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Haplotype structure and positive selection at TLR1

NCJ Number
European Journal of Human Genetics Volume: 22 Dated: 2014 Pages: 551-557
Date Published
7 pages

This paper reports on a research study that had the main goal of adding a global perspective to knowledge of variation at TLR1, a gene previously associated with the risk of leprosy, sepsis, and other diseases; the authors’ primary site of research interest was the functional amino acid, rs5743618.


Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T>G(p.(Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFκB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, the authors have typed all 7 high-frequency missense variants (>5 percent in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. The authors have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene. (Publisher Abstract Provided)

Date Published: January 1, 2014