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2011 NHGRI Strategic Plan PERSPECTIVE doi:10.1038/nature09764 Charting a course for genomic medicine from base pairs to bedside Eric D. Green1, Mark S. Guyer1 & National Human Genome Research Institute* There has been much progress in genomics in the ten years since a draft sequence of the human genome was published. Opportunities for understanding health and disease are now unprecedented, as advances in genomics are harnessed to obtain robust foundational knowledge about the structure and function of the human genome and about the genetic contributions to human health and disease. Here we articulate a 2011 vision for the future of genomics research and describe the path towards an era of genomic medicine. ince the end of the Human Genome Project (HGP) in 2003 and the quickly. Although genomics has already begun to improve diagnostics publication of a reference human genome sequence1,2, genomics has and treatments in a few circumstances, profound improvements in the S become a mainstay of biomedical research. The scientific commu­ effectiveness of healthcare cannot realistically be expected for many years nity’s foresight in launching this ambitious project3 is evident in the broad (Fig. 2). Achieving such progress will depend not only on research, but range of scientific advances that the HGP has enabled, as shown in Fig. 1 also on new policies, practices and other developments. We have illu­ (see rollfold). Optimism about the potential contributions of genomics for strated the kinds of achievements that can be anticipated with a few improving human health has been fuelled by new insights about cancer4–7, examples (Box 2) where a confluence of need and opportunities should the molecular basis of inherited diseases (http://www.ncbi.nlm.nih.gov/ lead to major accomplishments in genomic medicine in the coming omim and http://www.genome.gov/GWAStudies) and the role of structural decade. Similarly, we note three cross-cutting areas that are broadly variation in disease8, some of which have already led to new therapies9–13. relevant and fundamental across the entire spectrum of genomics and Other advances have already changed medical practice (for example, micro- genomic medicine: bioinformatics and computational biology (Box 3), arrays are now used for clinical detection of genomic imbalances14 and education and training (Box 4), and genomics and society (Box 5). pharmacogenomic testing is routinely performed before administration of certain medications15). Together, these achievements (see accompanying Understanding the biology of genomes paper16)documentthatgenomicsis contributing to a better understanding Substantial progress in understanding the structure of genomes has of human biology and to improving human health. revealed much about the complexity of genome biology. Continued As it did eight years ago17, the National Human Genome Research acquisition of basic knowledge about genome structure and function will Institute (NHGRI) has engaged the scientific community (http://www. be needed to illuminate further those complexities (Fig. 2). The contri­ genome.gov/Planning) to reflect on the key attributes of genomics (Box 1) bution of genomics will include more comprehensive sets (catalogues) of and explore future directions and challenges for the field. These discus­ data and new research tools, which will enhance the capabilities of all sions have led to an updated vision that focuses on understanding human researchers to reveal fundamental principles of biology. biology and the diagnosis, prevention and treatment of human disease, including consideration of the implications of those advances for society Comprehensive catalogues of genomic data (but these discussions, intentionally, did not address the role of genomics Comprehensive genomic catalogues have been uniquely valuable and in agriculture, energy and other areas). Like the HGP, achieving this vision widely used. There is a compelling need to improve existing catalogues is broader than what any single organization or country can achieve— and togeneratenew ones, suchas complete collections of genetic variation, realizing the full benefits of genomics will be a global effort. functional genomic elements, RNAs, proteins, and other biological This 2011 vision for genomics is organized around five domains extend­ molecules, for both human and model organisms. ing from basic research to health applications (Fig. 2). It reflects the view Genomic studies of the genes and pathways associated with disease- that, over time, the most effective way to improve human health is to related traits require comprehensive catalogues of genetic variation, which understand normal biology (in this case, genome biology) as a basis for provide both genetic markers for association studies and variants for iden­ understanding disease biology, which then becomes the basis for improving tifying candidate genes. Developing a detailed catalogue of variation in the health. At the same time, there are other connections among these domains. human genome has been an international effort that began with The SNP 20 21 Genomics offers opportunities for improving health without a thorough Consortium and the International HapMap Project (http://hapmap. 