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PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity [CUT&Run]

ABSTRACT: PRDM9 specifies meiotic recombination hotspots through a rapidly evolving C2H2 zinc-finger (ZNF) coding minisatellite that determines DNA-binding specificity. Although this minisatellite harbors extraordinary allelic diversity in humans, the functional consequences of most naturally occurring variants remain unknown. Here we functionally characterize 80 human PRDM9 alleles using genome-wide chromatin profiling. Despite extensive sequence diversity within the ZNF array, most alleles function indistinguishably from common A and C hotspot-specifying alleles, revealing that human PRDM9 function is more constrained than its sequence diversity predicts. In contrast, rare and infertility-associated variants occupy two functional extremes: either abundant and novel DNA binding specificity or minimal DNA binding, suggesting that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis. Together, our findings define the functional landscape of human PRDM9 variation and provide a framework for interpreting the impact of newly discovered PRDM9 alleles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345508 | GEO | 2026/09/10

REPOSITORIES: GEO

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PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity [ChIP-seq]

Project description:PRDM9 specifies meiotic recombination hotspots through a rapidly evolving C2H2 zinc-finger (ZNF) coding minisatellite that determines DNA-binding specificity. Although this minisatellite harbors extraordinary allelic diversity in humans, the functional consequences of most naturally occurring variants remain unknown. Here we functionally characterize 80 human PRDM9 alleles using genome-wide chromatin profiling. Despite extensive sequence diversity within the ZNF array, most alleles function indistinguishably from common A and C hotspot-specifying alleles, revealing that human PRDM9 function is more constrained than its sequence diversity predicts. In contrast, rare and infertility-associated variants occupy two functional extremes: either abundant and novel DNA binding specificity or minimal DNA binding, suggesting that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis. Together, our findings define the functional landscape of human PRDM9 variation and provide a framework for interpreting the impact of newly discovered PRDM9 alleles.

2026-09-10 | GSE345507 | GEO

The evolutionary dynamics of meiotic recombination initiation in mice

Project description:Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. The DNA double strand breaks (DSBs) that initiate meiotic recombination are directed by sequence-specific DNA binding of the PRDM9 protein. Gradual elimination of PRDM9 binding sites by gene conversion is thought to result in the hotspot erosion while mutations affecting DNA binding specificity of PRDM9 will create the new sets of hotspots. To better understand evolutionary turnover of recombination hotspots we mapped DSB hotspots in six inbred mouse strains representing all four major subspecies of Mus musculus and in their F1 hybrids. We found that hotspot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hotspots that become active in the hybrids. As crossovers are disfavored at such hotspots, we propose that sequence divergence generated by hotspot turnover creates impediments for recombination in hybrids, potentially leading to reduction in fertility and eventually, speciation.

2016-02-03 | GSE75419 | GEO

Cataloging human PRDM9 variability utilizing long-read sequencing technologies reveals PRDM9 population-specificity and two distinct groupings of related alleles

Project description:The PRDM9 protein determines sites of meiotic recombination in humans by directing meiotic DNA double strand breaks to specific loci. Targeting specificity is encoded by a long array of C2H2 zinc fingers that binds to DNA. This zinc finger array is hypervariable, resulting in innumerable alleles, each with a potentially different DNA binding preference. Assessment of PRDM9 diversity is important for understanding the complexity of human population genetics, inheritance linkage patterns, and the predisposition to genetic disease. Due to the repetitive nature of the PRDM9 zinc finger array, large-scale sequencing of human PRDM9 is challenging. We therefore developed a long-read sequencing strategy to infer the diploid PRDM9 zinc finger array genotype in a high-throughput manner. From an unbiased study of PRDM9 allelic diversity in 716 individuals from 7 human populations, we detected 70 high-confidence PRDM9 alleles. Several alleles differ in frequency among human populations and 33 alleles had not been identified by previous studies, which were heavily biased to European populations. PRDM9 alleles are distinguished by their DNA binding site preferences and fall into two major categories related to the most common PRDM9-A and PRDM9-C alleles. We also find that inter-conversion between allele types is likely rare. By mapping meiotic DSBs in testis, we find that small variations in PRDM9 can substantially alter the meiotic recombination landscape, demonstrating that minor PRDM9 variants may play an under-appreciated role in shaping patterns of human recombination. In summary, our data greatly expands our knowledge of PRDM9 diversity in humans.

