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Cell Aug 2021Genetic recombination generates novel trait combinations, and understanding how recombination is distributed across the genome is key to modern genetics. The PRDM9...
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.
Topics: Animals; Base Composition; Chromosomes, Mammalian; DNA Breaks, Double-Stranded; DNA Replication; Genome; Germ Cells; Homologous Recombination; Humans; Male; Mammals; Meiosis; Mice; Replication Origin; S Phase; Telomere; Testis
PubMed: 34260899
DOI: 10.1016/j.cell.2021.06.025 -
Science China. Life Sciences Mar 2015Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous... (Review)
Review
Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous chromosomes pair and undergo DNA double strand breaks generated by the Spo11 endonuclease. These breaks can be repaired as crossovers that result in reciprocal exchange between chromosomes. The frequency of recombination along chromosomes is highly variable, for example, crossovers are rarely observed in heterochromatin and the centromeric regions. Recent work in plants has shown that crossover hotspots occur in gene promoters and are associated with specific chromatin modifications, including H2A.Z. Meiotic chromosomes are also organized in loop-base arrays connected to an underlying chromosome axis, which likely interacts with chromatin to organize patterns of recombination. Therefore, epigenetic information exerts a major influence on patterns of meiotic recombination along chromosomes, genetic variation within populations and evolution of plant genomes.
Topics: Chromatin; Crossing Over, Genetic; Epigenesis, Genetic; Meiosis; Plants; Recombination, Genetic
PubMed: 25651968
DOI: 10.1007/s11427-015-4811-x -
Science (New York, N.Y.) Dec 2023Meiotic recombination commences with hundreds of programmed DNA breaks; however, the degree to which they are accurately repaired remains poorly understood. We report...
Meiotic recombination commences with hundreds of programmed DNA breaks; however, the degree to which they are accurately repaired remains poorly understood. We report that meiotic break repair is eightfold more mutagenic for single-base substitutions than was previously understood, leading to de novo mutation in one in four sperm and one in 12 eggs. Its impact on indels and structural variants is even higher, with 100- to 1300-fold increases in rates per break. We uncovered new mutational signatures and footprints relative to break sites, which implicate unexpected biochemical processes and error-prone DNA repair mechanisms, including translesion synthesis and end joining in meiotic break repair. We provide evidence that these mechanisms drive mutagenesis in human germ lines and lead to disruption of hundreds of genes genome wide.
Topics: Humans; Male; DNA Breaks, Double-Stranded; DNA Repair; Genome, Human; Meiosis; Mutagenesis; Mutation; Ovum; Recombination, Genetic; Semen; Translesion DNA Synthesis; Female
PubMed: 38033082
DOI: 10.1126/science.adh2531 -
Philosophical Transactions of the Royal... Dec 2017Recombination promotes genomic integrity among cells and tissues through double-strand break repair, and is critical for gamete formation and fertility through a strict... (Review)
Review
Recombination promotes genomic integrity among cells and tissues through double-strand break repair, and is critical for gamete formation and fertility through a strict regulation of the molecular mechanisms associated with proper chromosomal disjunction. In humans, congenital defects and recurrent structural abnormalities can be attributed to aberrant meiotic recombination. Moreover, mutations affecting genes involved in recombination pathways are directly linked to pathologies including infertility and cancer. Recombination is among the most prominent mechanism shaping genome variation, and is associated with not only the structuring of genomic variability, but is also tightly linked with the purging of deleterious mutations from populations. Together, these observations highlight the multiple roles of recombination in human genetics: its ability to act as a major force of evolution, its molecular potential to maintain genome repair and integrity in cell division and its mutagenic cost impacting disease evolution.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'.
