Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Evolution of MHC Genes and MHC Gene Expression
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
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. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 736
Keywords [en]
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: urn:nbn:se:uu:diva-122011ISBN: 978-91-554-7792-9 (print)OAI: oai:DiVA.org:uu-122011DiVA, id: diva2:309254
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
List of papers
1. Understanding the phylogeographic patterns of European hedgehogs, Erinaceus concolor and E. europaeus using the MHC.
Open this publication in new window or tab >>Understanding the phylogeographic patterns of European hedgehogs, Erinaceus concolor and E. europaeus using the MHC.
2005 (English)In: Heredity, ISSN 0018-067X, Vol. 95, no 1, p. 84-90Article in journal (Refereed) Published
Abstract [en]

The genome of the European hedgehog, Erinaceus concolor and E. europaeus, shows a strong signal of cycles of restriction to glacial refugia and postglacial expansion. Patterns of expansion, however, differ for mitochondrial DNA (mtDNA) and preliminary analysis of nuclear markers. In this study, we determine phylogeographic patterns in the hedgehog using two loci of the major histocompatibility complex (MHC), isolated for the first time in hedgehogs. These genes show long persistence times and high polymorphism in many species because of the actions of balancing selection. Among 84 individuals screened for variation, only two DQA alleles were identified in each species, but 10 DQB alleles were found in E. concolor and six in E. europaeus. A strong effect of demography on patterns of DQB variability is observed, with only weak evidence of balancing selection. While data from mtDNA clearly subdivide both species into monophyletic subgroups, the MHC data delineate only E. concolor into distinct subgroups, supporting the preliminary findings of other nuclear markers. Together with differences in variability, this suggests that the refugia history and/or expansion patterns of E. concolor and E. europaeus differ.

Keywords
Animals, DNA; Mitochondrial/*genetics, Europe, Genome, Geography, Hedgehogs/*classification/*genetics, Major Histocompatibility Complex, Movement, Phylogeny, Population Dynamics, Research Support; Non-U.S. Gov't, Selection (Genetics)
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-76386 (URN)16077505 (PubMedID)
Available from: 2006-03-02 Created: 2006-03-02 Last updated: 2018-02-22
2. MHC promoter polymorphism in grey wolves and domestic dogs.
Open this publication in new window or tab >>MHC promoter polymorphism in grey wolves and domestic dogs.
2005 (English)In: Immunogenetics, ISSN 0093-7711, Vol. 57, no 3-4, p. 267-72Article 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.

Keywords
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
Genetics
Identifiers
urn:nbn:se:uu:diva-76387 (URN)15900498 (PubMedID)
Available from: 2006-03-02 Created: 2006-03-02 Last updated: 2011-01-11
3. Allelic combinations of promoter and exon 2 in DQB1 in dogs and wolves
Open this publication in new window or tab >>Allelic combinations of promoter and exon 2 in DQB1 in dogs and wolves
2008 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 67, no 1, p. 76-84Article in journal (Refereed) Published
Abstract [en]

Polymorphism of PBRs of the major histocompatibility complex (MHC) genes is well recognized, but the polymorphism also extends to proximal promoter regions. Examining DQB1 variability in dogs and wolves, we identified 7 promoter variants and 13 exon 2 alleles among 89 dogs, including a previously unknown DQB1 exon 2 allele, and 8 promoter variants and 9 exon 2 alleles among 85 wolves. As expected from previous studies and from a close chromosomal location, strong linkage disequilibrium was demonstrated in both wolves and dogs by having significantly fewer promoter/exon 2 combinations than expected from simulations of randomized data sets. Interestingly, we noticed weaker haplotypic associations in dogs than in wolves. Dogs had twice as many promoter/exon 2 combinations as wolves and an almost 2-fold difference in the number of exon 2 alleles per promoter variant. This difference was not caused by an admixture of breeds in our group of dogs because the high ratio of observed to expected number of haplotypes persisted within a single dog breed, the German Shepherd. Ewens-Watterson tests indicated that both the promoter and exon 2 are under the balancing selection, and both regions appear to be more recently derived in the dog than in the wolf. Hence, although reasons for the differences are unknown, they may relate to altered selection pressure on patterns of expression. Deviations from normal MHC expression patterns have been associated with autoimmune diseases, which occur frequently in several dog breeds. Further knowledge about these deviations may help us understand the source of such diseases.

Keywords
dog, DLA, DQB1, MHC, promoter, linkage disequilibrium, wolf
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-109175 (URN)10.1007/s00239-008-9126-0 (DOI)000258088000008 ()
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
4. Evolutionary history of DLA class II haplotypes in canine diabetes mellitus through single nucleotide polymorphism genotyping
Open this publication in new window or tab >>Evolutionary history of DLA class II haplotypes in canine diabetes mellitus through single nucleotide polymorphism genotyping
2010 (English)In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 75, no 3, p. 218-226Article 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

Keywords
canine major histocompatibility complex, diabetes mellitus, DLA, haplotypes
National Category
Genetics
Research subject
Biology with specialization in Evolutionary Genetics
Identifiers
urn:nbn:se:uu:diva-122009 (URN)10.1111/j.1399-0039.2009.01426.x (DOI)000274336000004 ()20047645 (PubMedID)
Available from: 2010-04-05 Created: 2010-04-05 Last updated: 2017-12-12Bibliographically approved
5. Linkage disequilibrium and haplotype patterns of the MHC class II region - a comparison between wolves and dogs.
Open this publication in new window or tab >>Linkage disequilibrium and haplotype patterns of the MHC class II region - a comparison between wolves and dogs.
(English)Manuscript (preprint) (Other academic)
Keywords
major histocompatibility complex, MHC, DLA, linkage disequilibrium, haplotype, wolves, dogs
National Category
Genetics
Research subject
Biology with specialization in Evolutionary Genetics
Identifiers
urn:nbn:se:uu:diva-122010 (URN)
Available from: 2010-04-05 Created: 2010-04-05 Last updated: 2010-04-07

Open Access in DiVA

fulltext(761 kB)943 downloads
File information
File name FULLTEXT01.pdfFile size 761 kBChecksum SHA-512
03e53658bca76745592e351fe875349f6abc996007a188e6566ed508dcbe5f6d7a932d8ad397fbec4370c7fe5f929da94b64fad7d474d9e6f6bb79c0d43e6276
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Berggren Bremdal, Karin
By organisation
Evolutionary Biology
Genetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 943 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1195 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf