Journal ArticleDOI
Exome sequencing as a tool for Mendelian disease gene discovery
Michael J. Bamshad,Sarah B. Ng,Abigail W. Bigham,Abigail W. Bigham,Holly K. Tabor,Holly K. Tabor,Mary J. Emond,Deborah A. Nickerson,Jay Shendure +8 more
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TLDR
Experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders and set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.Abstract:
Exome sequencing — the targeted sequencing of the subset of the human genome that is protein coding — is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits that have proved to be intractable to conventional gene-discovery strategies. Over the past 2 years, experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders. Additionally, exome sequencing is being adapted to explore the extent to which rare alleles explain the heritability of complex diseases and health- related traits. These advances also set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.read more
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Journal ArticleDOI
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Konrad J. Karczewski,Eric Vallabh Minikel,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Andrew J. Hill,Andrew J. Hill,Beryl B. Cummings,Beryl B. Cummings,Taru Tukiainen,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Laramie E. Duncan,Karol Estrada,Karol Estrada,Fengmei Zhao,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,Emma Pierce-Hoffman,Joanne Berghout,David Neil Cooper,Nicole A. Deflaux,Mark A. DePristo,Ron Do,Jason Flannick,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Samuel A. Rose,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Stacey Donnelly,Roberto Elosua,Jose C. Florez,Jose C. Florez,Stacey Gabriel,Gad Getz,Gad Getz,Stephen J. Glatt,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Steven A. McCarroll,Mark I. McCarthy,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Patrick F. Sullivan,Jaakko Tuomilehto,Ming T. Tsuang,Hugh Watkins,Hugh Watkins,James G. Wilson,Mark J. Daly,Mark J. Daly,Daniel G. MacArthur,Daniel G. MacArthur +106 more
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Journal ArticleDOI
Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2
TL;DR: PolyPhen‐2 (Polymorphism Phenotyping v2), available as software and via a Web server, predicts the possible impact of amino acid substitutions on the stability and function of human proteins using structural and comparative evolutionary considerations.
Journal ArticleDOI
Evolution and functional impact of rare coding variation from deep sequencing of human exomes
Jacob A. Tennessen,Abigail W. Bigham,Timothy D. O’Connor,Wenqing Fu,Eimear E. Kenny,Simon Gravel,Sean McGee,Ron Do,Ron Do,Xiaoming Liu,Goo Jun,Hyun Min Kang,Daniel M. Jordan,Suzanne M. Leal,Stacey Gabriel,Mark J. Rieder,Gonçalo R. Abecasis,David Altshuler,Deborah A. Nickerson,Eric Boerwinkle,Eric Boerwinkle,Shamil R. Sunyaev,Shamil R. Sunyaev,Carlos Bustamante,Michael J. Bamshad,Joshua M. Akey +25 more
TL;DR: The findings suggest that most human variation is rare, not shared between populations, and that rare variants are likely to play a role in human health, and show that large sample sizes will be required to associate rare variants with complex traits.
Posted ContentDOI
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Beryl B. Cummings,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Karol Estrada,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,David Neil Cooper,Mark A. DePristo,Ron Do,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Roberto Elosua,Jose C. Florez,Stacey Gabriel,Gad Getz,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Jaakko Tuomilehto,Hugh Watkins,James G. Wilson,Mark J. Daly,Daniel G. MacArthur +72 more
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
References
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Ivan Adzhubei,Steffen Schmidt,Leonid Peshkin,Vasily Ramensky,Anna Gerasimova,Peer Bork,Alexey S. Kondrashov,Shamil R. Sunyaev +7 more
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Finding the missing heritability of complex diseases
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Sequencing technologies-the next generation
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Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.
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