Patterns of selective constraint on bovine toll-like receptor genes

Toll-like receptors (TLRs) are pattern-recognition molecules expressed by cells of the innate immune system and cells at the interface between the host and environment. They recognise the presence of pathogens and signal alarm to the host immune system. Polymorphisms in these molecules may explain a proportion of the variability in disease resistance seen in most species from Drosophila where they were first discovered to mammals such as livestock and man. Thus TLRs have the potential to be candidates for selectable markers for disease resistance that could be exploited by the breeding industry. Our consortium aims to directly link single nucleotide polymorphisms (SNPs) with functional consequences in the innate immune cells, dendritic cells. We are undertaking a SNP discovery approach for all 10 TLRs in cattle in relevant breeds by direct sequencing. By combining this with sequencing of TLRs in related bovid Species including sheep, goats and ibex and other more exotic Species, we aim to undertake a phylogenetic analysis to identify signatures of selection on the nucleotide sequences of bovid TLRs. We will then test their functional relevance by transfecting polymorphic variants and measuring the down-stream effects of ligand binding. We will present phylogenetic evidence that the evolutionary pressures on bovine TLR2 and TLR4 appear to have differed and will speculate on the possible reasons for this, and the consequences for the host. Our overall approach aims to identify SNPs with the most likely potential as markers for selecting animals with enhanced disease resistance.