A map of constrained coding regions in the human genome
A map of constrained coding regions in the human genome
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DOI：
10.1038/s41588-018-0294-6
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发表时间：
2019-01-01
期刊：
影响因子：
30.8
通讯作者：
Quinlan, Aaron R.
中科院分区：
文献类型：
--
作者：
Havrilla, James M.;Pedersen, Brent S.;Quinlan, Aaron R.
来自数千人的遗传变异的深层目录使得能够通过识别具有稀缺变异的编码区域来检测种内约束。虽然现有的技术总结了整个基因的约束，单基因范围的指标隐藏每个基因内的区域约束变异性。因此，我们通过利用在来自基因组聚合数据库的123，136人中观察到的变异，创建了约束编码区（CCR）的详细图谱。最受限制的CCR富含ClinVar中的致病性变体和发育障碍基础突变。CCR突出高约束下的蛋白质结构域家族，并提示未注释或不完整的蛋白质结构域。在常染色体显性遗传病研究中评价新发突变时，最高百分位CCR补充了现有的变异优先排序方法。最后，我们在缺乏已知疾病关联的基因中识别出高度受限的CCR。这一观察结果表明，CCR可能会确定强纯化选择下的区域，当突变时，导致严重的发育表型或胚胎致死。
Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. The most constrained CCRs are enriched for pathogenic variants in ClinVar and mutations underlying developmental disorders. CCRs highlight protein domain families under high constraint and suggest unannotated or incomplete protein domains. The highest-percentile CCRs complement existing variant prioritization methods when evaluating de novo mutations in studies of autosomal dominant disease. Finally, we identify highly constrained CCRs within genes lacking known disease associations. This observation suggests that CCRs may identify regions under strong purifying selection that, when mutated, cause severe developmental phenotypes or embryonic lethality.