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Genomics May 2024Hybrid sterility, a hallmark of postzygotic isolation, arises from parental genome divergence disrupting meiosis. While chromosomal incompatibility is often implicated,...
Hybrid sterility, a hallmark of postzygotic isolation, arises from parental genome divergence disrupting meiosis. While chromosomal incompatibility is often implicated, the underlying mechanisms remain unclear. This study investigated meiotic behavior and genome-wide divergence in bighead catfish (C. macrocephalus), North African catfish (C. gariepinus), and their sterile male hybrids (important in aquaculture). Repetitive DNA analysis using bioinformatics and cytogenetics revealed significant divergence in satellite DNA (satDNA) families between parental species. Notably, one hybrid exhibited successful meiosis and spermatozoa production, suggesting potential variation in sterility expression. Our findings suggest that genome-wide satDNA divergence, rather than chromosome number differences, likely contributes to meiotic failure and male sterility in these catfish hybrids.
PubMed: 38795738
DOI: 10.1016/j.ygeno.2024.110868 -
BioRxiv : the Preprint Server For... Mar 2024A central basic feature of meiosis is pairing of homologous maternal and paternal chromosomes ("homologs") intimately along their lengths. Recognition between homologs...
A central basic feature of meiosis is pairing of homologous maternal and paternal chromosomes ("homologs") intimately along their lengths. Recognition between homologs and their juxtaposition in space are mediated by axis-associated DNA recombination complexes. Additional effects ensure that pairing occurs without ultimately giving entanglements among unrelated chromosomes. Here we examine the process of homolog juxtaposition in real time by 4D fluorescence imaging of tagged chromosomal loci at high spatio-temporal resolution in budding yeast. We discover that corresponding loci start coming together from a quite large distance (∼1.8 µm) and progress to completion of pairing in a very short time, usually less than six minutes (thus, "rapid homolog juxtaposition" or "RHJ"). Juxtaposition initiates by motion-mediated extension of a nascent interhomolog DNA linkage, raising the possibility of a tension-mediated trigger. In a first transition, homolog loci move rapidly together (in ∼30 sec, at speeds of up to ∼60 nm/sec) into a discrete intermediate state corresponding to canonical ∼400 nm axis distance coalignment. Then, after a short pause, crossover/noncrossover differentiation (crossover interference) mediates a second short, rapid transition that brings homologs even closer together. If synaptonemal complex (SC) component Zip1 is present, this transition concomitantly gives final close pairing by axis juxtaposition at ∼100 nm, the "SC distance". We also find that: (i) RHJ occurs after chromosomes acquire their prophase chromosome organization; (ii) is nearly synchronously over thirds (or more) of chromosome lengths; but (iii) is asynchronous throughout the genome. Furthermore, cytoskeleton-mediated movement is important for the timing and distance of RHJ onset and also for ensuring normal progression. Potential implications for local and global aspects of pairing are discussed.
PubMed: 38586034
DOI: 10.1101/2024.03.23.586418 -
Nature Communications Apr 2024Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous...
Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.
Topics: Mice; Animals; Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA; Meiosis; Synaptonemal Complex; Recombination, Genetic; Homologous Recombination
PubMed: 38580643
DOI: 10.1038/s41467-024-47020-1 -
Molecular and Cellular Endocrinology Jun 2024Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects...
RESEARCH QUESTION
Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects 1-3.7% women. Genetic factors explain 20-30% of POI cases, but most causes remain unknown despite genomic advancements.
DESIGN
We used whole exome sequencing (WES) in four Iranian families, validated variants via Sanger sequencing, and conducted the Acyl-cLIP assay to measure HHAT enzyme activity.
