Schäfer Alexandra, Leist Sarah R, Gralinski Lisa E, Martinez David R, Winkler Emma S, Okuda Kenichi, Hawkins Padraig E, Gully Kendra L, Graham Rachel L, Scobey D Trevor, Bell Timothy A, Hock Pablo, Shaw Ginger D, Loome Jennifer F, Madden Emily A, Anderson Elizabeth, Baxter Victoria K, Taft-Benz Sharon A, Zweigart Mark R, May Samantha R, Dong Stephanie, Clark Matthew, Miller Darla R, Lynch Rachel M, Heise Mark T, Tisch Roland, Boucher Richard C, Pardo Manuel de Villena Fernando, Montgomery Stephanie A, Diamond Michael S, Ferris Martin T, Baric Ralph S
bioRxiv. 2022 Jun 2:2022.06.01.494461. doi: 10.1101/2022.06.01.494461.
Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to SARS-CoV disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse Chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, and that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2 and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species.
传染病塑造了人类群体的遗传结构，而基因变异会影响对多种病毒性疾病的易感性。然而，诸多挑战使得采用传统的全基因组关联研究（GWAS）方法来研究这些感染性结果颇具难度。相比之下，传染病的小鼠模型提供了实验对照和精确性，这有助于对基因变异在感染中所起作用进行分析和机制研究。在此，我们针对严重急性呼吸综合征冠状病毒（SARS-CoV）疾病结果，在两种不同的协作杂交小鼠品系之间进行了遗传定位杂交。我们发现，在SARS-CoV感染的背景下，有几个基因座控制着多种性状的不同疾病结果。重要的是，我们在小鼠9号染色体上鉴定出一个基因座，它与人类SARS-CoV-2重症疾病的GWAS基因座显示出保守的同线性。我们对该基因座的作用进行了后续研究并予以证实，还鉴定出两个候选基因，它们在调节SARS-CoV、SARS-CoV-2以及一种远缘相关的蝙蝠乙型冠状病毒疾病结果的严重程度方面均发挥关键作用。因此，我们提供了一个模板，用于利用实验性小鼠杂交来鉴定和表征调控跨物种致病性感染结果的多性状基因座。
