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MHC promoter polymorphism in grey wolves and domestic dogs.
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi. (Conservation Genetics)
2005 (English)In: Immunogenetics, ISSN 0093-7711, Vol. 57, no 3-4, 267-72 p.Article in journal (Refereed) Published
Abstract [en]

A functional immune system requires a tight control over major histocompatibility complex (MHC) gene transcription, as the abnormal MHC expression patterns of severe immunodeficiency and autoimmune diseases demonstrate. Although the regulation of MHC expression has been well documented in humans and mice, little is known in other species. In this study, we detail the level of polymorphism in wolf and dog MHC gene promoters. The promoter regions of the DRB, DQA and DQB locus were sequenced in 90 wolves and 90 dogs. The level of polymorphism was high in the DQB promoters, with variation found within functionally relevant regions, including binding sites for transcription factors. Clear associations between DQB promoters and exon 2 alleles were noted in wolves, indicating strong linkage disequilibrium in this region. Low levels of polymorphism were found within the DRB and DQA promoter regions. However, a variable site was identified within the T box, a TNF-alpha response element, of the DQA promoter. Furthermore, we identified a previously unrecognised 18-base-pair deletion within exon 1 of the DQB locus.

Place, publisher, year, edition, pages
2005. Vol. 57, no 3-4, 267-72 p.
Keyword [en]
Alleles, Animals, Base Sequence, Comparative Study, DNA/genetics, Dogs/*genetics/*immunology, Exons, Linkage Disequilibrium, Major Histocompatibility Complex, Molecular Sequence Data, Polymorphism; Genetic, Promoter Regions (Genetics), Research Support; Non-U.S. Gov't, Sequence Deletion, Sequence Homology; Nucleic Acid, Species Specificity, Variation (Genetics), Wolves/*genetics/*immunology
National Category
URN: urn:nbn:se:uu:diva-76387PubMedID: 15900498OAI: oai:DiVA.org:uu-76387DiVA: diva2:104299
Available from: 2006-03-02 Created: 2006-03-02 Last updated: 2011-01-11
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 736
major histocompatibilty complex, dog leukocyte antigen, balancing selection, linkage disequilibrium, promoter, diabetes mellitus, Canis familiaris, Canis lupus, Erinaceus europaeus, Erinaceus concolor
National Category
Research subject
Biology with specialization in Evolutionary Genetics
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)
Available from: 2010-04-29 Created: 2010-04-05 Last updated: 2010-04-29Bibliographically approved

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