Genetic susceptibility to severe childhood asthma and rhinovirus-C maintained by balancing selection in humans for 150,000 years.

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ID: 73317
2019
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Abstract
Selective pressures imposed by pathogens have varied among human populations throughout their evolution, leading to marked inter-population differences at some genes mediating susceptibility to infectious and immune-related diseases. Here, we investigated the evolutionary history of a common polymorphism resulting in a T529 versus C529 change in the Cadherin-Related Family Member 3 (CDHR3) receptor which underlies variable susceptibility to rhinovirus-C infection and is associated with severe childhood asthma. The protective variant is the derived allele and is found at high frequency worldwide (69-95%). We detected genome-wide significant signatures of natural selection consistent with a rapid increase of the haplotypes carrying the allele, suggesting non-neutral processes have acted on this locus across all human populations. However, the allele has not fixed in any population despite multiple lines of evidence suggesting the mutation predates human migrations out of Africa. Using an approximate Bayesian computation method, we estimate the age of the mutation while explicitly accounting for past demography and positive or frequency-dependent balancing selection. Our analyses indicate a single emergence of the mutation in anatomically modern humans ~150,000 years ago and indicate that balancing selection has maintained the beneficial allele at high equilibrium frequencies worldwide. Apart from the well-known cases of the MHC and ABO genes, this study provides the first evidence that negative frequency-dependent selection plausibly acted on a human disease susceptibility locus, a form of balancing selection compatible with typical transmission dynamics of communicable respiratory viruses that might exploit CDHR3.
Reference Key
oneill2019genetichuman Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors O'Neill, Mary B;Laval, Guillaume;Teixeira, João C;Palmenberg, Ann C;Pepperell, Caitlin S;
Journal Human molecular genetics
Year 2019
DOI
ddz304
URL
Keywords
central nervous system inflammasome pyroptosis neuron glia caspase regulated cell death

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