Meiotic recombination regulation - in functional meiosis and in hybrid sterility
Evolution, Anthropology
Evolutionary Cell and Developmental Biology (Zoology)
Final Report Abstract
Infertility affects 17.5% of the adult population worldwide and relies on chromosomal normal eggs and sperm generated by meiotic cell division. Understanding meiotic recombination regulation is crucial for understanding aneuploidy and infertility. However, while nearly all eukaryotic organisms reproduce sexually and genetic recombination is universally present – the regulation of meiotic recombination has remained enigmatic. The main goal of this grant was to gain detailed mechanistic insight into meiotic recombination phenotypes in two different fertile hybrid mouse models to further the understanding of PRDM9 for genome evolution. We modified our initial objective to include understanding the role of transgressive X- chromosomal modifiers of recombination rate. We modulated PRDM9 and X-chromosomal variation in Mus musculus domesticus intrasubspecific cross and in an intersubspecific Mus musculus domesticus x Mus musculus castaneous cross and tested two hotspots for crossover frequencies and distribution. We purified and (Sanger-)sequenced hundreds of crossover positive PCRs to fine-map resolution points for each genotype separately. We then measured the fine-scale distribution and frequency of denovo recombination events in intrasubspecific B6xDBA hybrids (at Dom2 activated hotspot A3 and intersubspecific B6xCAST hybrids (at Prdm9Cst1 activated hotspot on Chr19, which had been characterised as a humanised hotspot). The data on the intraspecific hotspot suggested that the X-chromosomal loci affect the initiation stages of recombination rather than the resolution of recombination. The observed transgressive effect on testis weights when the Prdm9Hu allele is also present may point to the direct regulation of Prdm9 efficiency by the gene underlying this locus. In contrast, at the intersubspecific Prdm9Cst1-activated hotspot identified, our de-novo recombination analyses also showed that the frequencies changed, and the crossover resolution was subtly affected.
Publications
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Natural variation in the zinc-finger-encoding exon ofPrdm9affects hybrid sterility phenotypes in mice. Cold Spring Harbor Laboratory.
AbuAlia, Khawla FN; Damm, Elena; Ullrich, Kristian K.; Mukaj, Amisa; Parvanov, Emil; Forejt, Jiri & Odenthal-Hesse, Linda
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Orchestrating recombination initiation in mice and men. Current Topics in Developmental Biology, 27-42. Elsevier.
Damm, Elena & Odenthal-Hesse, Linda
