Identification of deleterious mutations within three human genomes
Sung Chun,Justin C. Fay +1 more
TLDR
Using a comparative genomics data set of 32 vertebrate species, it is shown that a likelihood ratio test (LRT) can accurately identify a subset of deleterious mutations that disrupt highly conserved amino acids within protein-coding sequences, which are likely to be unconditionally deleteriously.Abstract:
Each human carries a large number of deleterious mutations. Together, these mutations make a significant contribution to human disease. Identification of deleterious mutations within individual genome sequences could substantially impact an individual’s health through personalized prevention and treatment of disease. Yet, distinguishing deleterious mutations from the massive number of nonfunctional variants that occur within a single genome is a considerable challenge. Using a comparative genomics data set of 32 vertebrate species we show that a likelihood ratio test (LRT) can accurately identify a subset of deleterious mutations that disrupt highly conserved amino acids within protein-coding sequences, which are likely to be unconditionally deleterious. The LRT is also able to identify known human disease alleles and performs as well as two commonly used heuristic methods, SIFT and PolyPhen. Application of the LRT to three human genomes reveals 796–837 deleterious mutations per individual, ;40% of which are estimated to be at <5% allele frequency. However, the overlap between predictions made by the LRT, SIFT, and PolyPhen, is low; 76% of predictions are unique to one of the three methods, and only 5% of predictions are shared across all three methods. Our results indicate that only a small subset of deleterious mutations can be reliably identified, but that this subset provides the raw material for personalized medicine. [Supplemental material is available online at http://www.genome.org.]read more
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CADD: predicting the deleteriousness of variants throughout the human genome.
Philipp Rentzsch,Daniela Witten,Gregory M. Cooper,Jay Shendure,Martin Kircher,Martin Kircher +5 more
TL;DR: The latest updates to CADD are reviewed, including the most recent version, 1.4, which supports the human genome build GRCh38, and also present updates to the website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications.
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.
Journal ArticleDOI
REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Nilah M. Ioannidis,Joseph H. Rothstein,Joseph H. Rothstein,Vikas Pejaver,Sumit Middha,Shannon K. McDonnell,Saurabh Baheti,Anthony M. Musolf,Qing Li,Emily R. Holzinger,Danielle M. Karyadi,Lisa A. Cannon-Albright,Craig C. Teerlink,Janet L. Stanford,William B. Isaacs,Jianfeng Xu,Kathleen A. Cooney,Kathleen A. Cooney,Ethan M. Lange,Johanna Schleutker,John D. Carpten,Isaac J. Powell,Olivier Cussenot,Geraldine Cancel-Tassin,Graham G. Giles,Graham G. Giles,Robert J. MacInnis,Robert J. MacInnis,Christiane Maier,Chih-Lin Hsieh,Fredrik Wiklund,William J. Catalona,William D. Foulkes,Diptasri Mandal,Rosalind A. Eeles,Zsofia Kote-Jarai,Carlos Bustamante,Daniel J. Schaid,Trevor Hastie,Elaine A. Ostrander,Joan E. Bailey-Wilson,Predrag Radivojac,Stephen N. Thibodeau,Alice S. Whittemore,Weiva Sieh,Weiva Sieh +45 more
TL;DR: This work developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, LRT, GERP, SiPhy, phyloP, and phastCons.
