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Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard.

ABSTRACT: In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility in the absence of PRDM9 have been reported in mice, canines, and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain fertility. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that, in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation.

SUBMITTER: Powers NR

PROVIDER: S-EPMC7608834 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

Project description:The locations of mammalian recombination hotspots are determined by PRDM9, a zinc finger histone methyltransferase that locally trimethylates histone H3 at residues K4 and K36. Here we report Prdm9-EP, a glu365pro mutation that severely reduces catalytic activity in vivo. This mutation causes sterility with complete meiotic arrest in homozygous males, while homozygous females are able to produce live offspring in natural matings. These H3K4me3 ChIP-seq data from Prdm9-EP homozygous spermatocytes show the extent to which H3K4 methyltransferase activity is compromised by this mutation, while the DMC1 ChIP-seq data show its effect on meiotic double-strand breaks in spermatocytes. For comparison, we mapped previously reported H3K4me3 ChIP-seq data from wild-type C57BL/6J spermatocytes (GSE52628) to mm10, merging the two biological replicates (SRX381465 and SRX381466) before mapping, and proceeding with processing. We did the same with published DMC1 ChIP-seq data, merging three previously reported DMC1 ChIP-seq biological replicates, isolated from wild-type C57BL/6N males (GSE112110; SRX3825301, SRX3825302, and SRX3825303). Processed data files are presented here.

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Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

Project description:Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

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Project description: Not available

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Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes.

Project description:Meiotic recombination is required for correct segregation of chromosomes to gametes and to generate genetic diversity. In mice and humans, DNA double-strand breaks (DSBs) are initiated by SPO11 at recombination hotspots activated by PRDM9-catalyzed histone modifications on open chromatin. However, the DSB-initiating and repair proteins are associated with a linear proteinaceous scaffold called the chromosome axis, the core of which is composed of cohesin proteins. STAG3 is a stromalin subunit common to all meiosis-specific cohesin complexes. Mutations of meiotic cohesin proteins, especially STAG3, perturb both axis formation and recombination in the mouse, prompting determination of how the processes are mechanistically related. Protein interaction and genetic analyses revealed that PRDM9 interacts with STAG3 and REC8 in cooperative relationships that promote normal levels of meiotic DSBs at recombination hotspots in spermatocytes. The efficacy of the Prdm9-Stag3 genetic interaction in promoting DSB formation depends on PRDM9-mediated histone methyltransferase activity. Moreover, STAG3 deficiency has a major effect on DSB number even in the absence of PRDM9, showing that its role is not restricted to canonical PRDM9-activated hotspots. STAG3 and REC8 promote axis localization of the DSB-promoting proteins HORMAD1, IHO1, and MEI4, as well as SPO11 activity. These results establish that PRDM9 and axis-associated cohesin complexes together coordinate and facilitate meiotic recombination by recruiting key proteins for initiation of DSBs, thereby associating activated hotspots with DSB-initiating complexes on the axis.

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Refined genetic maps reveal sexual dimorphism in human meiotic recombination at multiple scales.

Project description:In humans, males have lower recombination rates than females over the majority of the genome, but the opposite is usually true near the telomeres. These broad-scale differences have been known for decades, yet little is known about differences at the fine scale. By combining data sets, we have collected recombination events from over 100,000 meioses and have constructed sex-specific genetic maps at a previously unachievable resolution. Here we show that, although a substantial fraction of the genome shows some degree of sexually dimorphic recombination, the vast majority of hotspots are shared between the sexes, with only a small number of putative sex-specific hotspots. Wavelet analysis indicates that most of the differences can be attributed to the fine scale, and that variation in rate between the sexes can mostly be explained by differences in hotspot magnitude, rather than location. Nonetheless, known recombination-associated genomic features, such as THE1B repeat elements, show systematic differences between the sexes.

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PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination.

Project description:Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion.

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The cohesin subunit RAD21L functions in meiotic synapsis and exhibits sexual dimorphism in fertility.

Project description:The cohesin complex is a ring-shaped proteinaceous structure that entraps the two sister chromatids after replication until the onset of anaphase when the ring is opened by proteolytic cleavage of its ?-kleisin subunit (RAD21 at mitosis and REC8 at meiosis) by separase. RAD21L is a recently identified ?-kleisin that is present from fish to mammals and biochemically interacts with the cohesin subunits SMC1, SMC3 and STAG3. RAD21L localizes along the axial elements of the synaptonemal complex of mouse meiocytes. However, its existence as a bona fide cohesin and its functional role awaits in vivo validation. Here, we show that male mice lacking RAD21L are defective in full synapsis of homologous chromosomes at meiotic prophase I, which provokes an arrest at zygotene and leads to total azoospermia and consequently infertility. In contrast, RAD21L-deficient females are fertile but develop an age-dependent sterility. Thus, our results provide in vivo evidence that RAD21L is essential for male fertility and in females for the maintenance of fertility during natural aging.

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