Nature 580(7801):119–123. https://doi.org/10.1038/s41586-019-1882-z

Zhao S, Wang C, Luo H, Li F, Wang Q, Xu J, Huang Z, Liu W, Zhang W (2024) A role for retinoblastoma 1 in hindbrain morphogenesis by regulating GBX family. J Genet Genomics. https://doi.org/10.1016/j.jgg.2024.03.008

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Acknowledgements

We sincerely thank Dr. Yuji Kohara, Program Director of NBRP; Dr. Yuichi Obata, Program Officer of NBRP; and Dr. Toshihiko Shiroishi, Director of RIKEN BRC for their thoughtful leadership and guidance. We are grateful to Drs. Ayumi Koso and Asuka Mukai, NBRP Public Relations Team for providing accurate information and advice. The NBRP is supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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Sawako Yoshina

Gene Engineering Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki, 305-0074, Japan

Yoshihiro Miwa

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S.M.-I. made a conceptualization and wrote the main manuscript text. S.K. prepared Fig. 4. M.A., T.M., S.W., K.N., K.-I.N., H.O., K.S., S.Y., Y.M., Y.N., and M.O. provided accurate information and data. A.Y. supervised the manuscripts. All authors reviewed and revised the manuscript.

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Mizuno-Iijima, S., Kawamoto, S., Asano, M. et al. Mammalian genome research resources available from the National BioResource Project in Japan. Mamm Genome (2024). https://doi.org/10.1007/s00335-024-10063-2

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The Human Genome Project

The Human Genome Project is an ambitious research effort aimed at deciphering the chemical makeup of the entire human genetic code (i.e., the genome). The primary work of the project is to develop three research tools that will allow scientists to identify genes involved in both rare and common diseases. Another project priority is to examine the ethical, legal, and social implications of new genetic technologies and to educate the public about these issues. Although it has been in existence for less than 6 years, the Human Genome Project already has produced results that are permeating basic biological research and clinical medicine. For example, researchers have successfully mapped the mouse genome, and work is well under way to develop a genetic map of the rat, a useful model for studying complex disorders such as hypertension, diabetes, and alcoholism.

The Human Genome Project is an international research project whose primary mission is to decipher the chemical sequence of the complete human genetic material (i.e., the entire genome), identify all 50,000 to 100,000 genes contained within the genome, and provide research tools to analyze all this genetic information. This ambitious project is based on the fact that the isolation and analysis of the genetic material contained in the DNA 1 ( figure 1 ) can provide scientists with powerful new approaches to understanding the development of diseases and to creating new strategies for their prevention and treatment. Nearly all human medical conditions, except physical injuries, are related to changes (i.e., mutations) in the structure and function of DNA. These disorders include the 4,000 or so heritable “Mendelian” diseases that result from mutations in a single gene; complex and common disorders that arise from heritable alterations in multiple genes; and disorders, such as many cancers, that result from DNA mutations acquired during a person’s lifetime. (For more information on the genetics of alcoholism, see the articles by Goate, pp. 217–220, and Grisel and Crabbe, pp. 220–227.)

Artist’s rendering of the DNA molecule from a single cell.

Although scientists have performed many of these tasks and experiments for decades, the Human Genome Project is unique and remarkable for the enormity of its effort. The human genome contains 3 billion DNA building blocks (i.e., nucleotides), enough to fill approximately one thousand 1,000-page telephone books if each nucleotide is represented by one letter. Given the size of the human genome, researchers must develop new methods for DNA analysis that can process large amounts of information quickly, cost-effectively, and accurately. These techniques will characterize DNA for family studies of disease, create genomic maps, determine the nucleotide sequence of genes and other large DNA fragments, identify genes, and enable extensive computer manipulations of genetic data.

Focus of the Human Genome Project

The primary work of the Human Genome Project has been to produce three main research tools that will allow investigators to identify genes involved in normal biology as well as in both rare and common diseases. These tools are known as positional cloning ( Collins 1992 ). These advanced techniques enable researchers to search for disease-linked genes directly in the genome without first having to identify the gene’s protein product or function. (See the article by Goate, pp. 217–220.) Since 1986, when researchers first found the gene for chronic granulomatous disease 2 through positional cloning, this technique has led to the isolation of considerably more than 40 disease-linked genes and will allow the identification of many more genes in the future ( table 1 ).

Disease Genes Identifed Using Positional Cloning

Each of the three tools being developed by the Human Genome Project helps bring the specific gene being sought into better focus (see sidebar , pp. 192–193). The first of these tools, the genetic map, consists of thousands of landmarks—short, distinctive pieces of DNA—more or less evenly spaced along the chromosomes. With this tool, researchers can narrow the location of a gene to a region of the chromosome. Once this region has been identified, investigators turn to a second tool, the physical map, to further pinpoint the specific gene. Physical maps are sets of overlapping DNA that may span an entire chromosome. These sets are cloned and frozen for future research. Once the physical map is complete, investigators will simply be able to go to the freezer and pick out the actual piece of DNA needed, rather than search through the chromosomes all over again. The final tool will be the creation of a complete sequence map of the DNA nucleotides, which will contain the exact sequence of all the DNA that makes up the human genome.

