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Genome Biology and Evolution Jan 2024Meiotic recombination landscapes differ greatly between distantly and closely related taxa, populations, individuals, sexes, and even within genomes; however, the...
Meiotic recombination landscapes differ greatly between distantly and closely related taxa, populations, individuals, sexes, and even within genomes; however, the factors driving this variation are yet to be well elucidated. Here, we directly estimate contemporary crossover rates and, for the first time, noncrossover rates in rhesus macaques (Macaca mulatta) from four three-generation pedigrees comprising 32 individuals. We further compare these results with historical, demography-aware, linkage disequilibrium-based recombination rate estimates. From paternal meioses in the pedigrees, 165 crossover events with a median resolution of 22.3 kb were observed, corresponding to a male autosomal map length of 2,357 cM-approximately 15% longer than an existing linkage map based on human microsatellite loci. In addition, 85 noncrossover events with a mean tract length of 155 bp were identified-similar to the tract lengths observed in the only other two primates in which noncrossovers have been studied to date, humans and baboons. Consistent with observations in other placental mammals with PRDM9-directed recombination, crossover (and to a lesser extent noncrossover) events in rhesus macaques clustered in intergenic regions and toward the chromosomal ends in males-a pattern in broad agreement with the historical, sex-averaged recombination rate estimates-and evidence of GC-biased gene conversion was observed at noncrossover sites.
Topics: Pregnancy; Animals; Male; Humans; Female; Macaca mulatta; Placenta; Chromosome Mapping; Genome; Linkage Disequilibrium; Meiosis; Mammals; Histone-Lysine N-Methyltransferase
PubMed: 38051960
DOI: 10.1093/gbe/evad223 -
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 -
Vavilovskii Zhurnal Genetiki I Selektsii Oct 2023Germline-restricted chromosomes (GRCs) are present in the genomes of germline cells and absent from somatic cells. A GRC is found in all species of the songbirds...
Germline-restricted chromosomes (GRCs) are present in the genomes of germline cells and absent from somatic cells. A GRC is found in all species of the songbirds (Passeri) and in none of the other bird orders studied to date. This indicates that GRC originated in the common ancestor of the songbirds. The germline-restricted chromosome is permanently absent from somatic cells of the songbird, while female germline cells usually contain two copies of GRC and male ones have one copy. In females, GRCs undergo synapsis and restricted recombination in their terminal regions during meiotic prophase. In males, it is almost always eliminated from spermatocytes. Thus, GRC is inherited almost exclusively through the maternal lineage. The germline-restricted chromosome is a necessary genomic element in the germline cells of songbirds. To date, the GRC genetic composition has been studied in four species only. Some GRC genes are actively expressed in female and male gonads, controlling the development of germline cells and synthesis of the proteins involved in the organization of meiotic chromosomes. Songbird species vary in GRC size and genetic composition. The GRC of each bird species consists of amplified and modified copies of genes from the basic genome of that species. The level of homology between GRCs of different species is relatively low, indicating a high rate of genetic evolution of this chromosome. Transmission through the maternal lineage and suppression of the recombination contribute significantly to the accelerated evolution of GRCs. One may suggest that the rapid coordinated evolution between the GRC genes and the genes of the basic genome in the songbirds might be responsible for the explosive speciation and adaptive radiation of this most species-rich and diverse infraorder of birds.
PubMed: 38023808
DOI: 10.18699/VJGB-23-75 -
Frontiers in Cell and Developmental... 2023The telomere bouquet is a specific chromosomal configuration that forms during meiosis at the zygotene stage, when telomeres cluster together at the nuclear envelope....
The telomere bouquet is a specific chromosomal configuration that forms during meiosis at the zygotene stage, when telomeres cluster together at the nuclear envelope. This clustering allows cytoskeleton-induced movements to be transmitted to the chromosomes, thereby facilitating homologous chromosome search and pairing. However, loss of the bouquet results in more severe meiotic defects than can be attributed solely to recombination problems, suggesting that the bouquet's full function remains elusive. Despite its transient nature and the challenges in performing analyses, information is emerging that points to a remarkable suite of non-canonical functions carried out by the bouquet. Here, we describe how new approaches in quantitative cell biology can contribute to establishing the molecular basis of the full function and plasticity of the bouquet, and thus generate a comprehensive picture of the telomeric control of meiosis.
PubMed: 38020928
DOI: 10.3389/fcell.2023.1278571 -
Genome Biology and Evolution Jan 2024Tardigrada is an ecdysozoan lineage famed for its resilience. Tardigrades can tolerate high doses of radiation, low-oxygen environments, desiccation, and both high and...
