Reply to Barton et al: signatures of natural selection during the Black Death

Abstract

AbstractBartonet al.1raise several statistical concerns regarding our original analyses2that highlight the challenge of inferring natural selection using ancient genomic data. We show here that these concerns have limited impact on our original conclusions. Specifically, we recover the same signature of enrichment for high FSTvalues at the immune loci relative to putatively neutral sites after switching the allele frequency estimation method to a maximum likelihood approach, filtering to only consider known human variants, and down-sampling our data to the same mean coverage across sites. Furthermore, using permutations, we show that the rs2549794 variant nearERAP2continues to emerge as the strongest candidate for selection (p = 1.2×10−5), falling below the Bonferroni-corrected significance threshold recommended by Bartonet al. Importantly, the evidence for selection onERAP2is further supported by functional data demonstrating the impact of theERAP2genotype on the immune response toY. pestisand by epidemiological data from an independent group showing that the putatively selected allele during the Black Death protects against severe respiratory infection in contemporary populations.