scholarly journals Cataloging Human PRDM9 Allelic Variation Using Long-Read Sequencing Reveals PRDM9 Population Specificity and Two Distinct Groupings of Related Alleles

2021 ◽  
Vol 9 ◽  
Author(s):  
Benjamin Alleva ◽  
Kevin Brick ◽  
Florencia Pratto ◽  
Mini Huang ◽  
Rafael Daniel Camerini-Otero
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Meiotic Recombination ◽  
Allelic Variation ◽  
Allelic Diversity ◽  
Double Strand Breaks ◽  
Human Populations ◽  
Strand Breaks ◽  
Long Read ◽  
Zinc Finger Array

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 bind to DNA. This zinc finger array is hypervariable, and the resulting alleles each have a potentially different DNA binding preference. The assessment of PRDM9 diversity is important for understanding the complexity of human population genetics, inheritance linkage patterns, and predisposition to genetic disease. Due to the repetitive nature of the PRDM9 zinc finger array, the 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 720 individuals from seven human populations, we detected 69 PRDM9 alleles. Several alleles differ in frequency among human populations, and 32 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 found that it is likely that inter-conversion between allele types is rare. By mapping meiotic double-strand breaks (DSBs) in the testis, we found 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 knowledge of PRDM9 diversity in humans.

scholarly journals Dual histone methyl reader ZCWPW1 facilitates repair of meiotic double strand breaks in male mice

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mohamed Mahgoub ◽  
Jacob Paiano ◽  
Melania Bruno ◽  
Wei Wu ◽  
Sarath Pathuri ◽  
...  
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Histone Methylation ◽  
Genetic Recombination ◽  
Binding Activity ◽  
Double Strand Breaks ◽  
Gene Promoters ◽  
Male Mice ◽  
Strand Breaks ◽  
Dna Binding Activity

Meiotic crossovers result from homology-directed repair of DNA double-strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes tri-methylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9, as an essential meiotic recombination factor required for efficient repair of PRDM9-dependent DSBs and for pairing of homologous chromosomes in male mice. In sum, our results indicate that the evolution of a dual histone methylation writer/reader (PRDM9/ZCWPW1) system in vertebrates remodeled genetic recombination hotspot selection from an ancestral static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.

scholarly journals Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

2019 ◽  
Author(s):  
Mohamed Mahgoub ◽  
Jacob Paiano ◽  
Melania Bruno ◽  
Wei Wu ◽  
Sarath Pathuri ◽  
...  
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Histone Methylation ◽  
Zinc Finger Protein ◽  
Genetic Recombination ◽  
Binding Activity ◽  
Double Strand Breaks ◽  
Gene Promoters ◽  
Strand Breaks ◽  
Dna Binding Activity

SummaryMeiotic crossovers result from homology-directed repair of double strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates, DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes tri-methylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9 and co-evolved with Prdm9 in vertebrates, as an essential meiotic recombination factor required for efficient synapsis and repair of PRDM9-dependent DSBs. In sum, our results indicate that the evolution of a dual histone methylation writer/reader system in vertebrates facilitated a shift in genetic recombination away from a static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.

scholarly journals Epigenetic activation of meiotic recombination in Arabidopsis centromeres via loss of H3K9me2 and non-CG DNA methylation

2017 ◽  
Author(s):  
Charles J. Underwood ◽  
Kyuha Choi ◽  
Christophe Lambing ◽  
Xiaohui Zhao ◽  
Heïdi Serra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Meiotic Recombination ◽  
Double Strand Breaks ◽  
Pericentromeric Heterochromatin ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Histone 3 ◽  
Differential Control

AbstractEukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis centromeres are suppressed for crossovers, as recombination in these regions can cause chromosome mis-segregation. Plant centromeres are surrounded by repetitive, transposon-dense heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. Here we show that disruption of Arabidopsis H3K9me2 and non-CG DNA methylation pathways increases meiotic DNA double strand breaks (DSBs) within centromeres, whereas crossovers increase within pericentromeric heterochromatin. Increased pericentromeric crossovers in H3K9me2/non-CG mutants occurs in both inbred and hybrid backgrounds, and involves the interfering crossover repair pathway. Epigenetic activation of recombination may also account for the curious tendency of maize transposon Ds to disrupt CHROMOMETHYLASE3 when launched from proximal loci. Thus H3K9me2 and non-CG DNA methylation exert differential control of meiotic DSB and crossover formation in centromeric and pericentromeric heterochromatin.

scholarly journals Numerical and Spatial Patterning of Yeast Meiotic DNA Breaks by Tel1

2016 ◽  
Author(s):  
Neeman Mohibullah ◽  
Scott Keeney
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Deep Sequencing ◽  
Meiotic Recombination ◽  
Double Strand Breaks ◽  
Genome Integrity ◽  
Spatial Patterning ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Context Dependent

AbstractThe Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to examine the contribution of the DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM) to this regulation in Saccharomyces cerevisiae. A tel1Δ mutant had globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing. A kinase-dead tell mutation also increased Spo11-oligonucleotide levels, but mutating known Tel1 phosphotargets on Hop1 and Rec114 did not. Deep sequencing of Spo11 oligonucleotides from tel1Δ mutants demonstrated that Tel1 shapes the nonrandom DSB distribution in ways that are distinct but partially overlapping with previously described contributions of the recombination regulator Zip3. Finally, we uncover a context-dependent role for Tel1 in hotspot competition, in which an artificial DSB hotspot inhibits nearby hotspots. Evidence for Tel1-dependent competition involving strong natural hotspots is also provided.

Double–strand breaks on YACs during yeast meiosis may reflect meiotic recombination in the human genome

1996 ◽  
Vol 13 (4) ◽  
pp. 481-484 ◽  
Author(s):  
Shoshana Klein ◽  
Drora Zenvirth ◽  
Amir Sherman ◽  
Karin Ried ◽  
Gudrun Rappold ◽  
...  
Keyword(s):  
Human Genome ◽  
Meiotic Recombination ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Yeast Meiosis

scholarly journals Targeted induction of meiotic double-strand breaks reveals chromosomal domain-dependent regulation of Spo11 and interactions among potential sites of meiotic recombination

2007 ◽  
Vol 36 (3) ◽  
pp. 984-997 ◽  
Author(s):  
Tomoyuki Fukuda ◽  
Kazuto Kugou ◽  
Hiroyuki Sasanuma ◽  
Takehiko Shibata ◽  
Kunihiro Ohta
Keyword(s):  
Meiotic Recombination ◽  
Double Strand Breaks ◽  
Strand Breaks

scholarly journals A global view of meiotic double-strand break end resection

Science ◽  
2017 ◽  
Vol 355 (6320) ◽  
pp. 40-45 ◽  
Author(s):  
Eleni P. Mimitou ◽  
Shintaro Yamada ◽  
Scott Keeney
Keyword(s):  
Meiotic Recombination ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Naked Dna ◽  
Global View ◽  
Genome Wide ◽  
End Resection

DNA double-strand breaks that initiate meiotic recombination are exonucleolytically processed. This 5′→3′ resection is a central, conserved feature of recombination but remains poorly understood. To address this lack, we mapped resection endpoints genome-wide at high resolution inSaccharomyces cerevisiae. Full-length resection requires Exo1 exonuclease and the DSB-responsive kinase Tel1, but not Sgs1 helicase. Tel1 also promotes efficient and timely resection initiation. Resection endpoints display pronounced heterogeneity between genomic loci that reflects a tendency for nucleosomes to block Exo1, yet Exo1 also appears to digest chromatin with high processivity and at rates similar to naked DNA in vitro. This paradox points to nucleosome destabilization or eviction as a defining feature of the meiotic resection landscape.

Sign in / Sign up

Export Citation Format

Share Document