Genetic Maps Provide Blueprint for Human Genome

A primary focus of the Human Genome Project is to develop tools that will enable investigators to analyze large amounts of hereditary material quickly and efficiently. The success of this project hinges on the accurate mapping of each chromosome. The Human Genome Project is using primarily three levels of maps, each of which helps to increase understanding not only of the construction of individual genes but also of their relation to each other and to the entire chromosomal structure.

Genetic Mapping

Genetic mapping, also called linkage mapping, provides the first evidence that a disease or trait (i.e., a characteristic) is linked to the gene(s) inherited from one’s parents. Through genetic mapping, researchers can approximate the location of a gene to a specific region on a specific chromosome; the process is like establishing towns on a road map ( figure 1 ). For example, Interstate 10 runs from Florida to California. It would be difficult to find a landmark along that highway if the only cities mapped were Jacksonville and Los Angeles. It would be much easier, however, to pinpoint the landmark if one knew that it was located between markers that are closer together (e.g., El Paso and San Antonio).

Genetic mapping begins with the collection of blood or tissue samples from families in which a disease or trait is prevalent. After extracting the DNA from the samples, researchers track linearly the frequency of a recurring set of nucleotides (represented, for example, by the letters “CACACA”) along a region of a chromosome. If this sequence is shared among family members who have the disease, the scientists may have identified a marker for the disease-linked gene. Mapping additional DNA samples from other people with and without the disease allows researchers to determine the statistical probability that the marker is linked to the development of the disease.

Genetic Map. Just as locating a landmark on a particular highway is easier if one can narrow the area of the search to between two nearby points, or markers (e.g., El Paso and San Antonio on Interstate 10), researchers first try to narrow their search for particular genes to a segment of chromosome denoted by a specific sequence of nucleotides (e.g., CACACA).

Physical Mapping

Physical mapping generates sets of overlapping DNA fragments that span regions of—or even whole—chromosomes. These DNA fragments, which can be isolated and stored for future analysis ( figure 2 ), serve as a resource for investigators who want to isolate a gene after they have mapped it to a particular chromosome or chromosomal region. The physical map allows scientists to limit the gene search to a particular subregion of a chromosome and thus zero in on their target more rapidly.

One early goal of the physical mapping component of the Human Genome Project was to isolate contiguous DNA fragments that spanned at least 2 million nucleotides. Considerable progress has been made in this area, with sets of contiguous DNA fragments (“contigs”) now frequently ranging from 20 to 50 million nucleotides in length. Because the order of DNA fragments in a physical map should reflect their actual order on a chromosome, correct alignment of contigs also requires a set of markers to serve as mileposts, similar to those of an interstate highway. Genome scientists have developed a physical map that currently contains about 23,000 markers, called sequence tagged sites (STS’s). Scientists likely will meet their ultimate goal of establishing 30,000 STS markers on the physical map—one every 100,000 nucleotides—within the next year or two. This detailed STS map will allow researchers to pinpoint the exact location of any gene within 50,000 nucleotides of an STS marker.

Physical Map. Using various methods, A) whole chromosomes are B) snipped into large fragments of DNA (i.e., sequences of nucleotides) and then cloned. C) These cloned DNA pieces then are realigned in the order in which they originally occurred in the chromosomes and stored. The stored pieces can be used for further studies such as D) finding specific genes.

Part of the DNA sequence map of a virus containing 10,000 nucleotide bases. For comparison, the human genome contains approximately 3 billion nucleotide bases.

Researchers also are attempting to use fragments of expressed genes known as expressed sequence tags (EST’s), which are made from complimentary DNA, as markers on the physical genome map. By using EST’s, they hope to increase the power of maps for finding specific genes. A recent collaboration between Merck and Co. (a major pharmaceutical corporation) and researchers at Washington University in St. Louis, Missouri, will provide a resource for placing tens of thousands of such markers derived from actual genes on the physical map.

Marker development to be used in creating both the linkage and the physical maps also takes into account the need for connectivity between these two types of maps. Information learned from one stage of the gene-finding process must be easily translatable to the next.

The DNA Sequence Map

The Human Genome Project’s most challenging goal is to determine the order (i.e., sequence), unit by unit, of all 3 billion nucleotides that make up the human genome. Once the genetic and physical maps are completed, a sequence map can be constructed, which will allow scientists to find genes, characterize DNA regions that control gene activity, and link DNA structure to its function.