Journal ArticleDOI
Association analysis identifies 65 new breast cancer risk loci
Kyriaki Michailidou,Kyriaki Michailidou,Sara Lindström,Sara Lindström,Joe Dennis,Jonathan Beesley,Shirley Hui,Siddhartha Kar,Audrey Lemaçon,Penny Soucy,Dylan M. Glubb,Asha Rostamianfar,Manjeet K. Bolla,Qin Wang,Jonathan Tyrer,Ed Dicks,Andy C. H. Lee,Zhaoming Wang,Jamie Allen,Renske Keeman,Ursula Eilber,Juliet D. French,Xiaoqing Chen,Laura Fachal,Karen McCue,Amy E. McCart Reed,Maya Ghoussaini,Jason S. Carroll,Xia Jiang,Hilary K. Finucane,Hilary K. Finucane,Marcia Adams,Muriel A. Adank,Habibul Ahsan,Kristiina Aittomäki,Hoda Anton-Culver,Natalia Antonenkova,Volker Arndt,Kristan J. Aronson,Banu Arun,Paul L. Auer,Paul L. Auer,Francois Bacot,Myrto Barrdahl,Caroline Baynes,Matthias W. Beckmann,Sabine Behrens,Javier Benitez,Marina Bermisheva,Leslie Bernstein,Carl Blomqvist,Natalia Bogdanova,Stig E. Bojesen,Stig E. Bojesen,Bernardo Bonanni,Anne Lise Børresen-Dale,Judith S. Brand,Hiltrud Brauch,Hiltrud Brauch,Hiltrud Brauch,Paul Brennan,Hermann Brenner,Louise A. Brinton,Per Broberg,Ian W. Brock,Annegien Broeks,Angela Brooks-Wilson,Angela Brooks-Wilson,Sara Y. Brucker,Thomas Brüning,Barbara Burwinkel,Barbara Burwinkel,Katja Butterbach,Qiuyin Cai,Hui Cai,Trinidad Caldés,Federico Canzian,Angel Carracedo,Brian D. Carter,Jose E. Castelao,Tsun Leung Chan,Tongguang Cheng,Kee Seng Chia,Ji Yeob Choi,Hans Christiansen,Christine L. Clarke,Margriet Collée,Don M. Conroy,Emilie Cordina-Duverger,Sten Cornelissen,David G. Cox,David G. Cox,Angela Cox,Simon S. Cross,Julie M. Cunningham,Kamila Czene,Mary B. Daly,Peter Devilee,Kimberly F. Doheny,Thilo Dörk,Isabel dos-Santos-Silva,Martine Dumont,Lorraine Durcan,Miriam Dwek,Diana Eccles,Arif B. Ekici,A. Heather Eliassen,A. Heather Eliassen,Carolina Ellberg,Mingajeva Elvira,Christoph Engel,Mikael Eriksson,Peter A. Fasching,Peter A. Fasching,Jonine D. Figueroa,Dieter Flesch-Janys,Olivia Fletcher,Henrik Flyger,Lin Fritschi,Valerie Gaborieau,Marike Gabrielson,Manuela Gago-Dominguez,Yu Tang Gao,Susan M. Gapstur,José A. García-Sáenz,Mia M. Gaudet,Vassilios Georgoulias,Graham G. Giles,Graham G. Giles,Gord Glendon,Mark S. Goldberg,David E. Goldgar,Anna González-Neira,Grethe I. Grenaker Alnæs,Mervi Grip,Jacek Gronwald,Anne Grundy,Pascal Guénel,Lothar Haeberle,Eric Hahnen,Christopher A. Haiman,Niclas Håkansson,Ute Hamann,N Hamel,Susan E. Hankinson,Patricia Harrington,Steven N. Hart,Jaana M. Hartikainen,Mikael Hartman,Mikael Hartman,Alexander Hein,Jane Heyworth,Belynda Hicks,Peter Hillemanns,Dona N. Ho,Antoinette Hollestelle,Maartje J. Hooning,Robert N. Hoover,John L. Hopper,Ming-Feng Hou,Chia-Ni Hsiung,Guanmengqian Huang,Keith Humphreys,Junko Ishiguro,Hidemi Ito,Motoki Iwasaki,Hiroji Iwata,Anna Jakubowska,Wolfgang Janni,Esther M. John,Esther M. John,Nichola Johnson,Kristine Jones,Michael Jones,Arja Jukkola-Vuorinen,Rudolf Kaaks,Maria Kabisch,Katarzyna Kaczmarek,Daehee Kang,Daehee Kang,Yoshio Kasuga,Michael J. Kerin,Sofia Khan,Elza Khusnutdinova,Elza Khusnutdinova,Johanna I. Kiiski,Sung-Won Kim,Julia A. Knight,Julia A. 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Yang,Cheng Har Yip,Keun-Young Yoo,Jyh-Cherng Yu,Wei Zheng,Ying Zheng,Bin Zhu,Argyrios Ziogas,Elad Ziv,Sunil R. Lakhani,Sunil R. Lakhani,Antonis C. Antoniou,Arnaud Droit,Irene L. Andrulis,Irene L. Andrulis,Christopher I. Amos,Fergus J. Couch,Paul D.P. Pharoah,Jenny Chang-Claude,Jenny Chang-Claude,Per Hall,David J. Hunter,Roger L. Milne,Roger L. Milne,Montserrat Garcia-Closas,Marjanka K. Schmidt,Stephen J. Chanock,Alison M. Dunning,Stacey L. Edwards,Gary D. Bader,Georgia Chenevix-Trench,Jacques Simard,Peter Kraft,Douglas F. Easton +396 more
TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Journal ArticleDOI
Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants
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TL;DR: The results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.
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