Genome-wide identification of susceptibility alleles for viral infections through a population genetics approach

Abstract

Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure. Results showed an excess of variants correlated with virus diversity in genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors; a significantly higher than expected number of variants was also seen in genes encoding proteins that directly interact with viral components. Genome-wide analyses identified 441 variants significantly associated with virus-diversity; these are more frequently located within gene regions than expected, and they map to 139 human genes. Analysis of functional relationships among genes subjected to virus-driven selective pressure identified a complex network enriched in viral products-interacting proteins. The novel approach to the study of infectious disease epidemiology presented herein may represent an alternative to classic genome-wide association studies and provides a large set of candidate susceptibility variants for viral infections.

Figure 1. Network analysis of genes associated with virus diversity.

Interactions between human proteins are delimited by the hatched grey circle. Genes are represented as nodes; edges indicate known interactions (sold lines depicts direct and hatched lines depict indirect interaction). Human genes are colour-coded as follows: orange, genes with at least one SNP significantly associated with virus diversity; yellow, genes with at least one SNP that did not withstand genome-wide Bonferroni correction but displayed a rank higher than the 99^th and a p value lower than 10⁻⁵ (these genes were not included in the input IPA list used to generate networks); grey, genes covered by at least one SNP in the HGDP-CEPH panel; white, genes with no SNPs in the panel. Virus-host interactions are shown for genes subjected to virus-driven selection only; genes interacting with viral products that display no SNP significantly associated with virus diversity are denoted with an asterisk. Viral products are reported outside the hatched circle and colour coded as follows: purple, HIV-1; green, Human herpesvirus; blue, Human rotavirus G3; cyan, Human adenovirus 2; black, Human T-lymphotropic virus 1.