To date, the technology for this work has been developed and implemented primarily in model organisms. For example, researchers now have sequenced 25 million DNA nucleotides from the roundworm—about 25 percent of the animal’s genome—and, in the process, have increased their annual sequencing rate to 11 million nucleotide bases ( figure 3 ). The investigators expect to finish sequencing the roundworm genome by the end of 1998. The complete DNA sequence of yeast and E. coli genomes will be determined even sooner.

—Francis S. Collins and Leslie Fink

To make all this information available to researchers worldwide, the project has the additional goal of developing computer methods for easy storage, retrieval, and manipulation of data. Moreover, because researchers often can obtain valuable information about human genes and their functions by comparing them with the corresponding genes of other species, the project has set goals for mapping and sequencing the genomes of several important model organisms, such as the mouse, rat, fruit fly, roundworm, yeast, and the common intestinal bacterium E. coli .

Technological Advances in Genomic Research

The need for large-scale approaches to DNA sequencing has pushed technology toward both increasing capacity and decreasing instrument size. This demand has led, for example, to the development of automated machines that reduce the time and cost of the biochemical processes involved in sequencing, improve the analysis of these reactions, and facilitate entering the information obtained into databases. Robotic instruments also have been developed that expedite repetitive tasks inherent in large-scale research and reduce the chance for error in several sequencing and mapping steps.

Miniaturization technology is facilitating the sequencing of more—and longer—DNA fragments in less time and increasing the portability of sequencing processes, a capability that is particularly important in clinical or field work. In 1994, for example, the National Institutes of Health (NIH), through its National Center for Human Genome Research (NCHGR), began a new initiative for the development of microtechnologies to reduce the size of sequencing instrumentation and thereby increase the speed of the sequencing process. NCHGR also is exploring new strategies for minimizing time-consuming sequencing bottlenecks by developing integrated, matched components that will help ensure that each step in the sequencing process proceeds as efficiently as possible. The overall sequencing rate is only as fast as its slowest step.

Other developments in DNA sequencing have aimed to reduce the costs associated with the technology. Through refinements in current sequencing methods, the cost has been lowered to about $0.50 per nucleotide. Research on new DNA sequencing techniques is addressing the need for rapid, inexpensive, large-scale sequencing processes for comparison of complex genomes and clinical applications. Further improvements in the efficiency of current processes, along with the development of entirely new approaches, will enable researchers to determine the complete sequence of the human genome perhaps before the year 2005.

Applications of the Human Genome Project

The detailed genetic, physical, and sequence maps developed by the Human Genome Project also will be critical to understanding the biological basis of complex disorders resulting from the interplay of multiple genetic and environmental influences, such as diabetes; heart disease; cancer; and psychiatric illnesses, including alcoholism. In 1994, for example, researchers used genetic maps to discover at least five different chromosome regions that appear to play a role in insulin-dependent (i.e., type 1) diabetes ( Davies et al. 1994 ). Analyses to identify the genetic components of these complex diseases require high-resolution genetic maps and must be conducted on a scale much larger than was previously possible. Automated microsatellite marker technology 3 now makes it possible to determine the genetic makeup (i.e., the genotype) of enough subjects so that genes for common diseases can be mapped reliably in a reasonable amount of time. NCHGR is planning a technologically advanced genotyping facility to assist investigators in designing research studies; performing genetic analyses; and developing new techniques for analyzing common, multigene diseases.

Molecular Medicine

Efforts to understand and treat disease processes at the DNA level are becoming the basis for a new molecular medicine. The discovery of disease-associated genes provides scientists with the foundation for understanding the course of disease, treating disorders with synthetic DNA or gene products, and assessing the risk for future disease. Thus, by going directly to the genetic source of human illness, molecular medicine strategies will offer a more customized health management based on the unique genetic constitution of each person. Molecular medicine also will increase clinicians’ focus on prevention by enabling them to predict a person’s risk for future disease and offer prevention or early treatment strategies. This approach will apply not only to classical, single-gene hereditary disorders but also to more common, multi-gene disorders, such as alcoholism.

During the past 3 years, positional cloning has led to the isolation of more than 30 disease-associated genes. Although this number has increased dramatically, compared with the years predating the Human Genome Project, it is still a small fraction of the 50,000 to 100,000 genes that await discovery in the entire genome. NCHGR has helped develop efficient biological and computer techniques to identify all the genes in large regions of the genome. One technique was used successfully last year to isolate BRCA1 , the first major gene linked to inherited breast cancer. The location of BRCA1 first was narrowed to a DNA fragment of several hundred thousand nucleotides containing many genes. A process that isolates the protein-coding sequences of a gene (i.e., exon trapping) allowed researchers to identify and examine not only the correct BRCA1 gene in that region but also several new genes that now serve as disease-gene candidates for future investigations.

