PRDM9 and Its Role in Genetic Recombination

Paigen, Kenneth; Petkov, Petko M.

doi:10.1016/j.tig.2017.12.017

Cited by 134 publications

(121 citation statements)

References 97 publications

(154 reference statements)

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“…Therefore, introgression generates selection on both local and global modifiers to reduce the recombination rate. Local modifiers of recombination include structural rearrangements (Kirkpatrick 2010), alterations to the binding sites of recombination-specifying proteins (Paigen and Petkov 2018;Grey et al 2018), and mutations that affect local chromatin structure in meiotic prophase [e.g., Stack et al (2017)]. On global modification, note that, even though reducing chromosome number is the most effective way to reduce aggregate recombination , introgression is not expected to select for reduced chromosome number, owing to fertility problems generally experienced by chromosome-number heterozygotes and hybrids (White 1978).…”

Section: Selection Against Introgressed Dnamentioning

confidence: 99%

Recombination and selection against introgressed DNA

Veller

Edelman

Muralidhar

et al. 2019

Preprint

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The genomic proportion that two relatives share identically by descent-their genetic relatednesscan vary depending on the patterns of recombination and segregation in their pedigree. Here, we calculate the precise connection between genome-wide genetic shuffling and variance in genetic relatedness. For the relationships of grandparent-grandoffspring and siblings, the variance in genetic relatedness is a simple decreasing function ofr, the average proportion of locus pairs that recombine in gametogenesis. These formulations explain several recent observations about variance in genetic relatedness. They further allow us to calculate the neutral variance of ancestry among F2s in a hybrid cross, enabling F2-based tests for various kinds of selection, such as Dobzhansky-Muller incompatibilities and hybrid vigor. Our calculations also allow us to characterize how recombination affects the rate at which selection eliminates deleterious introgressed DNA after hybridization-by modulating the variance of introgressed ancestry across individuals. Species with low aggregate recombination rates, like Drosophila, purge introgressed DNA more rapidly and more completely than species with high aggregate recombination rates, like humans. These conclusions also hold for different genomic regions. Within the genomes of several species, positive correlations have been observed between local recombination rate and introgressed ancestry. Our results imply that these correlations can be driven more by recombination's effect on the purging of deleterious introgressed alleles than its effect in unlinking neutral introgressed alleles from deleterious alleles. In general, our results demonstrate that the aggregate recombination process-as quantified byr and analogs-acts as a variable barrier to gene flow between species.

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Section: Selection Against Introgressed Dnamentioning

confidence: 99%

Recombination and selection against introgressed DNA

Veller

Edelman

Muralidhar

et al. 2019

Preprint

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“…been suggested to have a role in DSB repair post-cleavage that promotes crossover recombination 11,12 . Crossover resolution is facilitiated by PRDM9 binding symmetrically to the template (uncut) homolog which generates a NDR within which the DSB-initiating chromosome can stably engage [13][14][15] .…”

