A candidate tolerance gene identified in a natural population of field voles (Microtus agrestis)

Abstract

The animal immune response has hitherto been viewed primarily in the context of resistance only. However, individuals can also employ a tolerance strategy to maintain good health in the face of ongoing infection. To shed light on the genetic and physiological basis of tolerance, we use a natural population of field voles, Microtus agrestis, to search for an association between the expression of the transcription factor Gata3, previously identified as a marker of tolerance in this system, and polymorphism in 84 immune and nonimmune genes. Our results show clear evidence for an association between Gata3 expression and polymorphism in the Fcer1a gene, with the explanatory power of this polymorphism being comparable to that of other nongenetic variables previously identified as important predictors of Gata3 expression. We also uncover the possible mechanism behind this association using an existing protein-protein interaction network for the mouse model rodent, Mus musculus, which we validate using our own expression network for M. agrestis. Our results suggest that the polymorphism in question may be working at the transcriptional level, leading to changes in the expression of the Th2-related genes, Tyrosine-protein kinase BTK and Tyrosine-protein kinase TXK, and hence potentially altering the strength of the Th2 response, of which Gata3 is a mediator. We believe our work has implications for both treatment and control of infectious disease. K E Y W O R D Sdisease ecology, eco-immunology, Fcer1a, Gata3, immune strategy

Decomposing variation in immune response in a wild rodent population

“…subsets of animals that appear similar but respond more strongly to stimulation than others. Our own recent work, where we found an association between polymorphism in a single gene and a marker of a more tolerant immune response 27 , is an example of such genetic variation in immune response. Further supporting this hypothesis, here, we found more divergent markers among juvenile voles than mature voles.…”

“…Each site contained a trapping grid of regularly spaced traps (at approx. 5 m intervals) and was also used for other components of a larger field study (for more details see Wanelik et al 27 ).…”

Effects of an IgE receptor polymorphism acting on immunity, susceptibility to infection and reproduction in a wild rodent

“…So, in order to confirm these results, linear mixed effects models (LMMs), including a random term for assay plate number, were run for those immune genes for which expression appeared to be associated with haplotype (q ≤ 0.1). Immune gene expression variables were also Yeo-Johnson transformed (Yeo & Johnson, 2000) to achieve more normal and homoscedastic residuals (as in Wanelik et al 2018). Genotype was coded as the presence or absence of the GC haplotype, previously identified as being of interest .…”

“…This combined measure of macroparasite burden was modelled using the hapassoc package. See Jackson et al (2014) and Wanelik et al (2018) for full details of this approach. As microparasite infection status (infected or not) was assessed multiple times for the majority of individuals in the longitudinal component of the study (mean = 2.8; range = 1-11), a generalised linear mixed-effects model (GLMM) with a binomial error distribution and a random term for individual, was used to test for an association between Fcer1a haplotype and the probability of an individual being infected with a microparasite.…”

“…Most notably, variability in the genes of the Major Histocompatibility Complex has been associated with resistance to intestinal nematodes in domestic sheep (Paterson, Wilson, & Pemberton, 1998) and with resistance to malaria, hepatitis, and AIDS in humans (Carrington et al, 1999;Hill et al, 1991;Thursz, Thomas, Greenwood, & Hill, 1997). The role of polymorphism elsewhere in the genome, for shaping immune phenotype, has also been studied (Turner, Begon, Jackson, & Paterson, 2012;Wanelik et al, 2018). However, in the vast majority of these studies, genotype by sex interactions were not considered.…”