RESULTS
Despite ethnic homogeneity, WES revealed diverse genetic causes, including a novel homozygous nonsense variant in SYCP2L, impacting synaptonemal complex (SC) assembly, in the first family. Interestingly, the second family had two independent causes for amenorrhea - the mother had POI due to a novel homozygous loss-of-function variant in FANCM (required for chromosomal stability) and her daughter had primary amenorrhea due to a novel homozygous GNRHR (required for gonadotropic signalling) frameshift variant. WES analysis also provided cytogenetic insights. WES revealed one individual was in fact 46, XY and had a novel homozygous missense variant of uncertain significance in HHAT, potentially responsible for complete sex reversal although functional assays did not support impaired HHAT activity. In the remaining individual, WES indicated likely mosaic Turners with the majority of X chromosome variants having an allelic balance of ∼85% or ∼15%. Microarray validated the individual had 90% 45,XO.
CONCLUSIONS
This study demonstrates the diverse causes of amenorrhea in a small, isolated ethnic cohort highlighting how a genetic cause in one individual may not clarify familial cases. We propose that, in time, genomic sequencing may become a single universal test required for the diagnosis of infertility conditions such as POI.
Topics: Humans; Female; Adult; Male; Amenorrhea; Iran; Primary Ovarian Insufficiency; Mutation, Missense; Genomics; DNA Helicases
PubMed: 38521400
DOI: 10.1016/j.mce.2024.112212 -
PLoS Genetics Mar 2024The segregation of homologous chromosomes during meiosis typically requires tight end-to-end chromosome pairing. However, in Drosophila spermatogenesis, male flies... (Review)
Review
The segregation of homologous chromosomes during meiosis typically requires tight end-to-end chromosome pairing. However, in Drosophila spermatogenesis, male flies segregate their chromosomes without classic synaptonemal complex formation and without recombination, instead compartmentalizing homologs into subnuclear domains known as chromosome territories (CTs). How homologs find each other in the nucleus and are separated into CTs has been one of the biggest riddles in chromosome biology. Here, we discuss our current understanding of pairing and CT formation in flies and review recent data on how homologs are linked and partitioned during meiosis in male flies.
Topics: Animals; Male; Synaptonemal Complex; Recombination, Genetic; Meiosis; Chromosome Pairing; Drosophila; Chromosome Segregation
PubMed: 38489251
DOI: 10.1371/journal.pgen.1011185 -
Molecular Genetics & Genomic Medicine Feb 2024Recurrent miscarriage (RM) affects 1% to 5% of couples trying to conceive. Despite extensive clinical and laboratory testing, half of the RM cases remain unexplained. We...
BACKGROUND
Recurrent miscarriage (RM) affects 1% to 5% of couples trying to conceive. Despite extensive clinical and laboratory testing, half of the RM cases remain unexplained. We report the genetic analysis of a couple with eight miscarriages and the search for their potential genetic etiology.
METHODS
Short tandem repeat (STR) markers, single nucleotide polymorphic (SNP) microarray, and human DNA methylation microarray were used to analyze the genotypes of two miscarriages. Exomes sequencing was performed on DNA from the two partners and identified variants were validated by Sanger sequencing.
RESULTS
STR marker genotyping demonstrated that the two available miscarriages are triploid digynic and resulted from the failure of Meiosis II. SNP microarray analysis revealed an additional Meiosis I abnormality that is the segregation of the two maternal homologous chromosomes in one triploid miscarriage. Whole-exome sequencing on DNA from the two partners identified candidate variants only in the female partner in two genes with roles in female reproduction, a missense in EIF4ENIF1 (OMIM 607445) and a stop gain in HORMAD2 (OMIM 618842). EIF4ENIF1 is a eukaryotic translation initiation factor 4E nuclear import factor required for the oocyte germinal vesicle breakdown, and HORMAD2 is part of the synaptonemal complex that was hypothesized to act as a checkpoint mechanism to eliminate oocytes with asynapsis during meiotic prophase I in mice.
CONCLUSION
While both genes may contribute to the phenotype, the Meiosis I abnormalities in the conceptions favor the causal role of HORMAD2 in the etiology of RM in this couple. This report illustrates the importance of comprehensively analyzing the products of conception to guide the search for the genetic causation of RM.
