Abstract
Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene’s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<10−4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.
Highlights
Recent population expansion and limited purifying selection have led to an abundance of rare human genetic variation [1,2,3] including stop-gain and frameshift mutations
We considered transcripts from 16,260 autosomal protein coding genes annotated by the consensus coding sequence (CCDS) project [11], for which de novo mutation rate estimates were recently calculated [12], and where the number of synonymous variants in sequenced individuals followed expectation (Methods)
To test whether there is a subset of genes that are intolerant to heterozygous truncation, we simulated a model of generation of neutral de novo protein truncating variants (PTVs) for all genes
Summary
Recent population expansion and limited purifying selection have led to an abundance of rare human genetic variation [1,2,3] including stop-gain and frameshift mutations. There is increasing interest in the identification of natural human knockouts [3,4,5,6,7,8] through the cataloguing of homozygous truncations. Heterozygous truncation can lead to deleterious functional consequences through haploinsufficiency due to decreased gene dosage, or through a dominant-negative effect [9,10]. In order to quantify the importance of heterozygous protein truncating variation, we characterized genes showing fewer de novo truncations in the general population than expected under a neutral model. We hypothesized that there is a set of genes that cannot tolerate heterozygous protein truncating variants (PTVs) because of early life lethality
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