Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2123000119. doi: 10.1073/pnas.2123000119. Epub 2022 May 17.
Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.
人类基因组多样性受到来自病毒的古代和持续挑战的影响。目前由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起的 2019 年冠状病毒病（COVID-19）大流行对人口健康造成了毁灭性影响。然而，与 SARS-CoV-2 感染相关的宿主基因的遗传多样性和进化力量还没有得到很好的理解。我们研究了与 SARS-CoV-2 感染相关的宿主基因（血管紧张素转换酶 2 [ACE2]、跨膜丝氨酸蛋白酶 2 [TMPRSS2]、二肽基肽酶 4 [DPP4]和淋巴细胞抗原 6 复合体 E 基因座 [LY6E]）的全球遗传变异模式和自然选择特征。我们分析了来自 2012 名不同种族的非洲人和 15977 名具有电子健康记录的欧洲和非洲血统个体的数据，并与 1000 基因组计划的全球数据进行了整合。在 ACE2 中，我们发现了 41 个在大多数人群中罕见的非同义变异，其中一些影响蛋白质功能。然而，三个非同义变异（rs138390800、rs147311723 和 rs145437639）在来自喀麦隆的中非狩猎采集者中很常见（次要等位基因频率为 0.083 至 0.164），并且存在表现出正选择特征的单倍型上。我们确定了影响 ACE2 表达的调节区域变异的选择特征，这些特征在多个非洲人群中存在。在 TMPRSS2 中，我们发现了 13 个与黑猩猩基因组相比是适应性的和人类特有的氨基酸变化。自然选择的遗传变异与 COVID-19 患者常见的临床表型有关。我们的研究提供了有关与 SARS-CoV-2 感染相关的宿主基因的全球变异的见解，这些变异在一些人群中受到自然选择的影响，可能是由于先前的病毒感染。
