Our data show that TLR1, and more specifically the nonsynonymous T1805G variant (I602S), is the genuine target of positive selection detected in the TLR10-TLR1-TLR6 gene cluster in Europeans. First, TLR1 is ~2 times more diverse in non-African than in African populations, a pattern not compatible with the African origin of modern humans...This pattern has been observed only once among the 323 genes (0.3%) sequenced by the Seattle SNP consortium. Thus, the increased diversity observed in TLR1 among non-Africans probably results from ongoing hitchhiking between the selected allele and neutral variation at linked sites. Second, the 1805G (602S) mutation presents the highest level of population differentiation (FST = 0.54) of all SNPs located in this gene cluster...Third, among the three nonsynonymous variants composing the haplotype identified as being under positive selection in Europeans (H34, see Figure S5), only the TLR1 1805G (602S) variant has a remarkable impairment effect on agonist-induced NF-κB activation, showing a decreased signaling by up to 60%...These findings are consistent with previous studies showing that, homozygous, and to a lesser extent heterozygous, individuals for the 1805G allele present impaired TLR1-mediated immune responses after whole blood stimulation ...Taken together, it is tempting to speculate that an attenuated TLR1-mediated signaling, and a consequently reduced inflammatory response, has conferred a selective advantage in Europeans - a scenario that would explain the very high frequency (51%) of the "hypo-responsiveness" T1805G mutation in Europe. This observation raises questions about the possible evolutionary conflict between developing optimal mechanisms of pathogen recognition by TLRs, and more generally PRRs, and avoiding an excessive inflammatory response that can be harmful for the host.

Labels: Genetics