Diagnostics

Clinical tests that detect disease-causing mutations in DNA are the most immediate commercial application of gene discovery. These tests may positively identify the genetic origin of an active disease, foreshadow the development of a disease later in life, or identify healthy carriers of recessive diseases such as cystic fibrosis. 4 Genetic tests can be performed at any stage of the human life cycle with increasingly less invasive sampling procedures. Although DNA testing offers a powerful new tool for identifying and managing disease, it also poses several medical and technical challenges. The number and type of mutations for a particular disease may be few, as in the case of achondroplasia, 5 or many, as in the case of cystic fibrosis and hereditary breast cancer. Thus, it is essential to establish for each potential DNA test how often it detects disease-linked mutations and how often and to what degree detection of mutations correlates with the development of disease.

Therapeutics

Gene discovery also provides opportunities for developing gene-based treatment for hereditary and acquired diseases. These treatment approaches range from the mass production of natural substances (e.g., blood-clotting factors, growth factors and hormones, and interleukins and interferons 6 ) that are effective in treating certain diseases to gene-therapy strategies. Gene therapy is designed to deliver DNA carrying a functional gene to a patient’s cells or tissues and thereby correct a genetic alteration.

Currently, more than 100 companies conduct human clinical trials on DNA-based therapies ( Pharmaceutical Research and Manufacturers of America [PRMA] 1995 ). The top U.S. public biotechnology companies have an estimated 2,000 drugs in early development stages ( Ernst and Young 1993 ). Since 1988, NIH’s Recombinant DNA Advisory Committee has approved more than 100 human gene-therapy or gene-transfer protocols (Office of Recombinant DNA Activities, NIH, personal communication, April 1995). Seventeen gene-therapy products are now in commercial development for hereditary disorders, cancer, and AIDS ( PRMA 1995 ).

Ethical, Legal, and Social Concerns of the Human Genome Project

Implications for disease detection.

The translation of human genome technologies into patient care brings with it special concerns about how these tools will be applied. A principal arena in which psychosocial issues related to these technologies are being raised is the testing of people who may be at risk for a genetically transmitted disease but who do not yet show the disease’s symptoms (i.e., are asymptomatic). These concerns stem largely from the delay between scientists’ technical ability to develop DNA-based diagnostic tests that can identify a person’s risk for future disease and their ability to develop effective prevention or treatment strategies for the disorders those tests portend. In the meantime, people who undergo genetic tests run the risk of discrimination in health insurance and may have difficulty adapting to test results—particularly in families in which hereditary disease is common—regardless of whether a test indicates future disease. When no treatment is available and when no other medical course of action can be taken on the basis of such tests, the negative social, economic, and psychological consequences of knowing one’s medical fate must be carefully evaluated in light of the meager medical benefits of such knowledge.

To help ensure that medical benefits are maximized without jeopardizing psychosocial and economic well-being, the Human Genome Project, from its beginning, has allocated a portion of its research dollars to study the ethical, legal, and social implications (ELSI) of the new genetic technologies. A diverse funding program supports research in four priority areas: the ethical issues surrounding the conduct of genetic research, the responsible integration of new genetic technologies into the clinic, the privacy and fair use of genetic information, and the professional and public education about these issues.

Because of the many unresolved questions surrounding DNA testing in asymptomatic patients, in 1994 NCHGR’s advisory body released a statement urging health care professionals to offer DNA testing for the predisposition to breast, ovarian, and colon cancers only within approved pilot research programs until more is known about the science, psychology, and sociology of genetic testing for some diseases ( National Advisory Council for Human Genome Research 1994 ). The American Society of Human Genetics and the National Breast Cancer Coalition have issued similar statements. More recently, the NIH–DOE [Department of Energy] Working Group on ELSI launched a task force to perform a comprehensive, 2-year evaluation of the current state of genetic testing technologies in the United States. The task force will examine safety, accuracy, predictability, quality assurance, and counseling strategies for the responsible use of genetic tests.

In a related project, NCHGR’s ELSI branch spearheaded a new group of pilot studies shortly after researchers isolated BRCA1 and several genes for colon cancer predisposition. These 3-year studies are examining the psychosocial and patient-education issues related to testing healthy members of families with high incidences of cancer for the presence of mutations that greatly increase the risk of developing cancer. The results will provide a thorough base of knowledge on which to build plans for introducing genetic tests for cancer predisposition into medical practice.

Implications for Complex Traits

Research in human genetics focuses not only on the causes of disease and disability but also on genes and genetic markers that appear to be associated with other human characteristics, such as height, weight, metabolism, learning ability, sexual orientation, and various behaviors ( Hamer et al. 1993 ; Brunner et al. 1993 ). Associating genes with human traits that vary widely in the population raises unique and potentially controversial social issues. Genetic studies elucidate only one component of these complex traits. The findings of these studies, however, may be interpreted to mean that such characteristics can be reduced to the expression of particular genes, thus excluding the contributions of psychosocial or environmental factors. Genetic studies can also be interpreted in a way that narrows the range of variation considered “normal” or “healthy.”

