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Abstract:
Meiotic recombination between homologsis initiated in accessible chromatin loops along the genomes of many mammalian species. To induce recombination, chro-matin is first made locally accessible for the meiotic recombination machinery through interprotein collaborations between the central Zinc finger protein PRDM9 with HELLS and Zcwpw1 as well asthe proteins of the COMPASS-Complex. Re-combination itself is induced by a number of recombinases, including Rec8, DMC1 and SPO11, which introduce double-strandedbreaks (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 through DSB-repair. The Results of such meiotic recombination events are either rare reciprocal cross-overs (CO) or, more frequently, non-reciprocal non-crossovers (NCO). While all these processes appear to be standardized at first sight, the di-verse outcomes of meiotic recombination, observable as haploid gametes with unique genomes, but also as a wide spectrum of fertility phenotypes. Especially in F1 hybrid males from crosses between female PWD (Laboratory strain ofMus mus-culus musculus)and male B6 mice (Laboratory strain ofMus musculus domesticus), F1 hybrid sterility (HS) results from allelic incompatibilities between heterozygous intersubspecific PRDM9 variants. Cytologically, 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 as other hybrid offspring, including the reciprocal cross of HS, remains fertile. This model led to the discovery of the X-linked hybrid sterility locus HstX2, which struc-turally differs betweenPWD and B6 miceand leads to sterility when the HstX2PWDis active in the PWDXB6genome. This work investigates which mechanistic role variants of PRDM9 and HstX2 play in functional meiosis of intra-(B6XDBA) and intersubspecific (B6XCAST) hybrids atthe initiation stages of meiotic recombination.
The presented analyses reveal that HstX2 impacts spermatogenic processes at an earlier timepoint in intrasubspecific hybrids than in intersubspecific hybrids. Fur-thermore, a very active hybrid recombinationhotspot is characterized, in intersub-specific B6XCAST hybrids, undermining the role of novel PRDM9-directed hotspots for hybrid fertility. ChIP-sequencingtogether with insilicopredictions con-firm that, while this hotspot is unknown to both parental genomes, it allows func-tional homologous meiotic recombination in intersubspecific hybrids.
