Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.
Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.
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DOI：
10.1073/pnas.2123000119
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发表时间：
2022-05-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
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在人类进化史上，病毒是自然选择压力的重要来源。研究遗传多样性并检测与严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染相关的宿主基因的自然选择特征有助于识别功能上重要的变异。我们对在 SARS-CoV-2 感染中发挥作用的宿主基因的全球基因组变异进行了一项大型研究，重点关注代表性不足的非洲人群。我们在 ACE2 上发现了非同义变异和调控变异，这些变异似乎是一些非洲人群近期自然选择的目标。我们在人类谱系中的 TMPRSS2 上发现了古代适应性进化的证据。作为自然选择目标的基因变异与 2019 年冠状病毒病患者常见的临床表型相关。人类基因组多样性是由古老和持续的病毒挑战所塑造的。当前由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 2019 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，影响 SARS-CoV-2 感染相关宿主基因的遗传多样性和进化力量尚不清楚。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]、跨膜蛋白酶丝氨酸 2 [TMPRSS2]、二肽基肽酶 4 [DPP4] 和淋巴细胞抗原 6 复合基因座 E [LY6E]）的遗传变异和自然选择特征的全局模式。我们分析了 2,012 名不同种族的非洲人以及 15,977 名欧洲和非洲血统的人的电子健康记录数据，并与千人基因组计划的全球数据进行了整合。在 ACE2，我们鉴定了 41 个在大多数人群中罕见的非同义变异，其中一些会影响蛋白质功能。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），并且其单倍型表现出正选择的特征。我们确定了影响多个非洲人群中 ACE2 表达的调控区域变异的选择特征。在 TMPRSS2 中，与黑猩猩基因组相比，我们鉴定了 13 个氨基酸变化，这些变化对人类谱系具有适应性和特异性。作为自然选择目标的遗传变异与 COVID-19 患者常见的临床表型相关。我们的研究提供了对与 SARS-CoV-2 感染相关的宿主基因的全球变异的见解，这些变异是由某些人群中的自然选择形成的，可能是由于之前的病毒感染所致。
Viruses are strong sources of natural selection pressure during human evolutionary history. Investigating genetic diversity and detecting signatures of natural selection at host genes related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection help to identify functionally important variation. We conducted a large study of global genomic variation at host genes that play a role in SARS-CoV-2 infection with a focus on underrepresented African populations. We identified nonsynonymous and regulatory variants at ACE2 that appear to be targets of recent natural selection in some African populations. We detected evidence of ancient adaptive evolution at TMPRSS2 in the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with coronavirus disease 2019. 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.
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影响因子：
4.7
作者：
Biswas S;Thakur V;Kaur P;Khan A;Kulshrestha S;Kumar P
通讯作者：
Kumar P
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
影响因子：
12.8
作者：
Gloss BS;Dinger ME
通讯作者：
Dinger ME
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan