Ancient polymorphism and functional variation in the primate MHC-DQA1 5' cis-regulatory region - PubMed (original) (raw)

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

Dagan A Loisel et al. Proc Natl Acad Sci U S A. 2006.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Incongruity of primate species tree and DQA1 promoter region gene tree. (A) Species tree of the nine species from which DQA1 promoter sequences were obtained. (B) The most probable DQA1 promoter tree topology from the Bayesian analysis, with posterior probabilities of branch support. Branch lengths for both trees are arbitrary. Species and gene tree were reconciled by using Page's method (38) for reconciling phylogenetic trees (69).

Fig. 2.

Fig. 2.

Transcription factor binding site motifs in the DQA1 proximal promoter in primates. Letters A–H refer to unique transcription factor binding site motifs, with the corresponding sequence represented above. W, NF-κB, S, J, X1, X2, and Y refer to binding sites identified in the DQA1 promoter (3, 11, 12). Branch lengths of the species phylogeny on the left (27, 28) are roughly proportional to the timeline indicated below it. MYA, million years ago.

Fig. 3.

Fig. 3.

Luciferase activity induced by baboon DQA1 promoter haplotypes in a transient transfection reporter assay. Bars represent luciferase activity of 12 different baboon DQA1 promoter constructs calculated as the ratio of firefly to Renilla (coreporter) luminescence. Error bars represent standard error of the mean estimated from three replicate experiments. Numbers on the x axis correspond to the unique baboon DQA1 promoter haplotypes, and “Empty” refers to the promoter-less pGL3 basic reporter construct.

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