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PMID: 17053068 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Ancient polymorphism and functional variation in the primate MHC-DQA1 5' cis-regulatory region.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 44 ·2006-10-31 ·Pages 16331-6

Loisel DA, Rockman MV, Wray GA, Altmann J, Alberts SC

Abstract

Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5' proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5' proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.

MeSH Terms
Animals Binding Sites HLA-DQ Antigens/genetics,metabolism Haplotypes/genetics Humans Molecular Sequence Data Phylogeny Polymorphism, Genetic/genetics Primates/genetics Promoter Regions, Genetic/genetics Protein Binding Regulatory Sequences, Nucleic Acid Transcription Factors/metabolism Transcription, Genetic/genetics
Chemicals
HLA-DQ Antigens Transcription Factors
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Loisel Dagan A
Department of Biology, Duke University, Durham, NC 27705, USA. dagan.loisel@duke.edu
Rockman Matthew V
Wray Gregory A
Altmann Jeanne
Alberts Susan C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0607662103
Email
dagan.loisel@duke.edu
Published
2006-10-31
Epub
2006-00-19
Pages
16331-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1637582
Subset
IM
Databases
GENBANK
DQ924453, DQ924454, DQ924455, DQ924456, DQ924457, DQ924458, DQ924459, DQ924460, DQ924461, DQ924462, DQ924463, DQ924464, DQ924465, DQ924466, DQ924467, DQ924468, DQ924469, DQ924470, DQ924471, DQ924472, DQ924473, DQ924474, DQ924475, DQ924476, DQ924477, DQ924478, DQ924479, DQ924480, DQ924481, DQ924482, DQ924483, DQ924484, DQ924485, DQ924486, DQ924487, DQ924488
External Links
PubMed source DOI: 10.1073/pnas.0607662103 PMC Full Text View journal details
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