Rausell Antonio, Luo Yufei, Lopez Marie, Seeleuthner Yoann, Rapaport Franck, Favier Antoine, Stenson Peter D, Cooper David N, Patin Etienne, Casanova Jean-Laurent, Quintana-Murci Lluis, Abel Laurent
Clinical Bioinformatics Laboratory, INSERM UMR1163, Necker Hospital for Sick Children, 75015 Paris, France;
University of Paris, Imagine Institute, 75015 Paris, France.
Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13626-13636. doi: 10.1073/pnas.1917993117. Epub 2020 Jun 2.
Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known variant that confers resistance to intestinal viruses, and an variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.
预测会导致相应蛋白质功能丧失（LoF）的纯合或半合子人类不一定会表现出明显的临床表型。我们在此报告了190个常染色体基因，它们带有207个预测的LoF变异，在来自五个主要祖先群体的至少一个人类群体中，纯合个体的频率超过1%。在X和Y染色体上未发现此类基因。人工筛选发现，28个变异（15%）被错误注释为LoF。在166个基因中的179个剩余变异中，只有11个基因中的11个等位基因先前已通过实验证实为LoF。这组166个可缺失基因在嗅觉受体基因（41个基因）中富集。这41个可缺失嗅觉受体基因表现出与其他嗅觉受体基因类似的选择限制放松。125个可缺失的非嗅觉受体基因也表现出与更高冗余度一致的选择限制放松。在这125个基因中，有62个在至少三个人类群体中被发现是可缺失的，这表明它们可能正在朝着假基因进化。在179个LoF变异中，68个可以进行两种中性统计测试，其中8个表现出强烈的正选择信号。后一种变异包括一个已知的赋予肠道病毒抗性的变异，以及一个参与寄生虫感染抗性的变异。总体而言，对166个基因的鉴定表明，相当一部分人类对于预测的LoF等位基因是纯合的，这揭示了此类缺陷对于人类生存的冗余性和优势。
