Remarkably LowKIRandHLADiversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the CentromericKIRRegion

Abstract

The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.

High‐resolution characterization of KIR genes polymorphism in healthy subjects from the Bulgarian population—A pilot study

“…Vargas et al 38 suggest a population‐specific manner of allelic pairwise LD. To better understand KIR allelic associations and patterns in Bulgarians, we have estimated the pairwise linkage disequilibrium for the 10 KIR loci.…”

Immunogenomics of Killer Cell Immunoglobulin-Like Receptor (KIR) and HLA Class I: Coevolution and Consequences for Human Health

“…However, in modern humans, KIR interaction with HLA-C is the only KIR/HLA interaction present in every individual, with rare exceptions highly prone to virus infections. 128 Low frequency of KIR interactions with HLA-A or -B in Amerindians 129 suggest KIR interactions with HLA-C may now have a greater impact on human survival than those with HLA-A and -B.…”

“…Balancing selection embodies frequency fluctuations of genetic variants accompanying the relative selective advantage of their respective phenotypes. In this respect, KIR-A haplotypes have arisen to very high frequency in East Asian and Amerindian populations through positive natural selection, 41,129,142,143 presumably in response to specific pathogens. However Hiby et al 135 first noticed that the preeclampsia pregnancy syndrome is most prevalent in women who are homozygous for KIR-A and who also carry a C2-ligand fetus.…”

“…66,140,154 In populations with high pathogen exposure, natural selection acting for and against specific KIR and HLA class I allotype pairs likely remains ongoing. 129,[155][156][157]…”

Exceptional diversity of KIR and HLA class I in Egypt

“…18 Highresolution studies have revealed enormous KIR allelic diversity across human populations, likely rivaling that of HLA. [19][20][21][22][23][24][25][26][27][28][29] Although this diversity is especially evident in groups representing the deep population structure of the African continent, previous studies have focused on sub-Saharan Africa. [24][25][26] To counter lack of knowledge concerning immunogenomic diversity in Northern Africa, we focus here on a population from Egypt.…”