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Functional characterization of adaptively relevant genes in the house mouse (Mus musculus L.)


Hasenkamp,  Natascha
Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

Tautz,  Diethard
Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Hasenkamp, N. (2014). Functional characterization of adaptively relevant genes in the house mouse (Mus musculus L.). PhD Thesis, Christian-Albrechts-Universität, Kiel.

One of the main themes in evolutionary biology is the characterization of the molecular basis of adaptation. A prerequisite for adaptation is the presence of heritable variation in the form of functionally distinct alleles which have differential effects on the lifetime reproductive success of an organism. That is why a lot of effort has been made in recent years to identify genes that are under positive selection and thus involved in adaptive processes in natural populations of different species. Through comprehensive genetic screens a large number of such candidate genes have been identified. However, knowledge about the allelic variation, its molecular function and phenotypic effects remains still rare. In this study, I took advantage of data about candidate genes for selective sweeps from previous hitchhiking mapping studies in four European wild mouse (Mus musculus L.) populations and of the extensive knowledge about mice through years of lab mouse research. Two candidate genes, namely Xpr1 and Dmrt1, with a generally well characterized function were analyzed to gain information about potential functional alleles, their variation and extent of the selective sweep across different populations and possible functional effects of the different alleles. Xpr1 is a cell-surface receptor which is especially known for its function in infection of cells by polytropic and xenotropic murine leukemia viruses (X/P-MLVs), which can cause leukemia and lymphomas in mice. The transcription factor Dmrt1 is a highly conserved member of the sex determination cascade in vertebrates and required for normal gonadal differentiation in mice. For both genes, I focused on coding sequence variation as potential target of positive selection in 11 wild mouse populations and several outgroups. Analyzed M. m. domesticus populations came from France, Germany and Iran, while the M. m. musulus populations came from Czech Republic and Kazakhstan. Additionally, microsatellites in a region of 200 kb around both loci were analyzed to survey the extent of the originally identified selective sweeps across populations. For the analysis of potential functional effects of the identified alleles, information about the general function of the genes was used. The two genes showed coding sequence variation among the populations. For Xpr1, 14 different alleles were identified which occurred as haplotypes. Two of these alleles were associated to a signature of positive selection and an introgression of one of these haplotypes from Iran to Southern France was observed. Furthermore, evidence for balancing selection on two haplotypes in three other populations was found. Analysis of potential functional effects of the receptor alleles focused in associations between these alleles and variation in transcribed P-MLVs in captive mice. However, no association could be found and no infectious virions were detected. Together with finding from previous studies, the here obtained results suggest that Xpr1 variation in wild mouse populations is shaped by ongoing adaptive evolution, but that to current knowledge other factors than disease induction by XPR1-dependent MLVs might drive this process. For Dmrt1, one amino acid exchange between Asparagine (N) and Serine (S) was observed, while data from other studies suggested that no differential expression or alternative splicing occurred. N seemed to be the derived allele and generated a potential N-linked glycosylation site. It was also found to be potentially under positive selection in five populations from France. The functional analysis focused on potential differences in target gene regulation due to the different Dmrt1 alleles. In a comparative microarray-based analysis across early postnatal stages I found that differential transcription of Dmrt1 target genes was increased between the different alleles when Dmrt1 was present. This result together with the population genetic data suggests that there is possibly a functional difference between the N and S allele that could be the target of positive selection, though more analyses will be necessary to gain insights into the potential beneficial nature of the N allele.