Tardigrada is an ecdysozoan lineage famed for its resilience. Tardigrades can tolerate high doses of radiation, low-oxygen environments, desiccation, and both high and low temperatures under a dormant state called "anhydrobiosis", which is a reversible halt of metabolism upon almost complete desiccation. A large amount of research has focused on the genetic pathways related to these capabilities, and a number of genes have been identified and linked to the extremotolerant response of tardigrades. However, the history of these genes is unclear, and the origins and history of extremotolerant genes within Tardigrada remain a mystery. Here, we generate the first phylogenies of six separate protein families linked with desiccation and radiation tolerance in Tardigrada: cytosolic abundant heat-soluble protein, mitochondrial abundant heat-soluble protein, secretory abundant heat-soluble protein, meiotic recombination 11 homolog, and the newly discovered Echiniscus testudo abundant heat-soluble proteins (alpha and beta). The high number of independent gene duplications found amongst the six gene families studied suggests that tardigrades have a complex history with numerous independent adaptations to cope with aridity within the limnoterrestrial environment. Our results suggest that tardigrades likely transitioned from a marine environment to a limnoterrestrial environment only twice, once in stem Eutardigrada and once in Heterotardigrada, which explains the unique adaptations to anhydrobiosis present in both classes.
Topics: Animals; Tardigrada; Temperature; Desiccation; Phylogeny; Mitochondrial Proteins
PubMed: 38019582
DOI: 10.1093/gbe/evad217 -
BioRxiv : the Preprint Server For... Nov 2023The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between...
The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80 percent of meiotic crossovers result from Mlh1-Mlh3 and Exo1 acting to resolve double-Holliday junction (dHJ) intermediates in a biased manner. Little is known about how Mlh1-Mlh3 is recruited to recombination intermediates and whether it interacts with other meiotic factors prior to its role in crossover resolution. We performed a haploinsufficiency screen in baker's yeast to identify novel genetic interactors with Mlh1-Mlh3 using sensitized alleles that disrupt the stability of the Mlh1-Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. We identified several genetic interactions between and the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 and at times in meiotic prophase when Dmc1 acts as a recombinase. Interestingly, restricting expression to roughly the time of crossover resolution resulted in a null-like phenotype for crossing over. Our data are consistent with a model in which Dmc1 nucleates a polymer of Mlh1-Mlh3 to promote crossing over.
PubMed: 38014100
DOI: 10.1101/2023.11.13.566911 -
The Journal of Cell Biology Feb 2024During meiosis, cohesin and meiosis-specific proteins organize chromatin into an axis-loop architecture, coordinating homologous synapsis, recombination, and ordered...
During meiosis, cohesin and meiosis-specific proteins organize chromatin into an axis-loop architecture, coordinating homologous synapsis, recombination, and ordered chromosome segregation. However, how the meiotic chromosome axis is assembled and differentiated with meiotic progression remains elusive. Here, we explore the dynamic recruitment of two long arms of the bivalent proteins, LAB-1 and LAB-2, in Caenorhabditis elegans. LAB proteins directly interact with the axis core HORMA complexes and weak interactions contribute to their recruitment. LAB proteins phase separate in vitro, and this capacity is promoted by HORMA complexes. During early prophase, synapsis oppositely regulates the axis enrichment of LAB proteins. After the pachytene exit, LAB proteins switch from a reciprocal localization pattern to a colocalization pattern, and the normal dynamic pattern of LAB proteins is altered in meiotic mutants. We propose that LAB recruitment senses axis differentiation, and phase separation of meiotic structures helps subdomain establishment and accurate segregation of the chromosomes.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Proteins; Chromosome Pairing; Chromosome Segregation; Chromosomes; Meiosis; Chromosomal Proteins, Non-Histone
PubMed: 38010234
DOI: 10.1083/jcb.202212035 -
International Journal of Molecular... Nov 2023The PR domain-containing 9 or is a gene recognized for its fundamental role in meiosis, a process essential for forming reproductive cells. Recent findings have...
