PMID- 34633459 OWN - NLM STAT- MEDLINE DCOM- 20220330 LR - 20220531 IS - 1537-1719 (Electronic) IS - 0737-4038 (Print) IS - 0737-4038 (Linking) VI - 39 IP - 1 DP - 2022 Jan 7 TI - Remarkably Low KIR and HLA Diversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the Centromeric KIR Region. LID - 10.1093/molbev/msab298 [doi] LID - msab298 AB - 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 (Ache); 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. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. FAU - Vargas, Luciana de Brito AU - Vargas LB AUID- ORCID: 0000-0002-9074-2010 AD - Programa de Pos-Graduacao em Genetica, Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR, Brazil. FAU - Beltrame, Marcia H AU - Beltrame MH AD - Programa de Pos-Graduacao em Genetica, Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR, Brazil. FAU - Ho, Brenda AU - Ho B AD - Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. FAU - Marin, Wesley M AU - Marin WM AD - Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. FAU - Dandekar, Ravi AU - Dandekar R AD - Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. FAU - Montero-Martin, Gonzalo AU - Montero-Martin G AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA. FAU - Fernandez-Vina, Marcelo A AU - Fernandez-Vina MA AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA. FAU - Hurtado, A Magdalena AU - Hurtado AM AD - School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA. FAU - Hill, Kim R AU - Hill KR AD - School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA. FAU - Tsuneto, Luiza T AU - Tsuneto LT AD - Departamento de Analises Clinicas, Universidade Estadual de Maringa, Maringa, PR, Brazil. FAU - Hutz, Mara H AU - Hutz MH AD - Departamento de Genetica, Instituto de Biociencias, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Salzano, Francisco M AU - Salzano FM AD - Departamento de Genetica, Instituto de Biociencias, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Petzl-Erler, Maria Luiza AU - Petzl-Erler ML AD - Programa de Pos-Graduacao em Genetica, Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR, Brazil. FAU - Hollenbach, Jill A AU - Hollenbach JA AD - Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. AD - Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. FAU - Augusto, Danillo G AU - Augusto DG AUID- ORCID: 0000-0001-5665-8547 AD - Programa de Pos-Graduacao em Genetica, Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR, Brazil. AD - Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. LA - eng GR - T32 GM067547/GM/NIGMS NIH HHS/United States GR - U19 NS095774/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Mol Biol Evol JT - Molecular biology and evolution JID - 8501455 RN - 0 (HLA Antigens) RN - 0 (Receptors, KIR) SB - IM MH - Alleles MH - Gene Frequency MH - Genetics, Population MH - *HLA Antigens/genetics MH - Haplotypes MH - Humans MH - Indians, South American/*genetics MH - Linkage Disequilibrium MH - *Receptors, KIR/genetics MH - Selection, Genetic PMC - PMC8763117 OTO - NOTNLM OT - evolution OT - high resolution OT - human leukocyte antigen OT - killer-cell immunoglobulin-like receptor OT - population EDAT- 2021/10/12 06:00 MHDA- 2022/03/31 06:00 PMCR- 2021/10/11 CRDT- 2021/10/11 12:26 PHST- 2021/10/12 06:00 [pubmed] PHST- 2022/03/31 06:00 [medline] PHST- 2021/10/11 12:26 [entrez] PHST- 2021/10/11 00:00 [pmc-release] AID - 6388041 [pii] AID - msab298 [pii] AID - 10.1093/molbev/msab298 [doi] PST - ppublish SO - Mol Biol Evol. 2022 Jan 7;39(1):msab298. doi: 10.1093/molbev/msab298.