English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Thesis

Characterization of pathogen-driven selection at B4galnt2 in house mice

MPS-Authors
/persons/resource/persons145210

Vallier,  Marie
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

/persons/resource/persons56580

Baines,  John F.
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

Locator
There are no locators available
Fulltext (public)
There are no public fulltexts available
Supplementary Material (public)
There is no public supplementary material available
Citation

Vallier, M. (2017). Characterization of pathogen-driven selection at B4galnt2 in house mice. PhD Thesis, Christian-Albrechts-Universität zu Kiel, Kiel.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002E-0DC9-8
Abstract
B4galnt2 is a blood group-related glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice. The wild type allele, found e.g. in the C57BL/6J laboratory mouse strain, directs intestinal expression of B4galnt2, which is the pattern observed among vertebrates, including humans. An alternative allele class found in the RIIIS/J strain and other mice instead drives expression in blood vessels, which leads to a phenotype similar to type 1 von Willebrand disease (VWD), a common human 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 in the intestine. 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. However, the conditions under which such trade-offs could lead to the long-term maintenance of disease-associated variation at B4galnt2 are unclear. 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 with a modified Wright-Fisher process, adjusted to implement diploid individuals. 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. However, the nature of the dominant protective function of the RIIIS/J allele remains unknown, as the model suggests that the associated vascular expression is not necessarily linked to the pathogen resistance. 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 associate several bacterial genera to patterns consistent with genotype-dependent host-pathogen interaction. One genus in particular, Morganella, is a likely candidate as it is a well-known opportunistic pathogen and its abundance, prevalence and activity patterns are associated with increased inflammation in mice with intestinal expression of B4galnt2. Finally, I could identify the relevant species of Morganella, which represents a new subspecies of the Morganella morganii group, and possesses virulence-related genes absent from the other Morganella species, which may account for its potential to drive selection at B4galnt2 via genotype-dependent host-pathogen interactions. In conclusion, my work provides new insights into the potential evolutionary dynamics taking place at B4galnt2 in wild populations of house mice, showing that pathogen-driven selection is a likely cause for the maintenance of both B4galnt2 alleles in the wild. Moreover, my work could be applied beyond the scope of murine glycosyltransferases, as the methods that I developed can easily be generalized to other biological models.