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Analysis of protein-coding genetic variation in 60,706 humans.

ABSTRACT: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe 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). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

SUBMITTER: Lek M

PROVIDER: S-EPMC5018207 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Analysis of protein-coding genetic variation in 60,706 humans.

Lek Monkol M Karczewski Konrad J KJ Minikel Eric V EV Samocha Kaitlin E KE Banks Eric E Fennell Timothy T O'Donnell-Luria Anne H AH Ware James S JS Hill Andrew J AJ Cummings Beryl B BB Tukiainen Taru T Birnbaum Daniel P DP Kosmicki Jack A JA Duncan Laramie E LE Estrada Karol K Zhao Fengmei F Zou James J Pierce-Hoffman Emma E Berghout Joanne J Cooper David N DN Deflaux Nicole N DePristo Mark M Do Ron R Flannick Jason J Fromer Menachem M Gauthier Laura L Goldstein Jackie J Gupta Namrata N Howrigan Daniel D Kiezun Adam A Kurki Mitja I MI Moonshine Ami Levy AL Natarajan Pradeep P Orozco Lorena L Peloso Gina M GM Poplin Ryan R Rivas Manuel A MA Ruano-Rubio Valentin V Rose Samuel A SA Ruderfer Douglas M DM Shakir Khalid K Stenson Peter D PD Stevens Christine C Thomas Brett P BP Tiao Grace G Tusie-Luna Maria T MT Weisburd Ben B Won Hong-Hee HH Yu Dongmei D Altshuler David M DM Ardissino Diego D Boehnke Michael M Danesh John J Donnelly Stacey S Elosua Roberto R Florez Jose C JC Gabriel Stacey B SB Getz Gad G Glatt Stephen J SJ Hultman Christina M CM Kathiresan Sekar S Laakso Markku M McCarroll Steven S McCarthy Mark I MI McGovern Dermot D McPherson Ruth R Neale Benjamin M BM Palotie Aarno A Purcell Shaun M SM Saleheen Danish D Scharf Jeremiah M JM Sklar Pamela P Sullivan Patrick F PF Tuomilehto Jaakko J Tsuang Ming T MT Watkins Hugh C HC Wilson James G JG Daly Mark J MJ MacArthur Daniel G DG

Nature 20160801 7616

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe 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). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence fo ...[more]

PMID: 27535533

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Project description:A phylogenetic analysis of 14 complete simian virus 40 (SV40) genomes was conducted in order to determine strain relatedness and the extent of genetic variation. This analysis included infectious isolates recovered between 1960 and 1999 from primary cultures of monkey kidney cells, from contaminated poliovaccines and an adenovirus seed stock, from human malignancies, and from transformed human cells. Maximum-parsimony and distance methods revealed distinct SV40 clades. However, no clear patterns of association between genotype and viral source were apparent. One clade (clade A) is derived from strain 776, the reference strain of SV40. Clade B contains isolates from poliovaccines (strains 777 and Baylor), from monkeys (strains N128, Rh911, and K661), and from human tumors (strains SVCPC and SVMEN). Thus, adaptation is not essential for SV40 survival in humans. The C terminus of the T-antigen (T-ag-C) gene contains the highest proportion of variable sites in the SV40 genome. An analysis based on just the T-ag-C region was highly congruent with the whole-genome analysis; hence, sequencing of just this one region is useful in strain identification. Analysis of an additional 16 strains for which only the T-ag-C gene was sequenced indicated that further SV40 genetic diversity is likely, resulting in a provisional clade (clade C) that currently contains strains associated with human tumors and human strain PML-1. Four other polymorphic regions in the genome were also identified. If these regions were analyzed in conjunction with the T-ag-C region, most of the phylogenetic signal could be captured without complete genome sequencing. This report represents the first whole-genome approach to establishing phylogenetic relatedness among different strains of SV40. It will be important in the future to develop a more complete catalog of SV40 variation in its natural monkey host, to determine if SV40 strains from different clades vary in biological or pathogenic properties, and to identify which SV40 strains are transmissible among humans.

Dataset Information

Analysis of protein-coding genetic variation in 60,706 humans.

Publications

Analysis of protein-coding genetic variation in 60,706 humans.

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