Characterization of Pathogen-Driven Selection at B4galnt2 in House Mice

B4galnt2 is a glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice: the wild type allele C57BL/6J, directs intestinal expression of B4galnt2 while the alternative allele RIIIS/J drives expression in blood vessels, which leads to a bleeding disorder. Previous studies showed that alternative B4galnt2 alleles are subject to long-term balancing selection in mice and that variation in B4galnt2 expression influences host-microbe interactions. This suggests that the cost of prolonged bleeding in RIIIS/J allele-bearing mice might be outweighed by benefits associated with resistance against gastrointestinal pathogens. To understand and characterize the potential pathogen-driven selection acting on B4galnt2 in the wild, I first developed a mathematical model based on an evolutionary game framework. In particular, I focused on heterozygous mice, which express B4galnt2 in both blood vessels and the gastrointestinal tract. By comparing simulated to natural populations, I found that the genotype frequencies observed in nature can be produced by pathogen-driven selection when (i) the fitness cost of bleeding is roughly half that of infection and (ii) both heterozygotes and RIIIS/J homozygotes are protected against infection. The resistance of the heterozygote individuals indicates that a dominant protective function of the RIIIS/J allele is more likely than a protective loss of intestinal expression. Furthermore, I aimed to identify potential pathogens driving the selection at B4galnt2 by sampling and phenotyping over 200 newly collected mice from Southern France, where an intermediate frequency of the RIIIS/J allele is present. Through the multilayer analysis of genetic patterns, signs of inflammation, and intestinal microbial communities, I could identify several bacterial genera to patterns consistent with genotype-dependent host-pathogen.