Both reducing complex human characteristics to the role of genes and restricting the definition of what is normal can have harmful—even devastating—consequences, such as the devaluation of human diversity and social discrimination based on a person’s genetic makeup. The Human Genome Project must therefore foster a better understanding of human genetic variation among the general public and health care professionals as well as offer research policy options to prevent genetic stigmatization, discrimination, and other misuses and misinterpretations of genetic information.

Progress on Genetic and Physical Maps

In the United States, NCHGR and DOE, through its Office of Environmental Health Research, are the primary public supporters of major genome research programs. In 1990, when the 15-year Human Genome Project began, NCHGR and DOE established ambitious goals to guide the research through its first years ( U.S. Department of Health and Human Services and U.S. Department of Energy 1990 ). After nearly 6 years, scientists involved in the Human Genome Project have met or exceeded most of those goals—some ahead of time and all under budget. Because scientific advances may rapidly make the latest technologies obsolete, a second 5-year plan was published in 1993 ( Collins and Galas 1993 ) to keep ahead of the project’s progress. Already, further technological advances make it likely that a new plan will be needed, perhaps as early as this year.

In 1994, an international consortium headed by the Genome Science and Technology Center in Iowa published a genetic map of the human genome containing almost 6,000 markers spaced less than 1 million nucleotides apart ( Cooperative Human Linkage Center et al. 1994 ). This map was completed more than 1 year ahead of schedule, and its density of markers is four to six times greater than that called for by the 1990 goals. This early achievement is largely a result of the discovery and development of micro-satellite DNA markers and of large-scale methods for marker isolation and analysis.

In a related project, technology developed so quickly that a high resolution genetic map of the mouse genome was completed in just 2 years. NCHGR is now helping to coordinate an initiative with other NIH institutes, particularly the National Heart, Lung, and Blood Institute and the National Institute on Alcohol Abuse and Alcoholism, to develop a high-resolution genetic map of the rat, a useful model for studying complex disorders such as hypertension, diabetes, and alcoholism.

The original 5-year goal to isolate contiguous DNA fragments that span at least 2 million nucleotides was met early on; soon, more than 90 percent of the human genome will be accounted for using sets of overlapping DNA fragments, each of which is at least 10 million nucleotides long. Complete physical maps now exist for human chromosomes 21, 22, and Y. Nearly complete maps have been developed for chromosomes 3, 4, 7, 11, 12, 16, 19, and X. 7

As the end of the first phase of the Human Genome Project draws near, its impact already is rippling through basic biological research and clinical medicine. From deciphering information in genes, researchers have gained new knowledge about the nature of mutations and how they cause disease. Even after someday identifying all human genes, scientists will face the daunting task of elucidating the genes’ functions. Furthermore, new paradigms will emerge as researchers and clinicians understand interactions between genes, the molecular basis of multigene disorders, and even tissue and organ function.

The translation of this increasing knowledge into improved health care already is under way; however, the value of gene discovery to the promising new field of molecular medicine will be fully realized only when the public is secure in the use of genetic technologies.

1 For a definition of this and other technical terms used in this article, see central glossary, pp. 182–183.

2 Chronic granulomatous disease is an inherited disease of the immune system.

3 Microsatellite markers are short DNA sequences that vary in length from person to person. The length of a particular marker is inherited from one’s parents, allowing researchers to track the markers through several generations of the same family.

4 For a recessive disease to develop, a person must inherit two altered gene copies, one from each parent. People who inherit only one altered gene copy usually are healthy (i.e., they do not show symptoms of the disease); these people are called asymptomatic carriers.

5 Achondroplasia is a disorder that results in defective skeletal development in the fetus and dwarfism. Affected children often die before or within their first year of life.

6 Interleukins and interferons are substances that stimulate and regulate the immune system.

7 Of the 23 chromosome pairs in human cells, 22 pairs are numbered according to their size, with chromosome 1 being the largest and chromosome 22 being the smallest chromosome. The gender-determining chromosomes are referred to as X and Y.

• Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science. 1993; 261 :321–327. [ PubMed ] [ Google Scholar ]
• Collins FS. Let’s not call it reverse genetics. Nature Genetics. 1992; 1 :3–6. [ PubMed ] [ Google Scholar ]
• Collins FS, Galas D. A new five-year plan for the U.S. human genome project. Science. 1993; 262 :43–46. [ PubMed ] [ Google Scholar ]
• Cooperative Human Linkage Center (CHLC) Murray JC, Buetow KH, Weber JL, Ludwigsen S, Scherpbier-Heddema T, Manion F, Quillen J, Sheffield VC, Sunden S, Duyk GM, et al. A comprehensive human linkage map with centimorgan density. Science. 1994; 265 :2049–2054. [ PubMed ] [ Google Scholar ]
• Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994; 371 :130–136. [ PubMed ] [ Google Scholar ]
• Ernst, Young . The Industry Annual Report. 1993. Biotech 94: Long-term Value, Short-term Hurdles; p. 31. [ Google Scholar ]
• Hamer DH, Hu S, Magnuson VL, Hu N, Pattatucci AML. A linkage between DNA markers on the X chromosome and male sexual orientation. Science. 1993; 262 :578–580. [ PubMed ] [ Google Scholar ]
• National Advisory Council for Human Genome Research. Statement on use of DNA testing for presymptomatic identification of cancer risk. Journal of the American Medical Association. 1994; 271 (10):785. [ PubMed ] [ Google Scholar ]
• Pharmaceutical Research and Manufacturers of America. Biotechnology Medicines in Development. Mar, 1995. [ Google Scholar ]
• U.S. Department of Health and Human Services and U.S. Department of Energy. The U.S. Human Genome Project: The First Five Years. Bethesda, MD: National Institutes of Health; 1990. Understanding Our Genetic Inheritance. NIH Publication No. 90–1590. [ Google Scholar ]

