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Evolutionary history of DLA class II haplotypes in canine diabetes mellitus through single nucleotide polymorphism genotyping
University of Queensland.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
University of Sydney.
2010 (English)In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 75, no 3, 218-226 p.Article in journal (Refereed) Published
Abstract [en]

Strong linkage disequilibrium (LD) is a characteristic of the major histocompatibility complex (MHC) region, as well as the genome in general in dogs as a consequence of demographic changes with domestication. Disease association studies of MHC haplotypes may be affected by high LD and the resultant shared genetic backgrounds of haplotypes giving associations with linked but non-causative mutations, and also by convergent haplotypes, in which combinations of alleles have arisen independently. This study provides preliminary tools for dog leukocyte antigen (DLA) class II haplotype analysis with 102 single nucleotide polymorphisms (SNPs) identified in 14.6 kb and genotyping of 20 of these SNPs to tag haplotypes in 60 dogs with diabetes mellitus and in 49 non-diabetic dogs. The pattern of LD and analysis of SNP patterns indicated combinations of exon 2 alleles have arisen through both recombination and convergence. For exon 2 haplotypes associated with susceptibility or protection from diabetes mellitus, a region of fixed differences in SNPs across the DQ region was observed, suggesting a region outside exon 2 may be implicated in disease association. Four new DQB1 promoter alleles restricted to diabetic dogs were identified, as well as a substitution difference in the X1 box of the DQB1 promoter that will potentially modify the effect of the protective haplotypes within diabetic dogs

Place, publisher, year, edition, pages
2010. Vol. 75, no 3, 218-226 p.
Keyword [en]
canine major histocompatibility complex, diabetes mellitus, DLA, haplotypes
National Category
Genetics
Research subject
Biology with specialization in Evolutionary Genetics
Identifiers
URN: urn:nbn:se:uu:diva-122009DOI: 10.1111/j.1399-0039.2009.01426.xISI: 000274336000004PubMedID: 20047645OAI: oai:DiVA.org:uu-122009DiVA: diva2:308090
Available from: 2010-04-05 Created: 2010-04-05 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Evolution of MHC Genes and MHC Gene Expression
Open this publication in new window or tab >>Evolution of MHC Genes and MHC Gene Expression
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polymorphism in coding regions and regions controlling gene expression is the major determinant of adaptive differences in natural populations. Genes of the major histocompatibility complex (MHC) possess a high level of genetic variation, which is maintained by selection over long coalescence times. MHC genes encode antigen-presenting molecules in the adaptive immune system, which protects the host from infectious diseases. However, MHC molecules may also present self-peptides and for most autoimmune diseases there is a genetic factor associated with the MHC.

MHC genes have been used to learn about the interplay of selection and historical population events. In domestic dogs and their progenitor, the wolf, I explored factors associated with domestication and breed formation and their influence not only on MHC coding regions but also on the haplotypic structure of the class II region. Polymorphism and strong selection was demonstrated in the proximal promoters of MHC genes in dogs and wolves. Hence, genetic variation associated with MHC gene expression may have at least equal importance for a well functioning immune system. Associations between promoter sequences and particular coding alleles suggested allele-specific expression patterns. SNP haplotypes of the MHC class II region revealed ancestral as well as convergent haplotypes, in which combinations of alleles are kept by selection. Interestingly, weaker allelic associations were found between different genes and between coding regions and promoters in dogs compared to wolves. Potentially, this could cause insufficient defense against infections and predispose dogs to autoimmune diseases. For example, I identified a site in the promoter region that showed a consistent difference between haplotypes conferring susceptibility and protection to diabetes in dogs, which should be investigated further.

Furthermore, I investigated how selection and demographic changes associated with glacial and inter-glacial periods have affected MHC variation in European hedgehogs and extended the prevailing knowledge concerning their population history.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 736
Keyword
major histocompatibilty complex, dog leukocyte antigen, balancing selection, linkage disequilibrium, promoter, diabetes mellitus, Canis familiaris, Canis lupus, Erinaceus europaeus, Erinaceus concolor
National Category
Genetics
Research subject
Biology with specialization in Evolutionary Genetics
Identifiers
urn:nbn:se:uu:diva-122011 (URN)978-91-554-7792-9 (ISBN)
Public defence
2010-05-21, Evolutionsbiologiskt centrum, Zootissalen, Villavägen 9, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-29 Created: 2010-04-05 Last updated: 2010-04-29Bibliographically approved

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