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Genetic modifiers of hybrid sterility during meiosis in subspecies of mice (Mus musculus)


Abualia,  Khawla
IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society;
Research Group Meiotic Recombination and Genome Instability, Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Abualia, K. (submitted). Genetic modifiers of hybrid sterility during meiosis in subspecies of mice (Mus musculus).

Cite as: http://hdl.handle.net/21.11116/0000-0007-9B4A-8
Meiotic recombination events are placed on the genome either through the recognition and the binding of the meiotic protein PRDM9 or independently of PRDM9. In mammals such as humans and mice, PRDM9 directsthe placement of the DSBs throughout the genome into a small interval of 1 to 2 kb region that is known as recombination hotspot. Prdm9is a highly variable gene, and this variation leads to changes in the recombination landscapes per the Prdm9 allele. Differences in the binding motifs of PRDM9 in heterozygous mice can lead to hybrid sterility-which is an evolutionary concept of reproductive isolation. A well-studied model of hybrid sterility is the house mouse of the wild-derived fromMus musculus musculusPWD and the lab inbred fromMus musculus domesticusB6. Several backcrossing experiments revealed a second factor that interacts withMSc1 and Dom2Prdm9and causes this hybrid sterility called X-linked hybrid sterility locus Hstx2 on theX-chromosomeof PWD mouse. The mechanism ofhow Prdm9and Hstx2 interact during meiosis and leads to hybrid sterility in the house mouse model is not yet fully understood. In my thesis, I investigated the role of the wild Prdm9alleles in inducing hybrid sterility inintersubspecific F1 hybrids ofMus musculus musculusandMus musculus domesticus. My results showed that all of the tested Prdm9alleles are fertility alleles and doesn’t cause sterility in their offspring, limiting the role of hybrid sterility only to the already published combinationof Prdm9alleles; Dom2 and MSc1 Prdm9. Interestingly, the sterility effect of these two alleles was not restricted to the laboratory genetic background as I showed in my results that even in the wild genetic background, Dom2and MSc1 induce hybrid sterility. Besides, I found a specific wild Prdm9allele that is associated with a particular introgressed chromosome 17 allele called the t-haplotypes. I found it in a high ratio among the wild Prdm9allele in three subspecies of Mus musculuswild mice and across a wide geographical range. In our 7mouse house populations, I found that 82% of our mice carry the t-haplotypes. Moreover, it showed differences in the amino acid sequence compared with all other Prdm9alleles of these subspecies and shows a phylogenetic pattern of introgression. Given these findings, I predicted that most of the binding sites of that Prdm9 allele to be eroded in the genome of the wild mice, hence, to act as sterility allele similar to Dom2 and MSc1. I found that the Prdm9allele that is associated with t-haplotypedoesn’t induce sterility in its carrier and is normally expressed during meiosis. In the last part of my thesis, I aimed to understand the function of the second meiotic sterility factor; Hstx2 in normal meiosis. I found that Hstx2 affect recombination even in normal meiosis, as I saw in intrasubspecific mice ofMus musculus domesticus. Furthermore, I explored a possible candidate factor within the Hstx2 locus. Initially, I confirmed that the miRNA _465 cluster that is located within the Hstx2 locus shows higher expression in the mice with PWD Hstx2 than in the mice with B6 Hstx2. I furthermore explored candidate genes that were predicted to be targeted by this miRNA cluster together with other genesthat act during recombination initiation. My results confirmed that the expression changes in these genes were associated with the Hstx2 origin.