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A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Alexandra Schäfer et al. bioRxiv. .

Update in

  • A Multitrait Locus Regulates Sarbecovirus Pathogenesis.
    Schäfer A, Leist SR, Gralinski LE, Martinez DR, Winkler ES, Okuda K, Hawkins PE, Gully KL, Graham RL, Scobey DT, Bell TA, Hock P, Shaw GD, Loome JF, Madden EA, Anderson E, Baxter VK, Taft-Benz SA, Zweigart MR, May SR, Dong S, Clark M, Miller DR, Lynch RM, Heise MT, Tisch R, Boucher RC, Pardo Manuel de Villena F, Montgomery SA, Diamond MS, Ferris MT, Baric RS. Schäfer A, et al. mBio. 2022 Aug 30;13(4):e0145422. doi: 10.1128/mbio.01454-22. Epub 2022 Jul 12. mBio. 2022. PMID: 35862771 Free PMC article.

Abstract

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, CCR9 and CXCR6 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.

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