2021-10-26 | GSE166483 | GEO

Genome-wide map of H3K4me3 and PRDM9-binding in 12 day post-partum mouse spermatocytes

Project description:PRDM9, a histone methyltransferase, 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 compared 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. Comparing these two strains, we find that haplotype differences at hotspots leads to qualitative and quantitative changes in PRDM9 binding and activity. Most variants affecting PRDM9Cst binding arose and were fixed in M.m castaneus, suppressing hotspot activity. Furthermore, M.m castaneus x M.m domesticus F1 hybrids exhibit novel hotspots, representing sites of historic evolutionary erosion. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion. Identify position of meiotic H3K4me3 from various sub-species of mice and F1 hybrids from crosses between subspecies. In addition, perform ChIP-seq analysis on the meiosis-specific methyltransferase PRDM9.

2015-01-13 | E-GEOD-60906 | biostudies-arrayexpress

Genome-wide map of H3K4me3 and PRDM9-binding in 12 day post-partum mouse spermatocytes

2015-01-13 | GSE60906 | GEO

Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility

Project description:Vertebrate recombination concentrates in meiotic chromatin regions (hotspots) that are opened in some species by the DNA-sequence-specific-binding histone H3 trimethyltransferase PRDM9, while other species recombine in regions with already opened chromatin and other function. Inactivation of the mouse Prdm9 gene induces the shift of hotspots to functional regions, gross fertility reduction in males, and sterility in females. In contrast, the other vertebrate species lacking PRDM9 remain fertile. To resolve this discrepancy, we generated Prdm9 deletions in 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, 40% to positions corresponding to Prdm9-independent mouse hotspots. Despite of hotspot relocation and of decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced apparently normal offspring. Rat PRDM9 thus makes recombination landscape unique, but it is unnecessary for recombination. This peculiarity is likely similar for human PRDM9 and may resolve the paradox between the apparently species-specific functions. PRDM9 is known to play a role in speciation, as it causes mouse hybrid sterility via meiotic asynapsis. Besides the expected mild meiotic arrest, we also detected apoptosis of postmeiotic spermatids, suggesting that PRDM9 has an additional role during spermatogenesis and perhaps also in speciation.

2021-03-25 | GSE163474 | GEO

Genome-wide map of H3K4me3 in HEK293 cells after PRDM9 expression

Project description:PRDM9 is a histone methyltransferase expressed in meiotic germ cells that determines the location of genetic recombination hotspots through binding of its allele-specific DNA binding domain. Here we characterize the genome-wide chromatin modification for two human PRDM9 alleles (A and C) in human cell lines. HEK293 cells were transfected with both alleles and an empty vector control. Resulting chromatin was subjected to H3K4me3 ChIP followed by high-throughput sequencing. We find that different PRDM9 allele largely modified chromatin in entirely different genomic regions in somatic cells determined by the protein's zinc-finger DNA binding domains. Many of the allele-specific peaks overlap sites of meiotic double-strand breaks found in vivo in human germ cells suggesting that transient expression of PRDM9 in somatic cells can reflect binding in vivo. Identify PRDM9-dependent H3K4me3 sites by comparing modified chromatin after expression of different human PRDM9 alleles in HEK293 cells.

