Adaptation and Constraint at Toll-Like Receptors in Primates

Abstract

Frequent positive selection is a hallmark of genes involved in the adaptive immune system of vertebrates, but the incidence of positive selection for genes underlying innate immunity in vertebrates has not been well studied. The toll-like receptors (TLRs) of the innate immune system represent the first line of defense against pathogens. TLRs lie directly at the host-environment interface, and they target microbial molecules. Because of this, they might be subject to frequent positive selection due to coevolutionary dynamics with their microbial counterparts. However, they also recognize conserved molecular motifs, and this might constrain their evolution. Here, we investigate the evolution of the ten human TLRs in the framework of these competing ideas. We studied rates of protein evolution among primate species and we analyzed patterns of polymorphism in humans and chimpanzees. This provides a window into TLR evolution at both long and short timescales. We found a clear signature of positive selection in the rates of substitution across primates in most TLRs. Some of the implicated sites fall in structurally important protein domains, involve radical amino acid changes, or overlap with polymorphisms with known clinical associations in humans. However, within species, patterns of nucleotide variation were generally compatible with purifying selection, and these patterns differed between humans and chimpanzees and between viral and nonviral TLRs. Thus, adaptive evolution at TLRs does not appear to reflect a constant turnover of alleles and instead might be more episodic in nature. This pattern is consistent with more ephemeral pathogen-host associations rather than with long-term coevolution.

Naturally occurring Toll-like receptor 11 (TLR11) and Toll-like receptor 12 (TLR12) polymorphisms are not associated with Toxoplasma gondii infection in wild wood mice

“…Furthermore, in a bottlenecked population of New Zealand robin (Petroica australis rakiura), seven out of nine analysed TLRs were polymorphic, with two to five amino acid variants each (Grueber et al, 2012). This relatively high genetic diversity observed in wildlife is in agreement with human studies (Mukherjee et al, 2009;Wlasiuk and Nachman, 2010), and shows that there is the potential for parasite-mediated selection to act on…”

Molecular evolution of vertebrate Toll-like receptors: Evolutionary rate difference between their leucine-rich repeats and their TIR domains

“…We can conclude that the LRR domains in most TLRs evolved faster than did the TIR domain. This indicates stronger purifying selection on the TIR domain than the LRR domain and thus greater functional constraint on the former than on the latter, as are TLRs from primates (Hughes and Piontkivska, 2008;Wlasiuk and Nachman, 2010). The evolutionary rates of the LRR domains differ significantly among the members (Fig.…”

Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

“…Furthermore, the Toll-like receptor 4 (TLR4) gene contained a 1-bp deletion, which generates a premature stop codon in its third exon in all three macaques (Supplementary Section 6). TLR4 has been reported to have been under positive selection in Old World primates 12 . Notably, some human disease-related genes also contain frameshifts in their macaque homologs.…”