Topics: Communicable Diseases; Evolution, Molecular; Genetic Linkage; Histone-Lysine N-Methyltransferase; Humans; Mutation; Recombination, Genetic
PubMed: 29109227
DOI: 10.1098/rstb.2016.0465 -
Seminars in Cell & Developmental Biology Jun 2016During the first division of meiosis, segregation of homologous chromosomes reduces the chromosome number by half. In most species, sister chromatid cohesion and... (Review)
Review
During the first division of meiosis, segregation of homologous chromosomes reduces the chromosome number by half. In most species, sister chromatid cohesion and reciprocal recombination (crossing-over) between homologous chromosomes are essential to provide tension to signal proper chromosome segregation during the first meiotic division. Crossovers are not distributed uniformly throughout the genome and are repressed at and near the centromeres. Rare crossovers that occur too near or in the centromere interfere with proper segregation and can give rise to aneuploid progeny, which can be severely defective or inviable. We review here how crossing-over occurs and how it is prevented in and around the centromeres. Molecular mechanisms of centromeric repression are only now being elucidated. However, rapid advances in understanding crossing-over, chromosome structure, and centromere functions promise to explain how potentially deleterious crossovers are avoided in certain chromosomal regions while allowing beneficial crossovers in others.
Topics: Animals; Centromere; Chromosome Segregation; DNA Breaks, Double-Stranded; Gene Conversion; Humans; Meiosis; Recombination, Genetic
PubMed: 26849908
DOI: 10.1016/j.semcdb.2016.01.042 -
Chromosoma Jun 2016Genome architecture is shaped by gene-rich and repeat-rich regions also known as euchromatin and heterochromatin, respectively. Under normal conditions, the... (Review)
Review
Genome architecture is shaped by gene-rich and repeat-rich regions also known as euchromatin and heterochromatin, respectively. Under normal conditions, the repeat-containing regions undergo little or no meiotic crossover (CO) recombination. COs within repeats are risky for the genome integrity. Indeed, they can promote non-allelic homologous recombination (NAHR) resulting in deleterious genomic rearrangements associated with diseases in humans. The assembly of heterochromatin is driven by the combinatorial action of many factors including histones, their modifications, and DNA methylation. In this review, we discuss current knowledge dealing with the epigenetic signatures of the major repeat regions where COs are suppressed. Then we describe mutants for epiregulators of heterochromatin in different organisms to find out how chromatin structure influences the CO rate and distribution.
Topics: Animals; Crossing Over, Genetic; DNA Methylation; Epigenomics; Heterochromatin; Humans; Meiosis; Recombination, Genetic
PubMed: 26801812
DOI: 10.1007/s00412-016-0574-9 -
Plant Physiology Oct 2023Meiotic recombination drives genetic diversity and crop genome optimization. In plant breeding, parents with favorable traits are crossed to create elite varieties....
Meiotic recombination drives genetic diversity and crop genome optimization. In plant breeding, parents with favorable traits are crossed to create elite varieties. Different hybridizations produce diverse types of segment reshuffling between homologous chromosomes. However, little is known about the factors that cause hybrid-specific changes in crossovers (COs). Here, we constructed 2 F2 populations from crosses between a semiwild and 2 domesticated cucumber (Cucumis sativus) accessions and examined CO events. COs mainly occurred around genes and differed unevenly along chromosomes between the 2 hybrids. Fine-scale CO distributions were suppressed in regions of heterozygous structural variations (SVs) and were accelerated by high sequence polymorphism. C. sativus RADiation sensitive 51A (CsRAD51A) binding, histone H3 lysine 4 trimethylation (H3K4me3) modification, chromatin accessibility, and hypomethylation were positively associated with global CO landscapes and in local DNA double-strand break (DSB) hotspots and genes. The frequency and suppression of COs could be roughly predicted based on multiomic information. Differences in CO events between hybrids could be partially traced to distinct genetic and epigenetic features and were significantly associated with specific DSB hotspots and heterozygous SVs. Our findings identify the genomic and epigenetic features that contribute to CO formation and hybrid-specific divergence in cucumber and provide theoretical support for selecting parental combinations and manipulating recombination events at target genomic regions during plant breeding.
