02051nas a2200361   4500000000100000008004100001260001300042653001200055653001700067653001500084653001100099653002700110653002300137653001500160653003600175653002800211653002300239653002500262100001900287700001400306700001200320700001300332700001200345700001100357700001500368700001200383700001300395245005600408300001000464490000700474520119400481022001401675       2014                            d  c2014 Apr10aAlleles10aGenetic Loci10aHaplotypes10aHumans10aLinkage Disequilibrium10aMutation, Missense10aNF-kappa B10aPolymorphism, Single Nucleotide10aReceptors, Cell Surface10aSelection, Genetic10aToll-Like Receptor 11 aHeffelfinger C1 aPakstis A1 aSpeed W1 aClark AP1 aHaigh E1 aFang R1 aFurtado MR1 aKidd KK1 aSnyder M00aHaplotype structure and positive selection at TLR1.  a551-70 v223 a<p>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, we have typed all 7 high-frequency missense variants (>5% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We 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. </p>  a1476-5438