2015-09-21 | E-GEOD-67673 | biostudies-arrayexpress

PRDM9 methyltransferase is essential for meiotic DSB formation

Project description:The programmed formation of hundreds DNA double strand breaks (DSBs) is essential for proper meiosis and fertility. In mice and humans, the location of these breaks is determined by the meiosis-specific protein PRDM9, through the DNA binding specificity of its zinc finger domain. PRDM9 also has methyltransferase activity. Here, we show that this activity is required for H3K4me3 and H3K36me3 deposition and for DSB formation at PRDM9 binding sites. By analyzing mice that express two PRDM9 variants with distinct DNA binding specificities, we reveal severalthe basic principles of PRDM9-dependent DSB site determination, in which an excess of sites are designated through PRDM9 binding and subsequent histone methylation, from which a subset are selected for DSB formation.

2018-02-09 | GSE108953 | GEO

Histone methyltransferase PRDM9 is not essential for meiosis in male mice

Project description:A hallmark of meiosis is the rearrangement of parental alleles to assure genetic diversity in gametes. These chromosome rearrangements are mediated by the repair of programmed DNA double-strand-breaks (DSBs) as genetic crossovers between parental homologs. In mice, humans, and many other mammals, meiotic DSB occur primarily at hotspots, determined by sequence-specific binding of the PRDM9 protein. Without PRDM9, meiotic DSBs occur near gene promoters and other functional sites. Studies in a limited number of mouse strains showed that functional PRDM9 is required to complete meiosis, but despite its apparent importance, Prdm9 has been repeatedly lost across many animal lineages. Both the reason for mouse sterility in the absence of PRDM9 and the mechanism by which Prdm9 can be lost remain unclear. Here, we explore if mice can tolerate the loss of Prdm9. By generating Prdm9 functional knockouts in an array of genetic backgrounds, we observe a wide range of fertility phenotypes and ultimately demonstrate that PRDM9 is not required for completion of meiosis. Although DSBs still form at a common subset of functional sites in all mice lacking PRDM9, meiotic outcomes differ substantially. We speculate that DSBs at functional sites are difficult to repair as a crossover and that by increasing the efficiency of crossover formation at these sites, genetic modifiers of recombination rates can allow for meiotic progression. This model implies that species with a sufficiently high recombination rate may lose Prdm9 yet remain fertile.

2019-06-07 | GSE109874 | GEO

Supression of genetic recombination in the pseudoautosomal region and at subtelomeres in mice with a hypomorphic spo11 allele

Project description:Homologous recombination is the key process that generates genetic diversity and drives evolution. SPO11 protein triggers recombination by introducing DNA double stranded breaks at discreet areas of the genome called recombination hotspots. The hotspot locations are largely determined by the DNA binding specificity of the PRDM9 protein in human, mice and most other mammals. In budding yeast Saccharomyces cerevisae, which lacks a Prdm9 gene, meiotic breaks are formed opportunistically in the regions of accessible chromatin, primarily at gene promoters. The genome-wide distribution of hotspots in this organism can be altered by tethering Spo11 protein to Gal4 recognition sequences in the strain expressing Spo11 attached to the DNA binding domain of the Gal4 transcription factor. To establish whether similar re-targeting of meiotic breaks can be achieved in PRDM9-containing organisms we have generated a Gal4BD-Spo11 mouse that expresses SPO11 protein joined to the DNA binding domain of yeast Gal4. We have mapped the genome-wide distribution of the recombination initiation sites in the Gal4BD-Spo11 mice. More than two hundred of the hotspots in these mice were novel and were likely defined by Gal4BD, as the Gal4 consensus motif was clustered around the centers in these hotspots. Surprisingly, meiotic DNA breaks in the Gal4BD-Spo11 mice were significantly depleted near the ends of chromosomes. The effect is particularly striking at the pseudoautosomal region of the X and Y chromosomes – normally the hottest region in the genome. Our data suggest that specific, yet-unidentified factors influence the initiation of meiotic recombination at subtelomeric chromosomal regions. Detection of meiotic double strand breaks in mice with a hypomorphic Spo11 allele.

2013-09-11 | E-GEOD-48493 | biostudies-arrayexpress

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