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−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.

测序研究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。由于此类变异大多以杂合状态被检出，其可用于评估基因对单倍体不足（haploinsufficiency）及显性功能丧失的耐受程度。本研究对11546名个体的16260个常染色体蛋白编码基因的截短变异分布展开分析，共发现39893个截短变异，涉及12062个基因；该观测结果与中性新发突变模型预期的12916个受影响基因存在显著统计学差异（p<10⁻⁴）。通过将该发现外推至更大规模的测序队列，我们估算有10.8%的人类基因无法耐受杂合截短变异。另有10%至15%的截短基因，可能因不完全外显（incomplete penetrance）、补偿突变（compensatory mutations），或该截短变异对基因功能影响有限而被“挽救”。对蛋白截短变异的研究不仅厘清了人类必需基因组的范畴，更从更广维度揭示：罕见杂合变异是表型性状与疾病多样性中尚未被充分探索的重要来源。