Zusammenfassung
B4galnt2 is a blood group-related glycosyltransferase expressed in the gastrointestinal
(GI) tract of most mammals. However, cis-regulatory variation at B4galnt2 in house
mice leads to different tissue-specific expression patterns affecting intestinal epithelium
and vascular endothelium according to the alleles present in the direct upstream region
(”C57BL6/J”’ or ”‘RIIIS/J” allele, respectively). Blood vessel expression of B4galnt2
leads to a phenotype in mice very similar to a common human bleeding disorder, von
Willebrand disease, but the consequences of altered expression in the intestine are unknown.
This dissertation combines poulation genetics with metagenomics with respect to
the B4galnt2 gene in natural populations of mice and enlightens the role of biogeography
in shaping intestinal micriobial communities in general.
The population genetic study of the B4galnt2 gene in all three subspecies of M. musculus
(i.e. M. m. domesticus, M. m. musculus and M. m. castaneus) and the sister species
M. spretus revealed the long-term maintenance of different allele classes present in the
direct upstream region of B4galnt2. Varying expression patterns could be identified to be
present for > 2.8 MY, since the divergence of M. famulus. The finding, that gut expression
was conserved in all mice exhibiting the C57BL6/J allele lead to the suggestion the
the gut is a likely target of selection. It is known, that glycosylation profiles in the GI
tract can influence both symbiotic/commensal and pathogenic bacteria. Together with the
long-term maintenance of alleles conferring differences in B4galnt2 expression suggests
that host-pathogen interactions in the gut are likely involved.
As not much was known about the biogeographic influences on the intestinal microbiota
we described and thus shed light on the effect of different factors (i.e. geography, host
population structure, maternal transmission) on them. We performed a survey of eight
house mouse populations throughout western Europe, by applying high throughput pyrosequencing
of the bacterial 16S rRNA gene, we obtained the microbiota composition
of those mice, microsatellites were used for estimating hosts population structure and sequencing
of the mitochondrial D-loop region for the inference of maternal inheritance.
Geography was found to be the most dominant factor shaping the bacterial composition,
followed by host population structure and the interaction of both. Additionally we could
identify several bacterial ”species” which showed significant correlation to the underlying
population structure of their host, maternal lineages and geography.
We also performed a survey of B4galnt2 allele frequencies of the eight sampled populations
in France and Germany. We detected a clear pattern of allele frequency distribution
with a clear decline of the RIIIS/J allele frequency in central France, where we would
thus locate the selective pressure(s). To shed light on the population dynamics concerning
B4galnt2 allele frequencies we analysed the frequency distribution pattern according to
population substructure (as estimated by microsatellites and mtDNA). To follow up on
the question of possible phenotypic consequences of B4galnt2 expression, likely on the
intestinal microbiota, we analysed the gut microbiota composition according to B4galnt2
genotype by keeping in mind the newly gained insights of Chapter 2. This survey allowed
us to infer that local adaptation is the most likely explanation for these dramatic
differences in allele frequencies, rather than population substructure (e.g. due to different
colonization waves). We could also confirm the influence of B4galnt2 expression on the
microbiota composition in wild-caught mice as already described for lab mice. A direct
pathogen-genotype association could not be detected, which might be due to our sampling
size. By identifying the long-term maintenance of different B4galnt2 expression patterns
and elucidating the role of biogeography on the intestinal microbiota we were able to further
characterize the evolutionary forces acting at B4galnt2. We shed light on the complex
dynamics acting at the B4galnt2 gene, but, until the beneficial consequence(s) of exhibiting
the RIIIS/J allele is known, the story of B4galnt2 will remain a mystery and has to be
further explored.