31-OR

Abstract

Evolution of the KIR genes was examined in the context of the entire human genome. Gene-content diversity and 125 SNPs in the KIR gene, and flanking regions, were compared to >650,000 genome-wide SNPs in 852 individuals from 52 populations of the human genome diversity panel (HGDP). KIR allelic diversity is further examined in a subset of the 852 individuals. In both African and Oceanic populations SNP diversity and linkage disequilibrium (LD) patterns in the telomeric KIR region show strong evidence for purifying selection in response to local pressures. This ongoing selection favors KIR3DL1 in Africa and KIR3DS1 in Oceania. In contrast, the generally high diversity worldwide for the centromeric KIR is region is consistent with balancing selection, particularly in Oceania. Highlighting the considerable fluctuation of selection pressures, East Asians exhibit ongoing purifying selection on the centromeric KIR that began before divergence of Amerindians, populations in which centromeric KIR diversity subsequently rebounded under balancing selection. Exons 7-9 of KIR3DL3 and KIR3DL2 mark the centromeric and telomeric boundaries of LD, respectively, within the KIR region in all populations. Contrasting with the instability of the centromeric and telomeric KIR regions is a segment of strong LD that extends from 40kb 5’ of the KIR locus to intron 5 of KIR3DL3 that remains relatively conserved worldwide. This segment is likely maintained by epistatic selection to maintain co-inheritance of functionally dependent polymorphisms. In conclusion, we find strong evidence of fluctuating and geographically specific selection in the KIR region that is independent of demographic history.