The PR domain-containing 9 or is a gene recognized for its fundamental role in meiosis, a process essential for forming reproductive cells. Recent findings have implicated alterations in the PRDM9, particularly its zinc finger motifs, in the onset and progression of cancer. This association is manifested through genomic instability and the misregulation of genes critical to cell growth, proliferation, and differentiation. In our comprehensive study, we harnessed advanced bioinformatic mining tools to delve deep into the intricate relationship between and cancer. We analyzed 136,752 breakpoints and found an undeniable association between specific PRDM9 motifs and the occurrence of double-strand breaks, a phenomenon evidenced in every cancer profile examined. Utilizing R statistical querying and the Regioner package, 55 unique sequence variations of were statistically correlated with cancer, from a pool of 1024 variations. A robust analysis using the Enrichr tool revealed prominent associations with various cancer types. Moreover, connections were noted with specific phenotypic conditions and molecular functions, underlining the pervasive influence of variations in the biological spectrum. The Reactome tool identified 25 significant pathways associated with cancer, offering insights into the mechanistic underpinnings linking to cancer progression. This detailed analysis not only confirms the pivotal role of in cancer development, but also unveils a complex network of biological processes influenced by its variations. The insights gained lay a solid foundation for future research aimed at deciphering the mechanistic pathways of , offering prospects for targeted interventions and innovative therapeutic approaches in cancer management.
Topics: Humans; Genomic Instability; Histone-Lysine N-Methyltransferase; Homologous Recombination; Meiosis; Neoplasms
PubMed: 38003713
DOI: 10.3390/ijms242216522 -
Genes Oct 2023Several meiotic events reshape the genome prior to its transfer (via gametes) to the next generation. The occurrence of new meiotic mutations is tightly linked to...
Several meiotic events reshape the genome prior to its transfer (via gametes) to the next generation. The occurrence of new meiotic mutations is tightly linked to homologous recombination (HR) and firmly depends on Spo11-induced DNA breaks. To gain insight into the molecular mechanisms governing mutagenicity during meiosis, we examined the timing of mutation and recombination events in cells deficient in various DNA HR-repair genes, which represent distinct functions along the meiotic recombination process. Despite sequence similarities and overlapping activities of the two DNA translocases, Rad54 and Tid1, we observed essential differences in their roles in meiotic mutation occurrence: in the absence of Rad54, meiotic mutagenicity was elevated 8-fold compared to the wild type (WT), while in the mutant, there were few meiotic mutations, nine percent compared to the WT. We propose that the presence of Rad54 channels recombinational repair to a less mutagenic pathway, whereas repair assisted by Tid1 is more mutagenic. A 3.5-fold increase in mutation level was observed in cells, suggesting that single-stranded DNA (ssDNA) may be a potential source for mutagenicity during meiosis. Taken together, we suggest that the introduction of de novo mutations also contributes to the diversification role of meiotic recombination. These rare meiotic mutations revise genomic sequences and may contribute to long-term evolutionary changes.
Topics: Saccharomyces cerevisiae; Mutagens; Saccharomyces cerevisiae Proteins; Meiosis; Homologous Recombination; DNA; DNA, Single-Stranded
PubMed: 38002960
DOI: 10.3390/genes14112017 -
Scientific Reports Nov 2023Meiotic recombination through chromosomal crossovers ensures proper segregation of homologous chromosomes during meiosis, while also breaking down linkage disequilibrium...
Meiotic recombination through chromosomal crossovers ensures proper segregation of homologous chromosomes during meiosis, while also breaking down linkage disequilibrium and shuffling alleles at loci located on the same chromosome. Rates of recombination can vary between species, but also between and within individuals, sex and chromosomes within species. Indeed, the Atlantic salmon genome is known to have clear sex differences in recombination with female biased heterochiasmy and markedly different landscapes of crossovers between males and females. In male meiosis, crossovers occur strictly in the telomeric regions, whereas in female meiosis crossovers tend to occur closer to the centromeres. However, little is known about the genetic control of these patterns and how this differs at the individual level. Here, we investigate genetic variation in individual measures of recombination in > 5000 large full-sib families of a Norwegian Atlantic salmon breeding population with high-density SNP genotypes. We show that females had 1.6 × higher crossover counts (CC) than males, with autosomal linkage maps spanning a total of 2174 cM in females and 1483 cM in males. However, because of the extreme telomeric bias of male crossovers, female recombination is much more important for generation of new haplotypes with 8 × higher intra-chromosomal genetic shuffling than males. CC was heritable in females (h = 0.11) and males (h = 0.10), and shuffling was also heritable in both sex but with a lower heritability in females (h = 0.06) than in males (h = 0.11). Inter-sex genetic correlations for both traits were close to zero, suggesting that rates and distribution of crossovers are genetically distinct traits in males and females, and that there is a potential for independent genetic change in both sexes in the Atlantic Salmon. Together, these findings give novel insights into the genetic architecture of recombination in salmonids and contribute to a better understanding of how rates and distribution of recombination may evolve in eukaryotes more broadly.
Topics: Humans; Animals; Female; Male; Recombination, Genetic; Salmo salar; Chromosome Mapping; Genome; Chromosomes; Meiosis
PubMed: 37993527
DOI: 10.1038/s41598-023-47208-3