Genome Biol Evol. 2014 Mar;6(3):551-8.

Global footprints of purifying selection on Toll-like receptor genes primarily associated with response to bacterial infections in humans.

Souvik Mukherjee1,2*, Debdutta Ganguli1, Partha P. Majumder1

1National Institute of BioMedical Genomics, Kalyani,West Bengal, India

2BioMedical Genomics Centre, Kolkata,West Bengal, India

*Corresponding Author: E-mail: sm2.bmgc@nibmg.ac.in, callsouvik@gmail.com

 

ABSTRACT:

Toll-like receptors (TLRs) are directly involved in host-pathogen interactions. Polymorphisms in these genes are associated with susceptibility to infectious diseases. To understand the influence of environment and pathogen diversity on the evolution of TLR genes, we have undertaken a large-scale population-genetic study. Our study included two hunter-gatherer tribal populations and one urbanized nontribal population fromIndia with distinct ethnicities (n = 266) and 14 populations inhabiting four different continents (n = 1,092). From the data on DNA sequences of cell-surface TLR genes, we observed an excess of rare variants and a large number of low frequency haplotypes in each gene. Nonsynonymous changes were few in every population and the commonly used statistical tests for detecting natural selection provided evidence of purifying selection. The evidence of purifying selection acting on the cell-surface TLRs of the innate immune system is not consistent with Haldane’s theory of coevolution of immunity genes, at least of innate immunity genes, with pathogens. Our study provides evidence that genes of the cell-surface TLRs, that is, TLR2 and TLR4, have been so optimized to defend the host against microbial infections that new mutations in these genes are quickly eliminated.

PMID: 24554585

 

Supplementary

In another recent publication, “Discovery of high frequencies of the Gly-Ile haplotype of TLR4 in Indian populations requires reformulation of the evolutionary model of its maintenance” (Infect Genet Evol. 2013 Oct;19:223-5; PMID:23892373) we have reported for the first time, the presence of high to moderate frequencies of the Gly–Ile haplotype across Indian populations. 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. Our findings contradict previous reports that claimed the absence of this haplotype in Asia and America (Ferwerda et al., 2007, 2008; Plantinga et al., 2012). Our finding is at variance with the prevailing model that is used to explain the evolutionary maintenance of polymorphisms in TLR4. The prevalent model to explain the distribution of the Gly–Ile haplotype (Ferwerda et al., 2007, 2008; Plantinga et al., 2012) needs to be reformed, considering its presence in both the pre- and post-agricultural populations in India.

fig1Fig 1: Average Heterozygosity Values of the TLR2 and TLR4 Genes in World Populations


 

fig2Fig 2: The Global Distribution of TLR4 Asp299Gly/Thr399Ile Haplotype


  

fig3

fig3-2Fig 3: Extended Haplotype Homozygosity Patterns for Both the TLR2 and TLR4 Genes in the 14 world Populations Included in the 1000 Genomes Project.

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