Regulatory dissection of the severe COVID-19 risk locus introgressed by Neanderthals
Evelyn Jagoda,
Davide Marnetto,
Gayani Senevirathne,
Victoria Gonzalez,
Kaushal Baid,
Francesco Montinaro,
Daniel Richard,
Darryl Falzarano,
Emmanuelle V LeBlanc,
Che C Colpitts,
Arinjay Banerjee,
Luca Pagani,
Terence D Capellini
Affiliations
Evelyn Jagoda
Department of Human Evolutionary Biology, Harvard University, Cambridge, United States
Davide Marnetto
Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia
Gayani Senevirathne
Department of Human Evolutionary Biology, Harvard University, Cambridge, United States
Victoria Gonzalez
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
Kaushal Baid
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
Francesco Montinaro
Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia; Department of Biology, University of Bari, Bari, Italy
Daniel Richard
Department of Human Evolutionary Biology, Harvard University, Cambridge, United States
Darryl Falzarano
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
Emmanuelle V LeBlanc
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada; Department of Biology, University of Waterloo, Waterloo, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Luca Pagani
Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia; Department of Biology, University of Padova, Padova, Italy
Individuals infected with the SARS-CoV-2 virus present with a wide variety of symptoms ranging from asymptomatic to severe and even lethal outcomes. Past research has revealed a genetic haplotype on chromosome 3 that entered the human population via introgression from Neanderthals as the strongest genetic risk factor for the severe response to COVID-19. However, the specific variants along this introgressed haplotype that contribute to this risk and the biological mechanisms that are involved remain unclear. Here, we assess the variants present on the risk haplotype for their likelihood of driving the genetic predisposition to severe COVID-19 outcomes. We do this by first exploring their impact on the regulation of genes involved in COVID-19 infection using a variety of population genetics and functional genomics tools. We then perform a locus-specific massively parallel reporter assay to individually assess the regulatory potential of each allele on the haplotype in a multipotent immune-related cell line. We ultimately reduce the set of over 600 linked genetic variants to identify four introgressed alleles that are strong functional candidates for driving the association between this locus and severe COVID-19. Using reporter assays in the presence/absence of SARS-CoV-2, we find evidence that these variants respond to viral infection. These variants likely drive the locus’ impact on severity by modulating the regulation of two critical chemokine receptor genes: CCR1 and CCR5. These alleles are ideal targets for future functional investigations into the interaction between host genomics and COVID-19 outcomes.