Topics: Cucumis sativus; DNA Breaks, Double-Stranded; Plant Breeding; Chromatin; Homologous Recombination; DNA; Meiosis
PubMed: 37530486
DOI: 10.1093/plphys/kiad432 -
Cytogenetic and Genome Research 2016Meiotic recombination is a process that increases genetic diversity and is fundamental for sexual reproduction. Determining by which mechanisms genetic variation is... (Review)
Review
Meiotic recombination is a process that increases genetic diversity and is fundamental for sexual reproduction. Determining by which mechanisms genetic variation is generated and maintained across different phylogenetic groups provides the basis for our understanding of biodiversity and evolution. In this review, we go through different aspects of this essential phenomenon, paying special attention to mammals. We provide a comprehensive view on the organization of meiotic chromosomes and the mechanisms involved in the formation and genomic distribution of recombination hotspots, focusing on the factors influencing the formation and repair of the massive amount of self-induced DNA breaks in early stages of meiosis. At the same time, we discuss the genetic and mechanistic factors that influence recombination landscapes in mammals, as reflected by several layers of regulation. These factors include the selective forces that affect the DNA sequence itself, which can be modulated by genome reshuffling and the evolutionary history of each taxon, and the forces that control how the DNA is packaged into chromosomes during meiosis.
Topics: Animals; Chromosomes, Mammalian; Crossing Over, Genetic; Evolution, Molecular; Homologous Recombination; Humans; Mammals; Meiosis
PubMed: 27926907
DOI: 10.1159/000452822 -
Genetics Oct 2023Meiosis is a specialized cell division program that is essential for sexual reproduction. The two meiotic divisions reduce chromosome number by half, typically...
Meiosis is a specialized cell division program that is essential for sexual reproduction. The two meiotic divisions reduce chromosome number by half, typically generating haploid genomes that are packaged into gametes. To achieve this ploidy reduction, meiosis relies on highly unusual chromosomal processes including the pairing of homologous chromosomes, assembly of the synaptonemal complex, programmed formation of DNA breaks followed by their processing into crossovers, and the segregation of homologous chromosomes during the first meiotic division. These processes are embedded in a carefully orchestrated cell differentiation program with multiple interdependencies between DNA metabolism, chromosome morphogenesis, and waves of gene expression that together ensure the correct number of chromosomes is delivered to the next generation. Studies in the budding yeast Saccharomyces cerevisiae have established essentially all fundamental paradigms of meiosis-specific chromosome metabolism and have uncovered components and molecular mechanisms that underlie these conserved processes. Here, we provide an overview of all stages of meiosis in this key model system and highlight how basic mechanisms of genome stability, chromosome architecture, and cell cycle control have been adapted to achieve the unique outcome of meiosis.
Topics: Recombination, Genetic; Saccharomycetales; Meiosis; Saccharomyces cerevisiae; Synaptonemal Complex
PubMed: 37616582
DOI: 10.1093/genetics/iyad125 -
Journal of Experimental Botany Apr 2021Meiosis generates genetic variation through homologous recombination (HR) that is harnessed during breeding. HR occurs in the context of meiotic chromosome axes and the...
Meiosis generates genetic variation through homologous recombination (HR) that is harnessed during breeding. HR occurs in the context of meiotic chromosome axes and the synaptonemal complex. To study the role of axis remodelling in crossover (CO) formation in a crop species, we characterized mutants of the axis-associated protein ASY1 and the axis-remodelling protein PCH2 in Brassica rapa. asy1 plants form meiotic chromosome axes that fail to synapse. CO formation is almost abolished, and residual chiasmata are proportionally enriched in terminal chromosome regions, particularly in the nucleolar organizing region (NOR)-carrying chromosome arm. pch2 plants show impaired ASY1 loading and remodelling, consequently achieving only partial synapsis, which leads to reduced CO formation and loss of the obligatory CO. PCH2-independent chiasmata are proportionally enriched towards distal chromosome regions. Similarly, in Arabidopsis pch2, COs are increased towards telomeric regions at the expense of (peri-) centromeric COs compared with the wild type. Taken together, in B. rapa, axis formation and remodelling are critical for meiotic fidelity including synapsis and CO formation, and in asy1 and pch2 CO distributions are altered. While asy1 plants are sterile, pch2 plants are semi-sterile and thus PCH2 could be an interesting target for breeding programmes.
Topics: Brassica rapa; Chromosome Pairing; DNA-Binding Proteins; Homologous Recombination; Meiosis; Plant Breeding; Synaptonemal Complex
PubMed: 33502451
DOI: 10.1093/jxb/erab035