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confidence: 99%

ATM and PRDM9 Regulate SPO11-bound Recombination Intermediates During Meiosis

Paiano

Yamada

et al. 2019

Preprint

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Meiotic recombination is initiated by genome-wide SPO11-induced double-strand breaks (DSBs) that are processed by MRE11-mediated release of SPO11. The DSB is then resected and loaded with DMC1/RAD51 filaments that invade homologous chromosome templates. In most mammals, DSB locations ("hotspots") are determined by the DNA sequence specificity of PRDM9. Here, we demonstrate the first direct detection of meiotic DSBs and resection in vertebrates by performing END-seq on mouse spermatocytes using low sample input. We find that DMC1 limits both the minimum and maximum lengths of resected DNA, whereas 53BP1, BRCA1 and EXO1 play surprisingly minimal roles in meiotic resection. Through enzymatic modifications to the END-seq protocol that mimic the in vivo processing of SPO11, we identify a novel meiotic recombination intermediate ("SPO11-RI") present at all hotspots. The SPO11-bound intermediate is dependent on PRDM9 and caps the 3' resected end during engagement with the homologous template. We propose that SPO11-RI is generated because chromatin-bound PRDM9 asymmetrically blocks MRE11 from releasing SPO11. In Atm -/spermatocytes, SPO11-RI is reduced while unresected DNA-bound SPO11 accumulate because of defective MRE11 initiation. Thus in addition to their global roles in governing SPO11 breakage, ATM and PRDM9 are critical local regulators of mammalian SPO11 processing. MainRecombination between homologous chromosomes during meiosis requires DNA double-strand break (DSB) formation by the topoisomerase-like protein SPO11 1 . After cutting, SPO11 remains covalently bound to a two-nucleotide, 5' overhang at both ends of the DNA via phosphotyrosyl linkage. Recombination then begins with the processing of SPO11-bound DSBs into resected 3' single-stranded DNA (ssDNA) tails that preferentially invade the homologous chromosome by the recombinases DMC1 and RAD51. Studies in budding yeast Saccharomyces cerevisiae determined that the MRE11/RAD50/NBS1 (MRN) complex detects SPO11 and cooperates with Sae2 to produce a nick on the SPO11-bound strand via MRE11 endonuclease activity 2 . The nick serves as an entry point for both short-range MRE11 3'-5' exonuclease activity to degrade back to the DSB, thereby removing covalently bound SPO11 attached to a ssDNA oligonucleotide, as well as for more extensive long-range processing of 5' strands (Extended Data Fig. 1a) 2 . In budding yeast, Exo1 nuclease is uniquely responsible for this long-range 5'-3' resection 3 .Moreover, short-and long-range resection are tightly coupled in a single processive reaction (Extended Data Fig. 1a). As a result, meiotic DSBs are maximally resected as soon as they appear and unresected SPO11-bound DSBs are extremely rare 4-6 . While ATM has been shown to regulate DSB numbers and locations 7,8 , its remains unclear whether it also functions downstream in regulating SPO11 processing and resection.Distinct from yeast, DSB hotspots in mice and humans are determined by the DNA binding specificity of the PRDM9 methyltransferase 9 . Besides positioning DSBs, PRDM9...

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“…mei-217/mei-218 was targeted for functional analysis based on its profile of rapid evolution between D. melanogaster and D. mauritiana (Brand et al 2018). PRDM9, a protein that positions recombination hot spots in house mice and humans through histone methylation (Myers et al 2010;Parvanov et al 2010;Grey et al 2011;Paigen and Petkov 2018), shows accelerated divergence across mammals (Oliver et al 2009). Although these examples demonstrate the promise of signatures of molecular evolution for illuminating recombination rate differences between species, patterns of divergence have yet to be reported for most genes involved in meiotic recombination.…”

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confidence: 99%

Molecular evolution of the meiotic recombination pathway in mammals

Dapper

Payseur

2019

Evolution

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Meiotic recombination shapes evolution and helps to ensure proper chromosome segregation in most species that reproduce sexually. Recombination itself evolves, with species showing considerable divergence in the rate of crossing‐over. However, the genetic basis of this divergence is poorly understood. Recombination events are produced via a complicated, but increasingly well‐described, cellular pathway. We apply a phylogenetic comparative approach to a carefully selected panel of genes involved in the processes leading to crossovers—spanning double‐strand break formation, strand invasion, the crossover/non‐crossover decision, and resolution—to reconstruct the evolution of the recombination pathway in eutherian mammals and identify components of the pathway likely to contribute to divergence between species. Eleven recombination genes, predominantly involved in the stabilization of homologous pairing and the crossover/non‐crossover decision, show evidence of rapid evolution and positive selection across mammals. We highlight TEX11 and associated genes involved in the synaptonemal complex and the early stages of the crossover/non‐crossover decision as candidates for the evolution of recombination rate. Evolutionary comparisons to MLH1 count, a surrogate for the number of crossovers, reveal a positive correlation between genome‐wide recombination rate and the rate of evolution at TEX11 across the mammalian phylogeny. Our results illustrate the power of viewing the evolution of recombination from a pathway perspective.

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PRDM9 and Its Role in Genetic Recombination

Cited by 134 publications

References 97 publications

Recombination and selection against introgressed DNA

Recombination and selection against introgressed DNA

ATM and PRDM9 Regulate SPO11-bound Recombination Intermediates During Meiosis

Molecular evolution of the meiotic recombination pathway in mammals

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