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      HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

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          Abstract

          Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I ( HLA-A, -B, -C), and class II ( HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/− B and -DRB1/− DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations.

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          Most cited references69

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          Arlequin (version 3.0): An integrated software package for population genetics data analysis

          Arlequin ver 3.0 is a software package integrating several basic and advanced methods for population genetics data analysis, like the computation of standard genetic diversity indices, the estimation of allele and haplotype frequencies, tests of departure from linkage equilibrium, departure from selective neutrality and demographic equilibrium, estimation or parameters from past population expansions, and thorough analyses of population subdivision under the AMOVA framework. Arlequin 3 introduces a completely new graphical interface written in C++, a more robust semantic analysis of input files, and two new methods: a Bayesian estimation of gametic phase from multi-locus genotypes, and an estimation of the parameters of an instantaneous spatial expansion from DNA sequence polymorphism. Arlequin can handle several data types like DNA sequences, microsatellite data, or standard multi-locus genotypes. A Windows version of the software is freely available on http://cmpg.unibe.ch/software/arlequin3.
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            Gene map of the extended human MHC.

            The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.
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              MHC heterozygosity confers a selective advantage against multiple-strain infections.

              Genetic heterozygosity is thought to enhance resistance of hosts to infectious diseases, but few tests of this idea exist. In particular, heterozygosity at the MHC, the highly polymorphic loci that control immunological recognition of pathogens, is suspected to confer a selective advantage by enhancing resistance to infectious diseases (the "heterozygote advantage" hypothesis). To test this hypothesis, we released mice into large population enclosures and challenged them with multiple strains of Salmonella and one of Listeria. We found that during Salmonella infections with three avirulent strains, MHC heterozygotes had greater survival and weight than homozygotes (unlike sham controls), and they were more likely to clear chronic Salmonella infection than homozygotes. In laboratory experiments, we found that MHC heterozygosity enhanced the clearance of multiple-strain Salmonella infections. Yet, contrary to what is widely assumed, the benefits of heterozygosity were due to resistance being dominant rather than overdominant, i.e., heterozygotes were more resistant than the average of parental homozygotes, but they were not more resistant than both. The fact that MHC heterozygotes were more resistant to infection and had higher fitness than homozygotes provides a functional explanation for MHC-disassortative mating preferences.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                23 September 2013
                : 8
                : 9
                : e74442
                Affiliations
                [1 ]Department of Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
                [2 ]HLA Laboratory, The American Red Cross Northeast Division, Dedham, Massachusetts, United States of America
                [3 ]Molecular Genetics Laboratory, National School of Anthropology and History, Mexico City, Mexico
                [4 ]Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
                [5 ]Tissue Engineering, Cell Therapy and Regenerative Medicine Research Unit, Instituto Nacional de Rehabilitación, Mexico City, Mexico
                [6 ]Laboratory of Genomics, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
                [7 ]Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
                [8 ]Department of Pathology, Stanford University, Stanford, California, United States of America
                [9 ]Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
                University of Hawaii Manoa, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JZ EJY NY RB JG MFV GVA TSRR. Performed the experiments: NY TL SA MO ACL. Analyzed the data: JZ EJY NY JG JGM MFV RB VAA. Contributed reagents/materials/analysis tools: JZ NY SA MO MY RB VAA TL. Wrote the paper: JZ TSRR EJY JG RB VAA.

                Article
                PONE-D-13-28292
                10.1371/journal.pone.0074442
                3781075
                24086347
                a50a6582-7e25-4d94-b5df-17712ea9ac57
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 June 2013
                : 31 July 2013
                Page count
                Pages: 15
                Funding
                No current external funding sources for this study.
                Categories
                Research Article

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