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Meiotic recombination mirrors patterns of germline replication in mice and humans

ABSTRACT: Genetic recombination generates novel trait combinations, and understanding how recombination is distributed across the genome is key to modern genetics. The PRDM9 protein defines recombination hotspots; however, megabase-scale recombination patterning is independent of PRDM9. The single round of DNA replication, which precedes recombination in meiosis, may establish these patterns; therefore, we devised an approach to study meiotic replication that includes robust and sensitive mapping of replication origins. We find that meiotic DNA replication is distinct; reduced origin firing slows replication in meiosis, and a distinctive replication pattern in human males underlies the subtelomeric increase in recombination. We detected a robust correlation between replication and both contemporary and historical recombination and found that replication origin density coupled with chromosome size determines the recombination potential of individual chromosomes. Our findings and methods have implications for understanding the mechanisms underlying DNA replication, genetic recombination, and the landscape of mammalian germline variation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE148327 | GEO | 2021/07/02

REPOSITORIES: GEO

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Identification of PRDM9 partners

Project description:PRDM9 specifies the sites of meiotic DNA double strand break that initiate meiotic recombination in mice and humans. PRDM9 is known to bind to specific DNA sequences with its DNA binding domain, to induce H3K4me3 and H3K36me3 to adjacent nucleosomes through its methyltransferase activity, and to recruit or activate the meiotic DSB machinery. To understand how PRDM9 executes these various steps, we set up to identify its partners. This was performed by a proteomic approach where protein extracts from mouse testis were immunoprecipitated with anti-PRDM9 antibody for mass spectrometry analysis.

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Genome wide map of DMC1 in testis of Stag3-/-, Rec8-/- and Stag3-/-Rec8-/- mice.

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Recombination initiation maps of individual human genomes

Project description:DNA double-strand breaks (DSBs) are introduced in meiosis to initiate recombination and to generate crossovers, the reciprocal exchanges of genetic material between parental chromosomes. Here we present the first high-resolution map of meiotic DSBs in individual human genomes. Comparing DSB maps between individuals shows that along with DNA binding by PRDM9, additional factors dictate the efficiency of DSB formation. Furthermore, we find that in human males, the frequency of DSB formation is the primary determinant of crossover rate. Patterns of sequence polymorphisms around meiotic DSB hotspots provide evidence for both GC-biased gene conversion and for a mutagenic role of DSB repair and/or recombination. Finally, we provide compelling evidence that the aberrant repair of meiotic DSBs is a driver of human genomic disorders. Detection of meiotic double strand breaks in testis of several human male individuals.

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CXXC1 is not essential for normal DNA double-strand break formation and meiotic recombination in mouse

Project description:In most mammals, including mice and humans, meiotic recombination is determined by the meiosis specific histone methytransferase PRDM9, which binds to specific DNA sequences and trimethylates histone 3 at lysine-4 and lysine-36 at the adjacent nucleosomes. These actions ensure successful DNA double strand break formation and repair that occur on the proteinaceous structure forming the chromosome axis. The process of hotspot association with the axis after their activation by PRDM9 is poorly understood. Previously, we and others have identified CXXC1, an ortholog of S. cerevisiae Spp1 in mammals, as a PRDM9 interactor. In yeast, Spp1 is a histone methyl reader that links H3K4me3 sites with the recombination machinery, promoting DSB formation. Here, we investigated whether CXXC1 has a similar function in mouse meiosis. We created two Cxxc1 conditional knockout mouse to deplete CXXC1 generally in germ cells, and before the onset of meiosis. Surprisingly, male knockout mice were fertile, and the loss of CXXC1 in spermatocytes had no effect on hotspot trimethylation, double-strand break formation or repair. Our results demonstrate that CXXC1 is not an essential link between PRDM9-activated recombination hotspot sites and DSB machinery and that the hotspot recognition pathway in mouse is independent of CXXC1.

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Project description:Homologous recombination is required for proper segregation of homologous chromosomes during meiosis. It predominantly occurs at recombination hotspots that are defined by the DNA binding specificity of the PRDM9 protein. PRDM9 contains three domains which are typically different families of proteins involved in regulation of transcription in other proteins, yet, the role of PRDM9 in gene expression control has not been evaluated. Here we analyze the germline transcriptome of the Prdm9-/- male mice in comparison to Prdm9+/+ males and find no apparent differences in the mRNA and miRNA profiles. We further explore the role of PRDM9 in meiosis by analyzing the activity of PRDM9 lacking effect of the KRAB, SSXRD and post-SET zinc finger domains deletion mutants in a cell expression system and the KRAB domain deletion in mice. We found that although the post-SET zinc finger and the KRAB domains are not essential for the methyltransferase activity of PRDM9 in a cell culture expression systemin vitro, mice lacking the KRAB domain mutant mice domain show only residual PRDM9 methyltransferase activity and undergo meiotic arrest. In aggregate, our data indicate that these domains that are classically involved in gene regulation do not serve that role in PRDM9, but instead are involved in PRDM9 function has likely diverged from the typical function of a transcription factor and adapted the new role in setting the proper chromatin environment for initiation and completion of homologous recombination.

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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.

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