Abstract
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.
Keywords: African diversity; SARS-CoV-2/COVID-19; genetic variation; natural selection; phenotype association.
【저자키워드】 Genetic variation, natural selection, SARS-CoV-2/COVID-19, African diversity, phenotype association., 【초록키워드】 COVID-19, coronavirus disease, viruses, SARS-CoV-2, Coronavirus disease 2019, ACE2, TMPRSS2, coronavirus, pandemic, adaptive, Positive selection, SARS-COV-2 infection, Human, Variation, Genome, Genetic, angiotensin converting enzyme 2, variant, haplotypes, protease, severe acute respiratory syndrome Coronavirus, angiotensin converting enzyme, viral infections, Electronic health record, Antigen, DPP4, Dipeptidyl peptidase 4, Protein, lymphocyte, Health, African, Genetic variation, Lineage, natural selection, phenotype, target, genetic diversity, genetic variants, targets, transmembrane protease serine 2, minor allele frequency, genomic, ACE2 expression, Haplotype, association, clinical phenotype, Amino acid, angiotensin, Electronic health records, in some, 1000 Genomes Project, acute respiratory syndrome, Serine, locus, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, enzyme, clinical phenotypes, individual, complex, transmembrane, host genes, dipeptidyl peptidase, regulatory region, LY6E, serine 2, populations, European, analyzed, amino acid change, identify, caused, investigated, provide, host gene, nonsynonymous variant, patients with COVID-19, 【제목키워드】 Impact, association, clinical phenotype, involved,