Current publicly available data sets of human DNA sequence variation contain only a small fraction of all sequenced samples: the Exome Variant Server, created as part of the NHLBI Exome Sequencing Project (ESP) 1, contains frequency information spanning 6,503 exomes and the 1000 Genomes Project (1000G), which includes individual-level genotype data from whole-genome and exome sequence data for 2,504 individuals 2.Дatabases of genetic variation are important for our understanding of human population history and biology 1, 2, 3, 4, 5, but also provide critical resources for the clinical interpretation of variants observed in patients who have rare Mendelian diseases 6, 7. In theory, these data represent a powerful source of information about the global patterns of human genetic variation, but in practice, are difficult to access for practical, logistical, and ethical reasons in addition, their utility is complicated by the heterogeneity in the experimental methodologies and variant calling pipelines used to generate them. Over the last five years, the widespread availability of high-throughput DNA sequencing technologies has permitted the sequencing of the whole genomes or exomes of hundreds of thousands of humans. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human вЂknockoutвЂ™ variants in protein-coding genes. 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. 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. 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). Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Nature volumeВ 536, pages 285вЂ“291 ( 2016) Cite this article

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

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