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.

A total of 337 Kaingang and Guarani Indians from two localities were studied in relation to 18 protein genetic loci. In one of the localities, members of these two groups live side by side but show little genetic similarity, emphasizing the influence of cultural factors in the mating behavior of human groups. Integrating the present results with previous ones, it was verified that the genetic relationships among six Kaingang populations do not follow the pattern expected from their geographical distribution. Comparisons made with three other Ge˜‐speaking tribes indicate that the Kaingang did not separate well from them. Most (96%) of the variability in the six polymorphic systems considered occur at the intrapopulational level. Am. J. Hum. Biol. 9:505–512, 1997. © 1997 Wiley‐Liss, Inc.

The American continent was the last to be occupied by modern humans, and native populations bear the marks of recent expansions, bottlenecks, natural selection, and population substructure. Here we investigate how this demographic history has shaped genetic variation at the strongly selected HLA loci. In order to disentangle the relative contributions of selection and demography process, we assembled a dataset with genome-wide microsatellites and HLA-A , -B , -C , and - DRB1 typing data for a set of 424 Native American individuals. We find that demographic history explains a sizeable fraction of HLA variation, both within and among populations. A striking feature of HLA variation in the Americas is the existence of alleles which are present in the continent but either absent or very rare elsewhere in the world. We show that this feature is consistent with demographic history (i.e., the combination of changes in population size associated with bottlenecks and subsequent population expansions). However, signatures of selection at HLA loci are still visible, with significant evidence selection at deeper timescales for most loci and populations, as well as population differentiation at HLA loci exceeding that seen at neutral markers.

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What is already known about this topic?  The multifactorial autoimmune blistering skin disease pemphigus foliaceus presents a genetic susceptibility component that is not fully understood.  Although pemphigus foliaceus is rare worldwide, it reaches the prevalence of 1.5% to 3% in some regions of Brazil, the highest ever reported for an autoimmune disease.  LncRNA polymorphisms have been associated with some complex diseases but were not yet studied in any form of pemphigus. What does this study add?  Genetic variation of lncRNA may influence susceptibility to pemphigus foliaceus via its effect on lncRNA structure, on transcription of nearby genes, and on microRNA-lncRNA interactions.