The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome

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.

测序项目已在人类基因组中鉴定出大量罕见的终止密码子获得（stop-gain）变异与移码（frameshift）变异。由于这类变异大多以杂合状态被观测到，因此可用于检测基因对单倍剂量不足（haploinsufficiency）与显性功能丧失的耐受性。我们对11546名个体中16260个常染色体蛋白编码基因上的截短变异（truncating variant）分布情况进行了分析。共观测到39893个截短变异，涉及12062个基因；该结果与中性新发突变（de novo mutation）模型下预期的12916个基因存在显著统计学差异（p<10^-4）。将该分析结果外推至更大规模的测序个体群体，我们估算有10.8%的人类基因无法耐受杂合型截短变异。另有10%至15%的携带截短变异的基因，可能通过不完全外显率（incomplete penetrance）、补偿性突变（compensatory mutation）得以挽救，或因该截短变异对基因功能的影响有限。对蛋白截短变异的研究不仅界定了人类必需基因组，更在更广泛的层面将罕见杂合变异鉴定为表型性状与疾病多样性的未被探索的来源。