Pathogen-mediated selection in the immune system of rodents : Exploring selection targets, functional effects and trade-offs

Sammanfattning: Pathogens cause disease and play an important role in shaping evolution of the host immune system. They create pressure on host immunity to evolve in numerous ways, most commonly by increasing divergence between species (positive selection) or increasing polymorphisms within a population (balancing selection). Especially with balancing selection, trade-offs between different traits, for example responses to different pathogens, are essential. Across five papers, questions related to what immune genes are under selection, how this translates to an effect on the immune response and what trade-offs occur, are addressed using rodents as study system. Paper I utilised genomes from 30 rodent species to identify signatures of positive selection in immune genes. In general, function of immune genes was a significant determinant for signs of positive selection. This effect was significant even after accounting for potential confounding factors like gene expression and protein-protein interactions. In Paper II, the focus is on a local population of bank voles in Sweden, to look for signatures of balancing selection in the complement system – a branch of innate immunity. One complement gene, FCNA, was found to be under strong balancing selection. In Paper III, FCNA polymorphism was linked to associations with natural infections of Borrelia afzelii, a common pathogen for bank voles. Papers IV and V look at how the immune response of bank voles of various genotypes differ on stimulation with B. afzelii and the human pathogen Streptococcus pyogenes, captured with transcriptome sequencing of spleen cells. In Paper IV, the analysis is focused on various genotypes of TLR2, an immune gene under balancing selection in bank voles and associated with infection prevalence of B. afzelii in the wild. A stimulation-specific effect of TLR2 on immune response was found, where the magnitude of immune response to B. afzelii, but not S. pyogenes, depends on TLR2 expression level in a TLR2 genotype-specific way. In Paper V, tradeoffs at the cis-regulatory level between the response to B. afzelii and S. pyogenes was tested by searching for polymorphisms where the alleles are expressed differently to these two stimulations. Abundant cis-regulatory variation for responses to the two bacteria was found, but there was no evidence for trade-offs. In summary, this work pushes our knowledge of what immune genes can be expected to be under pathogen-mediated selection, as heretofore understudied categories of immune function showed signs of selection. A novel basis – the combination of genotype and expression – was uncovered for functional effects of polymorphic genes. Finally, there was no evidence for trade-offs between responses to different pathogens. Investigating the nature of trade-offs in the immune system further would be necessary towards understanding the causes and consequences of pathogen-mediated selection.