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Making Hope Possible: American Parkinson Disease Association Supports Researchers With $2.6 Million in New Funding

Exciting New Parkinson’s Disease Research is Underway

On September 5, 2024, APDA announced 20 new Parkinson’s disease (PD) research grants, for a total of $ 2.6 million in funding for the year ahead. Our grant recipients are working tirelessly to understand the complexities of Parkinson’s disease (PD) and to develop new treatments and eventually, a cure. We are honored to support these researchers and their innovative and inspiring work.

We know you are as eager as we are for PD research progress, which is why we are sharing this important news with you. Below, we present the individual research projects APDA will be funding and specify why they are important for the PD community. You can click on any of the researchers below to learn more about them and their exciting work.

These new grants have been awarded in the form of five Post-Doctoral Fellowships, eight Research Grants, three Diversity in Parkinson’s Disease Research grants, and one George C. Cotzias Memorial Fellowship. In addition, APDA is funding nine APDA Centers for Advanced Research.

The 2024-2025 APDA Parkinson’s Disease Research Grants and Fellowships:

The george c. cotzias fellowship.

The George C. Cotzias Fellowship is APDA’s most prestigious award and is granted to a young physician-scientist with exceptional promise who is establishing a career in research, teaching, and clinical services relevant to PD. The award spans three years and is designed to fund a long-range project focused on PD.

This year’s awardee is:

William Zeiger, MD, PhD The Regents of the University of California, Los Angeles  Project Title:    Neuronal microcircuit mechanisms of posterior cortical dysfunction and cognitive impairment in a mouse model of Parkinson’s disease  Major question to be answered: How does alpha-synuclein (a-syn) pathology contribute to thinking and memory problems and, specifically, problems with processing of visual information in Parkinson’s disease? Why is this important? Aggregation of the protein a-syn is a pathological hallmark of PD. This research will analyze the role of a-syn in the parts of the brain responsible for processing visual information, helping us understand the role that a-syn plays in the development and progression of thinking and memory problems in people with PD. The work will help with the design of treatment strategies to try to restore the function of these brain cells affected by a-syn.   In addition to Dr. Zeiger, we continue to support two additional George C. Cotzias grantees, Krithi Irmady, MD, PhD and Gary Ho, MD, PhD , who are in the second and third year of their three-year grants, respectively.

Diversity in Parkinson’s Disease Research Grants

This grant supports the study of the health inequities and/or differences among under-studied PD communities, across the spectrum of ethnicity, ancestry, geography, socioeconomic conditions, and gender.

This year’s awardees are:

Ignacio Mata, PhD Cleveland Clinic Foundation, Cleveland, OH   Project Title:                                                  Machine-learning model for predicting levodopa-induced dyskinesias in a large cohort of Latinos with Parkinson ’ s disease   Major question to be answered: Can a computer-based tool predict who might develop levodopa-induced dyskinesia (LID) among Latino individuals with PD?     Why is this important? Genetic data from more than 2,000 Latinos with PD from the Latin American Research consortium in the Genetics of Parkinson’s Disease (LARGE-PD) will be analyzed using algorithms to try to predict who might develop LIDs. These findings have the potential to offer personalized care for people with PD at high risk of developing LID, while focusing on the Latino PD community, a historically underrepresented population group.

Melissa Nirenberg, MD, PhD Bronx Veterans Medical Research Foundation, New York, NY Project Title:   Parkinson’s disease phenotype in Black and Hispanic veterans  Major question to be answered: What are the clinical characteristics of Black and Hispanic veterans with PD?  Why is this important? This project seeks to determine the clinical features of PD specifically in Black and Hispanic veterans, a population which is under-represented and under-engaged in research. This information will therefore be useful in diagnosing PD, optimizing treatments, and identifying targeted therapies for people in these underrepresented groups.

