Cassa Christopher A, Weghorn Donate, Balick Daniel J, Jordan Daniel M, Nusinow David, Samocha Kaitlin E, O'Donnell-Luria Anne, MacArthur Daniel G, Daly Mark J, Beier David R, Sunyaev Shamil R
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
Nat Genet. 2017 May;49(5):806-810. doi: 10.1038/ng.3831. Epub 2017 Apr 3.
The evolutionary cost of gene loss is a central question in genetics and has been investigated in model organisms and human cell lines. In humans, tolerance of the loss of one or both functional copies of a gene is related to the gene's causal role in disease. However, estimates of the selection and dominance coefficients in humans have been elusive. Here we analyze exome sequence data from 60,706 individuals to make genome-wide estimates of selection against heterozygous loss of gene function. Using this distribution of selection coefficients for heterozygous protein-truncating variants (PTVs), we provide corresponding Bayesian estimates for individual genes. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, Mendelian disease-associated genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that are likely to have crucial functions but have not yet been thoroughly characterized.
基因丢失的进化成本是遗传学中的一个核心问题，并且已经在模式生物和人类细胞系中进行了研究。在人类中，对一个基因的一个或两个功能拷贝丢失的耐受性与该基因在疾病中的因果作用有关。然而，对人类中选择系数和显性系数的估计一直难以捉摸。在这里，我们分析了来自60706个人的外显子序列数据，以对针对基因功能杂合性丢失的选择进行全基因组估计。利用这种杂合性蛋白质截短变体（PTV）的选择系数分布，我们为单个基因提供了相应的贝叶斯估计。我们发现，受到最强选择的基因在胚胎致死性小鼠基因敲除、孟德尔疾病相关基因和转录调节因子中富集。通过必需性筛选，我们发现了大量受到强选择的基因，这些基因可能具有关键功能，但尚未得到充分表征。
