The very large sample size of ExAC also provides opportunities for a high-resolution analysis of the sensitivity of human genes to functional variation. While previous sample sizes have been adequately powered for the assessment of gene-level intolerance to missense variation11,14, ExAC provides for the first time sufficient power to investigate genic intolerance to PTVs, highlighting 3,230 highly LoF-intolerant genes, 72% of which have no established human disease phenotype in OMIM or ClinVar. While this extreme depletion of PTVs is likely to highlight genes where loss of a single copy has been reproductively disadvantageous over recent human history, not all high pLI genes will lead to lethal disease. Additionally, disease genes—particularly those that act after post-reproductive age—do not necessarily have high pLI values (e.g. the pLI of BRCA1 is 0). In independent work [Ruderfer et al., manuscript submitted] we show that ExAC similarly provides power to identify genes intolerant of copy number variation. Quantification of genic intolerance to both classes of variation will provide added power to disease studies.