Danielle Shpiner, MD  Miller School of Medicine of the University of Miami, Miami, FL   Project Title:                                                   Improving access to advance care planning for Hispanic people with Parkinson ’ s disease Major question to be answered: What are the reasons for barriers to advance care planning (ACP) engagement in the Hispanic, Miami-based Parkinson’s population? Why is this important? Focus groups and semi-structured interviews with Hispanic people with PD and their care partners will help to explore the reasons that people in this population have not been able to access ACP discussions. This will allow the implementation of appropriate interventions to overcome these barriers.  

Post-Doctoral Fellowships

This two-year fellowship is awarded to support post-doctoral scientists who recently completed their graduate degree work, and whose research holds promise to provide new insights into the pathophysiology, etiology, and treatment of PD.

Andrew Monaghan, PhD  Emory University, Atlanta, GA Project Title: Electrophysiological characterization of neural circuit pathophysiology underlying freezing of gait  Major question to be answered: What are the electrophysiological biomarkers of freezing of gait (FoG) that can be identified using mobile electroencephalography (EEG)? Why is this important? This study will use mobile EEG to characterize irregular brain activity patterns that occur before and during episodes of FoG. Knowing the electrophysiological signals in the brain before these events can help with anticipating, monitoring, and prevention of FoG.  They could also provide neurophysiological input for adaptive interventions, such as deep brain stimulators or wearable cueing devices, to intervene during FoG episodes.

Yuxiao Ning, PhD The Regents of the University of Minnesota, Twin Cities, Minneapolis-Saint Paul, MN Project Title: Multiregional neural population dynamics in PD and during directional deep brain stimulation (DBS)  Major question to be answered: How does PD disrupt the basal ganglia thalamocortical (BGTC) circuitry and how does DBS correct these disruptions?  Why is this important? PD impairs the brain’s BGTC network, which controls movement and cognition, whereas DBS in certain brain regions can improve PD symptoms. In this study, neuronal activity across multiple regions of the brain’s network will be recorded with and without DBS. The activity will be analyzed using advanced machine learning techniques to understand the role that DBS plays in correcting the disrupted circuitry.      

Brianne Rogers, PhD HudsonAlpha Institute for Biotechnology, Huntsville, AL Project Title:   Mechanisms of SNCA regulation  Major question to be answered: What are the genetic regulatory elements controlling expression of the a-syn gene SNCA? Why is this important? This project will explore the genetic elements that drive the expression of a-syn. A comprehensive understanding of SNCA regulatory elements and the genetic variation that affects SNCA expression, can help expand potential therapeutic avenues for PD treatment. 

Carlos Soto-Faguás, PhD Oregon Health & Science University, Portland, OR Project Title:                                                                         The effects of the ApoE Christchurch variant on Lewy body pathology development and spreading          Major question to be answered: What are the effects of the ApoE Christchurch mutation in the development and propagation of a-syn pathology using transgenic mouse models? Why is this important? Recently, a genetic mutation in the ApoE gene, called ApoE Christchurch, has been identified which appears to be protective against Alzheimer’s disease pathology and clinical dementia. This project will study whether the ApoE Christchurch mutation is also protective against the development and propagation of Lewy bodies, the pathological hallmark of PD.

Donghe Yang, PhD Memorial Sloan Kettering Cancer Center , New York, NY Project Title:                             Characterizing and modeling the development of human A9 midbrain dopaminergic neurons with pluripotent stem cells Major question to be answered: What are the key processes that lead to the development of the specific type of dopamine neurons that is susceptible to neurodegeneration in PD?  Why is this important? This project will identify factors that influence the development of the specific subtype of dopamine neurons that degenerate in PD and assess the functional properties of these neurons. The project will also evaluate the therapeutic efficacy of these neurons as a cell-based therapy in animal models of PD, advancing the understanding of using such therapies to treat PD.

We also continue to support Abdulmunaim Eid, MD who is in the second year of his two-year post-doctoral fellowship.

Research Grants

The APDA Research Grant is awarded to investigators performing innovative research into the pathophysiology, etiology, and/or treatment of PD.

Patricia Aguilar Calvo, PhD   University of Alabama at Birmingham, Birmingham, AL Project Title:    Heparan-sulfate mediated mechanisms of a-syn propagation in PD Major question to be answered: How do heparan sulfate proteoglycans modulate the propagation and clearance of a-syn aggregates in the nervous system? Why is this important? Heparan sulfate proteoglycans are found on the cell surface of many types of cells and are involved in a variety of biological activities. This project will investigate their role in cell-to-cell propagation, aggregation, and clearance of a-syn.

Athanasios Alexandris, MD                Johns Hopkins University School of Medicine, Baltimore, MD Project Title:    Investigating the role of a-synucleinopathy in axonal protein homeostasis and viability  Major question to be answered: How does a-syn aggregation affect axons, the nerve cell extensions that transmit brain signals? Why is this important? Axonal degeneration is an early event in neurodegenerative disease, impairing brain connectivity before nerve cells die. This project will focus on how a-syn disrupts axonal localization and translation of mRNA, the template for producing proteins in axons which are crucial for their maintenance, plasticity, and repair. An understanding of the connection between abnormal a-syn and axonal survival and function will offer new ideas about why axons are vulnerable in neurodegeneration.

