A novel perspective on PRDM9-directed meiotic recombination : How interallelic interactions between meiotic regulator PRDM9 and X-chromosomal hybrid sterility locus HstX2 regulate hybrid fertility phenotypes

Meiotic recombination is initiated in accessible chromatin loops along the genomes of mammals. To do so, chromatin is made locally accessible for the meiotic recombination machinery including Zinc finger protein PRDM9,HELLS, Zcwpw1 as well as the proteins of the COMPASS-Complex. Recombination itself is induced by recombinases, which introduce double-stranded breaks (DSBs) at a subset of PRDM9-directed positions, mediate homology search, guide the broken ends towards each and eventually accomplish the physical exchange of homologous parental alleles. The results of such recombination events are either  reciprocal cross-overs (CO) or non-reciprocal non-crossovers (NCO)- observable as haploid gametes with unique genomes and a wide spectrum of fertility phenotypes. Especially in F1 hybrid males from crosses between female PWD (Laboratory strain of Mus musculus musculus) and male B6 mice (Laboratory strain of Mus musculus domesticus), male F1 hybrid sterility (HS) results from allelic incompatibilities between heterozygous intersubspecific PRDM9 variants. The HS phenotype is characterized by asymmetric recombination landscapes with perturbated homology search, DSB repair and early meiotic breakdown. However, HS does not occur universally in hybrid offspring for example reciprocal cross of HS remains fertile. This model led to the discovery of the X-linked hybrid sterility locus HstX2, which structurally differs between PWD and B6 mice and leads to sterility when the HstX2PWD is active in the intersubspecific PWD X B6 hybrid genome. This work investigates which mechanistic role variants of PRDM9 and HstX2 play in functional meiosis of intra-(B6 X DBA) and intersubspecific (B6 X CAST) hybrids at the initiation stages of meiotic recombination.


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