Abstract
Selection pressures imposed by pathogens have varied among populations throughout human evolution, leading to inter-population differences at genetic loci mediating susceptibility to infectious diseases. A common polymorphism resulting in a C529 versus T529 change in the Cadherin-Related Family Member 3 (CDHR3) receptor is associated with severe childhood asthma exacerbations. Transfection of this nonsynonymous variant in lung epithelial cell lines results in increased cell surface expression of the protein and increased rhinovirus-C binding and replication. Given the morbidity and mortality associated with rhinovirus-C-dependent respiratory infections and asthma, we hypothesized that the ‘protective’ variant has been under positive selection in worldwide populations. Using publicly available phased, whole-genome sequence data for 2504 individuals from 26 human populations, we sought to determine the evolutionary history and role of selection acting on this infectious disease susceptibility locus. The ‘risk’ allele is the ancestral allele and is found at highest frequency in African populations and lowest frequency in East Asian populations. There is minimal population structure among haplotypes and strong evidence that the ‘protective’ allele arose in anatomically modern humans prior to their migrations out of Africa. We detect shared signatures of selection across human populations using haplotype based selection scans; however, the patterns observed here are not consistent with a classical selective sweep. We hypothesize that patterns may indicate short term balancing selection and/or polygenic selection.