Saar Anis, MD                          Cleveland Clinic Foundation, Cleveland, OH  Project Title:    Deep brain stimulation (DBS) neural recordings of varied stimulation during sleep in Parkinson’s disease (The DREAMS-PD Study)  Major question to be answered: What is the impact of DBS settings on sleep efficiency? Why is this important? This project will monitor 10 participants for six weeks in their home environment, with each participant alternating between three different DBS settings every two weeks. They will wear a device to track their sleep, with the goal of determining which setting best enhances sleep quality, a vital aspect of overall well-being for people with PD.

( Want to learn more about deep brain stimulation (DBS)? We covered Adaptive DBS – a new approach to improve PD symptoms in this article. )

Helen Hwang, MD, PhD                       Washington University School of Medicine, St. Louis, MO Project Title:    Characterization of inhibitors of a-syn fibril growth  Major question to be answered: Can a cell-based platform test potential drug candidates for the ability to inhibit a-syn fibril growth? Why is this important? A cellular platform will be developed to test potential drug compounds that can have disease-modifying effects in people with PD. This platform can then be used to screen for small molecules capable of inhibiting a-syn fibril growth. This tool will hopefully bring the field closer to identifying potential neuroprotective agents for PD. 

Francesca Magrinelli, MD, PhD                                  University College London Institute of Neurology, London, UK  Project Title:    Dissecting PSMF1 as a new gene for early-onset Parkinson’s disease/parkinsonism  Major question to be answered: How do genetic defects in PSMF1 cause neuronal death? Why is this important? PSMF1 has recently been identified as a new gene associated with early-onset PD and parkinsonism in multiple families, but its function is unknown. This project will unveil the biological mechanisms underpinning this newly identified genetic form of PD which likely also contributes to sporadic forms of PD.

Franchino Porciuncula, PT, DScPT, EdD      Trustees of Boston University, Boston, MA Project Title:    Does rhythmic auditory stimulus (RAS) reduce the cognitive demands of walking in PD?  Major question to be answered: What are the effects of RAS on cognitive demands as indexed by brain activation during walking ? Why is this important? This study will enroll 30 people with PD and investigate walking automaticity and its response to rhythmic cueing via RAS. Functional Near-Infrared Spectroscopy (fNIRS), a non-invasive, mobile device will monitor where brain activity occurs during walking and wearable sensors will measure leg movements during walking. Together, these measurements will give a thorough examination of walking automaticity and its response to rhythmic cueing via RAS and determine whether RAS reduces cognitive demand. This study will elucidate processes related to walking automaticity in PD, thereby allowing gait rehabilitation in PD to be more effective. 

Emily Rocha,  PhD                   University of Pittsburgh, Pittsburgh, PA Project Title:    Lysosomal dysfunction in PD  Major question to be answered: Could TRPML1 be a disease modifying therapy to slow neurodegeneration in PD? Why is this important? Accumulation of aggregated proteins is a pathological hallmark of PD and could be due to dysfunctional lysosomes, the garbage collectors of the cell. TRPML1 transports positively charged molecules such as calcium from inside the lysosome to the rest of the cell, a process which regulates lysosomal function and may promote lysosomal health.  This project seeks to determine if targeting TRPML1 could be a disease modifying strategy to improve lysosomal health and halt the progression of PD. 

Mariangela Scarduzio, PhD              University of Alabama at Birmingham, Birmingham, AL  Project Title:    Striatal acetylcholine dynamics in L-DOPA-induced dyskinesia  Major question to be answered: How do fluctuating levels of the neurotransmitter dopamine (DA) affect the levels of acetylcholine (ACh), another neurotransmitter involved in movement regulation, to contribute to levodopa induced dyskinesia (LID)?   Why is this important? Previous research has suggested that the loss of DA in PD is accompanied by an opposite increase in Ach signaling. Treatment with L-DOPA, while replacing DA and ameliorating motor symptoms, does not fix ACh transmission, which rather becomes more dysfunctional, possibly contributing to the development of the involuntary movements of LID. This project will focus on how striatal ACh spontaneous oscillations evolve as DA levels decrease, and LID develops in a mouse model of PD. Understanding the interplay between DA and Ach will contribute to new ways of controlling LID.

Tips & Takeaways

• Every grant APDA funds has been reviewed and evaluated by our  Scientific Advisory Board . The grants listed above were selected with extreme care and determined to be the most meritorious.
• The cutting-edge research described above is only possible  due to the support and generosity of our donors . If you’d like to support APDA’s work including research like you’ve just read about, please consider a donation today.
• We encourage you to learn more about  the research APDA has funded over the years .

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