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Prdm9 incompatibility controls oligospermia and delayed fertility but no selfish transmission in mouse intersubspecific hybrids.

ABSTRACT: PR-domain 9 (Prdm9) is the first hybrid sterility gene identified in mammals. The incompatibility between Prdm9 from Mus musculus domesticus (Mmd; the B6 strain) and the Hstx2 region of chromosome (Chr) X from M. m. musculus (Mmm; the PWD strain) participates in the complete meiotic arrest of mouse intersubspecific (PWD×B6)F1 hybrid males. Other studies suggest that also semisterile intersubspecific hybrids are relevant for mouse speciation, but the genes responsible remain unknown. To investigate the causes of this semisterility, we analyzed the role of Prdm9 and Chr X in hybrids resulting from the crosses of PWK, another Mmm-derived inbred strain. We demonstrate that Prdm9 and Chr X control the partial meiotic arrest and reduced sperm count in (PWK×B6)F1 males. Asynapsis of heterosubspecific chromosomes and semisterility were partially suppressed by removal of the B6 allele of Prdm9. Polymorphisms between PWK and PWD on Chr X but not in the Prdm9 region were responsible for the modification of the outcome of Prdm9-Chr X F1 hybrid incompatibility. Furthermore, (PWK×B6)F1 hybrid males displayed delayed fertility dependent on the Prdm9 incompatibility. While the Drosophila hybrid sterility gene Overdrive causes both delayed fertility and increased transmission of its own chromosome to the offspring, the segregation of Chr X and the Prdm9 region from the mouse (PWK×B6)F1 males was normal. Our results indicate extended functional consequences of Prdm9-Chr X intersubspecific incompatibility on the fertility of hybrids and should influence the design of fertility analyses in hybrid zones and of laboratory crosses between Mmm and Mmd strains.

SUBMITTER: Flachs P

PROVIDER: S-EPMC3995920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundVertebrate meiotic recombination events are concentrated in regions (hotspots) that display open chromatin marks, such as trimethylation of lysines 4 and 36 of histone 3 (H3K4me3 and H3K36me3). Mouse and human PRDM9 proteins catalyze H3K4me3 and H3K36me3 and determine hotspot positions, whereas other vertebrates lacking PRDM9 recombine in regions with chromatin already opened for another function, such as gene promoters. While these other vertebrate species lacking PRDM9 remain fertile, inactivation of the mouse Prdm9 gene, which shifts the hotspots to the functional regions (including promoters), typically causes gross fertility reduction; and the reasons for these species differences are not clear.ResultsWe introduced Prdm9 deletions into the Rattus norvegicus genome and generated the first rat genome-wide maps of recombination-initiating double-strand break hotspots. Rat strains carrying the same wild-type Prdm9 allele shared 88% hotspots but strains with different Prdm9 alleles only 3%. After Prdm9 deletion, rat hotspots relocated to functional regions, about 40% to positions corresponding to Prdm9-independent mouse hotspots, including promoters. Despite the hotspot relocation and decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced healthy offspring. The percentage of normal pachytene spermatocytes in SHR-Prdm9 mutants was almost double than in the PWD male mouse oligospermic sterile mutants. We previously found a correlation between the crossover rate and sperm presence in mouse Prdm9 mutants. The crossover rate of SHR is more similar to sperm-carrying mutant mice, but it did not fully explain the fertility of the SHR mutants. Besides mild meiotic arrests at rat tubular stages IV (mid-pachytene) and XIV (metaphase), we also detected postmeiotic apoptosis of round spermatids. We found delayed meiosis and age-dependent fertility in both sexes of the SHR mutants.ConclusionsWe hypothesize that the relative increased fertility of rat versus mouse Prdm9 mutants could be ascribed to extended duration of meiotic prophase I. While rat PRDM9 shapes meiotic recombination landscapes, it is unnecessary for recombination. We suggest that PRDM9 has additional roles in spermatogenesis and speciation-spermatid development and reproductive age-that may help to explain male-specific hybrid sterility.

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Prdm9 incompatibility controls oligospermia and delayed fertility but no selfish transmission in mouse intersubspecific hybrids.

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