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      Characterisation of major histocompatibility complex class IIa haplotypes in an island sheep population

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          Abstract

          The ovine MHC class IIa is known to consist of six to eight loci located in close proximity on chromosome 20, forming haplotypes that are typically inherited without recombination. Here, we characterise the class IIa haplotypes within the Soay sheep ( Ovis aries) on St. Kilda to assess the diversity present within this unmanaged island population. We used a stepwise sequence-based genotyping strategy to identify alleles at seven polymorphic MHC class IIa loci in a sample of 118 Soay sheep from four cohorts spanning 15 years of the long-term study on St. Kilda. DRB1, the most polymorphic MHC class II locus, was characterised first in all 118 sheep and identified six alleles. Using DRB1 homozygous animals, the DQA ( DQA1, DQA2 and DQA2-like) and DQB ( DQB1, DQB2 and DQB2-like) loci were sequenced, revealing eight haplotypes. Both DQ1/ DQ2 and DQ2/DQ2-like haplotype configurations were identified and a single haplotype carrying three DQB alleles. A test sample of 94 further individuals typed at the DRB1 and DQA loci found no exceptions to the eight identified haplotypes and a haplotype homozygosity of 21.3%. We found evidence of historic positive selection at DRB1, DQA and DQB. The limited variation at MHC class IIa loci in Soay sheep enabled haplotype characterisation but showed that no single locus could capture the full extent of the expressed variation in the region.

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          The online version of this article (10.1007/s00251-019-01109-w) contains supplementary material, which is available to authorized users.

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          Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1.

          The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II alpha beta heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
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            A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

            The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.
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              Evolution by the birth-and-death process in multigene families of the vertebrate immune system.

              Concerted evolution is often invoked to explain the diversity and evolution of the multigene families of major histocompatibility complex (MHC) genes and immunoglobulin (Ig) genes. However, this hypothesis has been controversial because the member genes of these families from the same species are not necessarily more closely related to one another than to the genes from different species. To resolve this controversy, we conducted phylogenetic analyses of several multigene families of the MHC and Ig systems. The results show that the evolutionary pattern of these families is quite different from that of concerted evolution but is in agreement with the birth-and-death model of evolution in which new genes are created by repeated gene duplication and some duplicate genes are maintained in the genome for a long time but others are deleted or become nonfunctional by deleterious mutations. We found little evidence that interlocus gene conversion plays an important role in the evolution of MHC and Ig multigene families.
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                Author and article information

                Contributors
                kara.dicks@gmail.com
                Journal
                Immunogenetics
                Immunogenetics
                Immunogenetics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0093-7711
                1432-1211
                22 February 2019
                22 February 2019
                2019
                : 71
                : 5
                : 383-393
                Affiliations
                [1 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Institute of Evolutionary Biology, School of Biological Sciences, , University of Edinburgh, ; Edinburgh, EH9 3FL UK
                [2 ]Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, EH26 OPZ UK
                Author information
                http://orcid.org/0000-0002-3764-4315
                Article
                1109
                10.1007/s00251-019-01109-w
                6525122
                30796497
                89a2c172-a4ca-422f-8073-51ea45dcf603
                © The Author(s) 2019

                OpenAccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 28 November 2018
                : 8 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: BB/J01446X/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: 731014KB
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Genetics
                major histocompatibility complex,soay sheep,haplotype,balancing selection
                Genetics
                major histocompatibility complex, soay sheep, haplotype, balancing selection

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