Analysis of protein - coding genetic variation in 60 , 706 humans 1 Exome Aggregation Consortium

50. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. 51. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. 2 3 4 * These authors contributed equally to this work and names appear in alphabetical order 5 † Corresponding author 6 # List of collaborators to appear in Supplementary 7. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. 4 Summary 1 Large-scale reference data sets of human genetic variation are critical for the medical 2 and functional interpretation of DNA sequence changes. Here we describe the 3 aggregation and analysis of high-quality exome (protein-coding region) sequence data 4 for 60,706 individuals of diverse ethnicities. The resulting catalogue of human genetic 5 diversity has unprecedented resolution, with an average of one variant every eight bases 6 of coding sequence and the presence of widespread mutational recurrence. The deep 7 catalogue of variation provided by the Exome Aggregation Consortium (ExAC) can be 8 used to calculate objective metrics of pathogenicity for sequence variants, and to identify 9 genes subject to strong selection against various classes of mutation; we identify 3,230 10 genes with near-complete depletion of truncating variants, 79% of which have no 11 currently established human disease phenotype. Finally, we show that these data can be 12 used for the efficient filtering of candidate disease-causing variants, and for the 13 discovery of human " knockout " variants in protein-coding genes. 14 15 Background 16 Over the last five years, the widespread availability of high-throughput DNA sequencing 17 technologies has permitted the sequencing of the whole genomes or exomes (the 18 protein-coding regions of genomes) of over half a million humans. In theory, these data 19 represent a powerful source of information about the global patterns of human genetic 20 variation, but in practice, are difficult to access for practical, logistical, and ethical 21 reasons; in addition, the inconsistent processing complicates variant-calling pipelines 22 used by different groups. Current publicly available datasets of human DNA sequence 23 variation contain only a small fraction of all sequenced samples: the Exome Variant 24 Server, created as part of the NHLBI Exome Sequencing Project (ESP) 1 , contains 25 frequency information …