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Human Molecular Genetics and Genomics — Important Advances and Exciting Possibilities Francis S The NEW ENGLAND JOURNAL of MEDICINE Perspective January 7, 2021 A Half-Century of Progress in Health: The National Academy of Medicine at 50 Human Molecular Genetics and Genomics — Important Advances and Exciting Possibilities Francis S. Collins, M.D., Ph.D., Jennifer A. Doudna, Ph.D., Eric S. Lander, Ph.D., and Charles N. Rotimi, Ph.D.​​ Human Molecular Genetics and Genomic he breathtaking progress in molecular genet- ing to understand the fundamen- ics that has occurred over the past five decades tals of the human genetic code to examining the ways in which Tand the transition to genomic medicine would this code varies among people, have been difficult to imagine in 1970, when the and then applying this knowl- edge to interventions that are Institute of Medicine (IOM), now quence the human genome seemed tailored to target, with precision, the National Academy of Medicine radical. the underlying causes of disease. (NAM), was formed. The term In 1987, the New York Times Mag- The development of genomic “genomics” hadn’t yet been coined, azine characterized the Human tools and data sets has trans- the tools and technologies that are Genome Project as the “biggest, formed the nature of medical the foundation of modern biotech- costliest, most provocative bio- discovery, enabling scientists to nology were in their infancy, and medical research project in his- undertake comprehensive and methods for sequencing even a few tory.”2 But in the years between powerful explorations rather than nucleotides were barely workable.1 the project’s launch in 1990 and being confined to testing hypoth- The IOM’s early years coincided its completion in 2003, genomic eses focused on candidate path- with paradigm-shifting discover- technology advanced dramatically. ways. With the completion of the ies related to DNA, as biologic re- DNA-sequencing throughput in- first reference sequence of the search swiftly incorporated Boyer creased from 1000 base pairs per human genome,3 attention shifted and Cohen’s recombinant method, day to more than 1000 base pairs from searching for genes to dis- Sanger’s DNA-sequencing work, per second, which opened the door covering their functions. System- and Mullis’s introduction of po- for low-cost sequencing tech- atic genetic mapping in families lymerase chain reaction (PCR) niques that are enabling genomic and populations helped scientists technology (see timeline). Yet even advances to be incorporated into pinpoint the genetic variants that against this backdrop, the notion routine medical care. Genomic contribute to human disease. of a “big science” endeavor to se- research has evolved from seek- The effects have been profound. n engl j med 384;1 nejm.org January 7, 2021 1 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on July 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. PERSPECTIVE human molecular genetics and genomics 1973: Herbert Boyer and Stanley Cohen develop recombinant DNA technology 1970s 1977: Walter Gilbert and Frederick Sanger devise techniques for sequencing DNA 1983: Kary Mullis invents the polymerase-chain-reaction (PCR) process First disease-associated gene is molecularly mapped to a human chromosome 1980s by James Gusella and Nancy Wexler 1986: Leroy Hood devises the automated DNA sequencer 1990: The NIH and Department of Energy launch the Human Genome Project (HGP) 1994: Human genetic mapping goals of HGP met 1995: Human physical mapping goals of HGP met 1990s 1996: The HGP starts testing strategies for large-scale sequencing of the human genome 1997: In what would come to be called the “Bermuda principles,” HGP researchers affirm the rapid, public release of genome-sequence data without restrictions on use 2001: The HGP international consortium publishes a first draft of the human genome sequence; J. Craig Venter’s group at Celera Genomics Corp. publishes another version of the sequence 2002: The International HapMap Project is launched to gather data on human genetic variation that could be used to speed identification of genes associated with common diseases 2000s 2003: The HGP is completed more than 2 yr ahead of schedule, producing a reference sequence of the human genome 2006: The NIH launches the Cancer Genome Atlas (TCGA) to molecularly characterize more than 20,000 samples spanning 33 cancer types 2008: The U.S. Genetic Information Nondiscrimination Act is enacted to protect against discriminatory use of genetic information in health insurance and employment 2009: In a clinical first, Wisconsin researchers sequence all of a 5-yr-old boy’s genes and use the data to pinpoint a new disease, leading to life-saving treatment 2012: The Human Heredity and Health in Africa (H3Africa) consortium holds its inaugural meeting in Addis Ababa, Ethiopia Emmanuelle Charpentier and Jennifer Doudna show that CRISPR can edit DNA in vitro (for which they win the 2020 Nobel Prize in Chemistry); about 6 mo 2010s later Feng Zhang and George Church independently demonstrate CRISPR editing in mammalian cells 2018: TCGA publishes the Pan-Cancer Atlas, a collection of cross-cancer analyses based on its complete data set The NIH begins enrollment for the “All of Us” research program, a large-scale research resource of more than 1 million participants who will contribute genetic, health, and environmental data 2020s 2020: First patient with sickle cell disease is treated with an ex vivo approach using CRISPR-Cas9 Highlights in Human Molecular Genetics and Genomics. Cas9 denotes CRISPR-associated protein 9, CRISPR clustered regularly interspaced short palin- dromic repeats, HGP Human Genome Project, and NIH National Institutes of Health. 