Abstract
Barton et al. raise concerns regarding the statistical analyses of our recent work, highlighting challenges of inferring natural selection from ancient genomic data. We have collected new data and conducted additional analysis, all of which support our original conclusions. First, when applying a maximum likelihood approach to allele frequency estimation, filtering sites to known human variants, and downsampling our data to the same mean coverage across sites, we continue to recover a consistent enrichment of high F(ST) values at immune loci relative to putatively neutral sites. Second, permutations show that rs2549794 near ERAP2 remains the strongest candidate for selection during the Black Death. Third, the evidence for selection on ERAP2 is supported by functional data demonstrating the impact of the ERAP2 genotype on the immune response to Y. pestis infection in immune cells. In particular, we show that the functional evidence linking the putatively selected ERAP2 allele to cytokine release and Y. pestis clearance is unusual relative to all immune loci SNPs tested. Finally, independent epidemiological data has recently emerged showing that the putatively selected ERAP2 allele does indeed protect against severe respiratory infection in contemporary populations. Together, all lines of evidence converge in support of selection on ERAP2 during the Black Death.