The Molecular Origin and Consequences of Escape from miRNA Regulation by HLA-C Alleles
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Carrington-2011-The Molecular Origin.pdf
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2.22 MB
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Author(s)
O'hUigin, Colm
Kulkarni, Smita
Xu, Yunping
Deng, Zhihui
Kidd, Judith
Kidd, Kenneth
Gao, Xiaojiang
Carrington, Mary
Date Issued
September 2011
Journal
American Journal of Human Genetics
Publisher
Elsevier B.V.
Citation
O’hUigin, Colm et al. “The Molecular Origin and Consequences of Escape from miRNA Regulation by HLA-C Alleles.” The American Journal of Human Genetics 89 (2011): 424-431. © 2011 The American Society of Human Genetics.
Version
Final published version
Abstract
Differential expression of human leukocyte antigen C (HLA-C) allotypes is mediated by the binding of a microRNA, miR-148a, to the 3′ untranslated region of some, but not all, HLA-C alleles. The binding results in lower levels of HLA-C expression, which is associated with higher levels of HIV-1 viral load among infected individuals. The alternative set of HLA-C alleles has several substitutions in the miR-148a binding site that prevent binding and HLA-C downregulation; these high-expression alleles associate with control of HIV-1 viral load. We show that the common ancestor of all extant HLA-C alleles was suppressed by miR-148a. Substitutions that prevent miR-148a binding arose by a sequence exchange event between an HLA-C allele and an HLA-B (MIM 142830) allele of a B∗07-like lineage. The event occurred 3–5 million years ago, resulting in an HLA-C variant that escape from miR-148a downregulation. We present evidence suggesting that selection played a role in the successful spread of the HLA-C escape alleles, giving rise to 7 of the 14 extant HLA-C lineages. Notably, critical peptide and KIR binding residues of the escape variants have selectively converged to resemble the sequence of their inhibited counterparts, such that the inhibited and escape groupings differ primarily by their levels of expression.
MIT Department
Ragon Institute of MGH, MIT and Harvard
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DOI of Published Version
https://doi.org/10.1016/j.ajhg.2011.07.024
