AUTHOR=Augusto Danillo G. , Norman Paul J. , Dandekar Ravi , Hollenbach Jill A. 

TITLE=Fluctuating and Geographically Specific Selection Characterize Rapid Evolution of the Human KIR Region

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00989

DOI=10.3389/fimmu.2019.00989

ISSN=1664-3224

ABSTRACT=<p>The <italic>killer-cell immunoglobulin-like receptor</italic> (<italic>KIR</italic>) region comprises a fast-evolving family of genes that encode receptors for natural killer (NK) cells and have crucial role in host defense. Evolution of <italic>KIR</italic> was examined in the context of the human genome. Gene-content diversity and single nucleotide polymorphisms (SNP) in the <italic>KIR</italic> genes and flanking regions were compared to &gt;660,000 genome-wide SNPs in over 800 individuals from 52 populations of the human genome diversity panel (HGDP). <italic>KIR</italic> allelic diversity was further examined using next generation sequencing in a subset of 56 individuals. We identified the SNP <italic>rs587560</italic> located in <italic>KIR3DL3</italic> as a marker of <italic>KIR2DL2</italic> and <italic>KIR2DL3</italic> and, consequently, Cen A and Cen B haplotypes. We also show that combinations of two <italic>KIR2DL4</italic> SNPs (<italic>rs35656676</italic> and <italic>rs592645</italic>) distinguish <italic>KIR3DL1</italic> from <italic>KIR3DS1</italic> and also define the major <italic>KIR3DL1</italic> high- and low-expressing alleles lineages. Comparing the diversity of the SNPs within the <italic>KIR</italic> region to remainder of the genome, we observed a high diversity for the centromeric <italic>KIR</italic> region consistent with balancing selection (<italic>p</italic> &lt; 0.01); in contrast, centromeric <italic>KIR</italic> diversity is significantly reduced in East Asian populations (<italic>p</italic> &lt; 0.01), indicating purifying selection. By analyzing SNP haplotypes in a region spanning ~500 kb that includes the <italic>KIR</italic> cluster, we observed evidence of strong positive selection in Africa for high-expressing <italic>KIR3DL1</italic> alleles, favored over the low-expressing alleles (<italic>p</italic> &lt; 0.01). In sharp contrast, the strong positive selection (<italic>p</italic> &lt; 0.01) that we also observed in the telomeric <italic>KIR</italic> region in Oceanic populations tracked with a high frequency of <italic>KIR3DS1</italic>. In addition, we demonstrated that worldwide frequency of high-expression <italic>KIR3DL1</italic> alleles was correlated with virus with virus (r = 0.64, <italic>p</italic> &lt; 10<sup>−6</sup>) and protozoa (r = 0.69, <italic>p</italic> &lt; 10<sup>−6</sup>) loads, which points to selection globally on <italic>KIR3DL1</italic> high-expressing alleles attributable to pathogen exposure.</p>