Homo sapiens Targeted Locus (Loci)

Pathogens have exerted strong selective pressures on the human immune system. Interestingly, many alleles that confer resistance to infections also increase risk to autoimmune diseases. To learn about the history of selective pressures acting on the immune system, we studied two autoimmunity SNPs associated with signals of positive natural selection. While the allele that increases disease risk is associated with the selection signal at one SNP, the protective allele behaves as advantageous at the other. This suggests that these variants experienced different evolutionary histories even though both influence autoimmune diseases in contemporary populations. We sequenced at high-depth 14 Europeans for large genomic segments spanning these variants and another advantageous variant associated with pigmentation traits. To estimate the ages of these alleles, we have developed an Approximate Bayesian Computation approach that assumes a plausible demographic scenario and a model of selection acting on new mutations.The age estimate for the advantageous allele that increases disease risk, i.e. 7,400 years (95% CI: 5,500–12,300), is consistent with an onset of selection associated with the spread of agriculture, but incompatible with the dispersal out-of-Africa. The opposite is true for the age of the advantageous allele that protects against autoimmunity, which is estimated to be 28,900 years old (95% CI: 19,200–100,000). These results indicate that these two transitions created different selective pressures on the immune system. The modal age of the pigmentation SNP is intermediate between the two immunity SNPs (16,400 years), coinciding with the retreat of the ice sheet in Europe.