Cytokine gene polymorphism and parasite susceptibility in free-living rodents: Importance of non-coding variants

Associations between genetic variants and susceptibility to infections have long been studied in free-living hosts so as to infer the contemporary evolutionary forces that shape the genetic polymorphisms of immunity genes. Despite extensive studies of proteins interacting with pathogen-derived ligands, such as MHC (major histocompatilbility complex) or TLR (Toll-like receptors), little is known about the efferent arm of the immune system. Cytokines are signalling molecules that trigger and modulate the immune response, acting as a crucial link between innate and adaptive immunity. In the present study we investigated how genetic variation in cytokines in bank voles Myodes glareolus affects their susceptibility to infection by parasites (nematodes: Aspiculuris tianjensis, Heligmosomum mixtum, Heligmosomoides glareoli) and microparasites (Cryptosporidium sp, Babesia microti, Bartonella sp.). We focused on three cytokines: tumour necrosis factor (TNF), lymphotoxin alpha (LTα), and interferon beta (IFNβ1). Overall, we identified four single nucleotide polymorphisms (SNPs) associated with susceptibility to nematodes: two located in LTα and two in IFNβ1. One of those variants was synonymous, another located in an intron. Each SNP associated with parasite load was located in or next to a codon under selection, three codons displayed signatures of positive selection, and one of purifying selection. Our results indicate that cytokines are prone to parasite-driven selection and that non-coding variants, although commonly disregarded in studies of the genetic background of host-parasite co-evolution, may play a role in susceptibility to infections in wild systems.