2 n engl j med 384;1 nejm.org January 7, 2021 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on July 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. PERSPECTIVE human molecular genetics and genomics The discovery of genes responsi- complete genome having dropped States. In addition, a risk hap- ble for more than 5000 rare from $3 billion during the Hu- lotype for type 2 diabetes in mendelian diseases has facilitat- man Genome Project to $600 to- SLC16A11 that is present in about ed genetic diagnostics for many day, there are growing efforts to half of Indigenous peoples of the patients, pregnancy-related coun- create large-scale biobanks of Americas and rare in peoples of seling, new drug treatments, and complete genome-sequencing and European or African ancestry ex- in some cases, gene therapies. The phenotype information from hun- plains about 20% of the in- discovery of more than 100,000 dreds of thousands of people. Ex- creased type 2 diabetes preva- robust associations between ge- amples include the U.K. Biobank lence among Mexican Americans nomic regions and common dis- (https://www . ukbiobank . ac . uk/ ) as compared with European Amer- eases has pointed to new biolog- and the U.S. “All of Us” research icans. Genomic research has also ic mechanisms, such as the role program (https://allofus . nih . gov/ ). shown that PCSK9 loss-of-func- of microglia in Alzheimer’s dis- The ultimate goal is for health tion mutations are more common ease, autophagy in inflammatory care systems to couple genomic in people of African ancestry bowel disease, and synaptic prun- information with medical records. than in other populations; such ing in schizophrenia. It has also Much work remains to be done mutations reduce cholesterol lev- enabled the development of poly- to enhance the study of human els and the risk of heart disease genic risk scores to identify pa- genetic variation. Despite the and are providing new insights tients at increased risk for heart promise of insights into biology for drug development. disease, breast cancer, and other and health disparities offered by Several initiatives designed to conditions, although additional studying people of diverse back- increase the involvement of in- rigorous testing of such scores is grounds, both the investigators vestigators and study participants needed, including evaluation of and the participants involved in from previously underrepresent- clinical outcomes. Studies of can- genomic research have largely ed populations are under way. cer genomes have revealed hun- been of European ancestry. This The Human Heredity and Health dreds of genes in which somatic lack of diversity hinders our un- in Africa (H3Africa) initiative mutations propel tumor initiation derstanding of biology, exacer- (https://h3africa . org/ ), for example, and growth, information that has bates already unacceptable health has developed a pan-African con- fueled the development of new disparities, and raises the ques- sortium of laboratories that has drugs. Genomic analysis is also tion of whether polygenic risk ensured access to genomic tech- helping to explain why some peo- scores, diagnostics, and therapeu- nologies for more than 500 Afri- ple have responses to certain ther- tics derived from genomic re- can scientists, enrolled more than apies or survive certain infec- search will benefit all populations 60,000 research participants, and tions, whereas others do not. equally. established a bioinformatics net- The focus of genomics research Studies of people of diverse work and three regional biore- has recently moved beyond ana- ancestral backgrounds have re- positories. Precision medicine’s lyzing DNA variation to studying vealed the ways in which genom- benefits are expected to be more patterns of gene expression in ic variation contributes to popu- equitably shared when long-over- individual cells, a step that has lation-level differences in disease due steps are taken to close gaps been driven by new methods for susceptibility, drug responses, and in genomic-research participation. single-cell RNA sequencing and the diagnostic accuracy of clini- Diagnosis of genetic diseases chromatin analysis. Tens of mil- cal approaches guided by genom- has advanced rapidly because of lions of cells have been charac- ic research.4 One insight from genomic-sequencing technology.
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