Quantitative genetic analysis of pathogenic response to SARS-CoV-2 and other coronaviruses in an F2 cross of Collaborative Cross strains
Authors: Ellen Risemberg; Sarah Leist; Alexandra Schaefer; Will Valdar; Martin Ferris; Ralph Baric
Affiliation: University of North Carolina at Chapel Hill
Keywords: Complex traits
Severe acute respiratory syndrome (SARS) is a viral respiratory illness that emerged in China in 2003 and became the first of three severe epidemics caused by zoonotic coronaviruses over the next 20 years. The ongoing COVID-19 pandemic and likelihood of future coronavirus outbreaks motivates greater understanding of host genetic factors contributing to variation in severity of coronavirus disease. Genetically diverse Collaborative Cross (CC) strains provide a powerful system for studying these factors and identifying mechanisms by which these genetic differences affect viral disease and pathogenesis. In this study, CC strains CC044/Unc (hereafter CC044) and CC006/TauUnc (hereafter CC006) were chosen for a genetic mapping experiment because preliminary data shows divergent phenotypic outcomes upon infection with SARS-CoV-1, including differential weight loss and immune cell infiltration into the lungs following infection. We perform a genome-wide quantitative trait loci (QTL) analysis in F2 offspring of a CC044 x CC006 cross to identify loci associated with variation in response to coronavirus infection. In addition to standard QTL mapping, we examine polygenic heritability of phenotypes, and how genetic correlations between phenotypes vary by pathogen (SARS-CoV-1, SARS-CoV-2, HKU3-CoV, saline), and evidence for the existence of substantial genetic effects on the phenotypic variability (vQTL). Here we report ongoing progress, including the identification of a QTL for infection-induced weight loss on chromosome 9, the homologous region of which has been reported to be associated with severe COVID-19 in humans.