Discovery of high frequencies of the Gly-Ile haplotype of TLR4 in Indian populations requires reformulation of the evolutionary model of its maintenance

摘要

The Out-of-Africa migration of modern humans has led to the evolution of immunity genes in general, particularly those related to direct host-pathogen interactions. The Toll-like receptor 4 (TLR4) is one such cell-surface pattern recognition receptor that has been associated with susceptibility and resistance to Gram-negative infections. In this report, we have studied the genetic variation in the TLR4 gene across pre- and post-agricultural populations in India. Two non-synonymous SNPs at the loci Asp299Gly and Thr399Ile are genotyped in 266 individuals from these populations. Previous studies have shown that specific alleles at these two loci are associated with inflammatory response and also claimed the complete absence of the Gly-Ile (double-mutated) haplotype in populations from Asia and America due to some evolutionary disadvantage owing to septic shock. Contrary to such claims, our study reports for the-first time, high (10%) to moderate (3-6%) frequencies of the Gly-Ile haplotype in one non-tribal and two tribal populations of India respectively. The presence of this haplotype in ancient tribal populations of India indicates the possibility of its important role in pathogen recognition or susceptibility to infections. Therefore, natural selection, not merely genetic drift, may have played an important role in shaping the frequency distribution of haplotypes at these two loci in TLR4. For a more global perspective, we have also estimated the frequency of this haplotype in all the 14 continental populations included in the 1000 Genomes Project. Our study provides direct evidence for the reformulation of existing models of evolutionary maintenance of these polymorphisms in the TLR4 gene.