22 understanding of disease (for example, cancer therapies can be selected ncbi.nlm.nih.gov), and is ongoing with the 1000 Genomes Project based on genomic profiles that identify tumour subtypes18,19), and clinical (http://www.1000genomes.org). discoveries can lead back to understanding disease or even basic biology. Over the past decade, these catalogues have been critical in the discovery The past decade has seen genomics contribute fundamental knowledge of the specific genes for roughly 3,000 Mendelian (monogenic) diseases about biology and its perturbation in disease. Further deepening this understanding will accelerate the transition to genomic medicine (clinical Figure 1 | Genomic achievements since the Human Genome Project c care based on genomic information). But significant change rarely comes (see accompanying rollfold). 1National Human Genome Research Institute, National Institutes of Health, 31 Center Dr., Bethesda, Maryland 20892-2152, USA. *Lists of participants and their affiliations appear at the end of the paper. 204 | NATURE | VOL 470 | 10 FEBRUARY 2011 ©2011 Macmillan Publishers Limited. All rights reserved Genomic achievements since the Human Genome Project Southern African genome sequences First personal genome Rhesus macaque NCBI's Database of Genotypes and sequenced using new technologies genome sequence Completion of the Mammalian Phenotypes (dbGaP) launched Gene Collection (MGC) 500th genome-wide 9 10 11 12 Phase I HapMap 3 6 7 8 association study 4 5 1 Watson & Crick 2 published describe the DNA double helix 19 21 Y 20 22 16 18 Chicken genome 15 17 1953 13 14 sequence X Human genetic variation is Mendel discovers Yoruba genome 1966 breakthrough of the year UK Biobank reaches laws of genetics CFH sequence Age-related macular 500,000 participants 1865 degeneration Nirenberg, 1 Khorana & Honeybee Holley determine First genome-wide genome sequence the genetic code association study International data release workshop >1,000 mouse published knockout mutations 1977 Wellcome Trust Case Control G A T C Rat genome Consortium publication 1982 sequence Platypus genome sequence Sanger and modENCODE publications Maxam & Gilbert 1990 develop DNA GenBank sequencing methods database established Human Genome Project Chimpanzee genome Sea urchin launched sequence genome sequence Bovine genome sequence Neanderthal genome sequence 1996 ENCODE pilot project complete First cancer genome sequence (AML) Publication of finished Yeast humanhuman genomegenome sequence (Saccharomyces cerevisiae) genome sequence 2004 CH3 1998 CH3 Roundworm 1000 Genomes pilot project DogDog genomegenom sequence CH3 (Caenorhabditis elegans) First personal genome sequenced complete genome sequence 1997 2005 Comprehensive genomic First human methylome map Escherichia coli genome sequence First direct-to-consumer analysis of glioblastoma wwhole-genomeh test Moore’s law 1 23 4 567 8 9 2000 Miller syndrome gene discovered by Fruitfly 2006 Coding exome sequencing (Drosophila melanogaster) UTR genome sequence c.56G>A Han Chinese c.403C>Tc.454G>A c.595C>Tc.605A/Cc.611delTc.730C>Tc.851C>T c.1036C>Tc.1175A>G 2003 ggenomee sequence Cost per human genome sequence 2010 2007 2008 Genetic Information 2001 2006 2004 Nuffield Council on Bioethics 2002 NondiscriminationNondiscrim Act (GINA) 2002 ppasseda in US publication on For details, see http://genome.gov/sequencingcosts 2008 Korean genome sequence personalized healthcare Draft human End of the Human genome sequence Mouse genome Genome Project sequence 2009 2010 Design by Darryl Leja (NHGRI, NIH). Watson and Crick photograph: A. Barrington Brown/Photo Researchers; images of Science covers courtesy of AAAS. © 2011 Macmillan Publishers Limited. All rights reserved PERSPECTIVE RESEARCH gene products such as RNAs (transcriptomics) and proteins (proteo­ BOX 1 mics), and indirect products of the genome such as metabolites (meta­ bolomics) and carbohydrates (glycomics). Undertaking such large efforts The essence of genomics will depend on both demand and the opportunity to cost-effectively Genomics grew primarily out of human assemble data sets of higher quality and greater comprehensiveness than genetics and molecular biology. would otherwise emerge from the combined output of individual Althoughthefieldshavemuchin research projects. Although the generation of some of
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