Genomic analyses of Tlr2 in voles
Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to primarily target ligand-binding domains and affect the specificity of recognition of different pathogens. Well-established examples of selection for PRR specificity are however rare. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection, and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate if Tlr2 is an example of selection for ligand-binding specificity, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the evolutionarily distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is ~4.6 kb upstream of the Tlr2 coding sequence, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via Tlr2-signaling rather than on polymorphisms affecting Tlr2 ligand-binding specificity.
Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to primarily target ligand-binding domains and affect the specificity of recognition of different pathogens. Well-established examples of selection for PRR specificity are however rare. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection, and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate if Tlr2 is an example of selection for ligand-binding specificity, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the evolutionarily distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is ~4.6 kb upstream of the Tlr2 coding sequence, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via Tlr2-signaling rather than on polymorphisms affecting Tlr2 ligand-binding specificity.
LUND UNIVERSITY