Topics: Female; Humans; Pregnancy; Abortion, Habitual; Codon, Terminator; DNA; Meiosis; Triploidy; Male
PubMed: 38400599
DOI: 10.1002/mgg3.2402 -
Nature Communications Feb 2024Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that...
Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.
Topics: R-Loop Structures; DNA Repair; DNA Breaks, Double-Stranded; Homologous Recombination; BRCA1 Protein; DNA; Rad51 Recombinase; Recombinational DNA Repair
PubMed: 38383600
DOI: 10.1038/s41467-024-45693-2 -
Science Advances Feb 2024The synaptonemal complex (SC) is a zipper-like protein assembly that links homologous chromosomes to regulate recombination and segregation during meiosis. The SC has...
The synaptonemal complex (SC) is a zipper-like protein assembly that links homologous chromosomes to regulate recombination and segregation during meiosis. The SC has been notoriously refractory to in vitro reconstitution, thus leaving its molecular organization largely unknown. Here, we report a moonlighting function of two paralogous S-phase kinase-associated protein 1 (Skp1)-related proteins (SKR-1 and SKR-2), well-known adaptors of the Skp1-Cul1-F-box (SCF) ubiquitin ligase, as the key missing components of the SC in . SKR proteins repurpose their SCF-forming interfaces to dimerize and interact with meiosis-specific SC proteins, thereby driving synapsis independent of SCF activity. SKR-1 enables the formation of the long-sought-after soluble complex with previously identified SC proteins in vitro, which we propose it to represent a complete SC building block. Our findings demonstrate how a conserved cell cycle regulator has been co-opted to interact with rapidly evolving meiotic proteins to construct the SC and provide a foundation for understanding its structure and assembly mechanisms.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Proteins; S-Phase Kinase-Associated Proteins; Synaptonemal Complex
PubMed: 38354250
DOI: 10.1126/sciadv.adl4876 -
BioRxiv : the Preprint Server For... Apr 2024The classical phenomenon of crossover interference is a one-dimensional spatial patterning process that produces evenly spaced crossovers during meiosis. Quantitative...
The classical phenomenon of crossover interference is a one-dimensional spatial patterning process that produces evenly spaced crossovers during meiosis. Quantitative analysis of diagnostic molecules along budding yeast chromosomes reveals that this process also sets up a second, interdigitated pattern of related but longer periodicity, in a "two-tiered" patterning process. The second tier corresponds to a previously mysterious minority set of crossovers. Thus, in toto, the two tiers account for all detected crossover events. Both tiers of patterning set up spatially clustered assemblies of three types of molecules ("triads") representing the three major components of meiotic chromosomes (crossover recombination complexes and chromosome axis and synaptonemal complex components), and give focal and domainal signals, respectively. Roles are suggested. All observed effects are economically and synthetically explained if crossover patterning is mediated by mechanical forces along prophase chromosomes. Intensity levels of domainal triad components are further modulated, dynamically, by the conserved protein remodeler Pch2/TRIP13.
PubMed: 38352537
DOI: 10.1101/2024.01.28.577645 -
G3 (Bethesda, Md.) Apr 2024A properly regulated series of developmental and meiotic events must occur to ensure the successful production of gametes. In Drosophila melanogaster ovaries, these...
A properly regulated series of developmental and meiotic events must occur to ensure the successful production of gametes. In Drosophila melanogaster ovaries, these early developmental and meiotic events include the production of the 16-cell cyst, meiotic entry, synaptonemal complex (SC) formation, recombination, and oocyte specification. In order to identify additional genes involved in early oocyte development and meiosis, we reanalyzed 3 published single-cell RNA-seq datasets from Drosophila ovaries, using vasa (germline) together with c(3)G, cona, and corolla (SC) as markers. Our analysis generated a list of 2,743 co-expressed genes. Many known SC-related and early oocyte development genes fell within the top 500 genes on this list, as ranked by the abundance and specificity of each gene's expression across individual analyses. We tested 526 available RNAi lines containing shRNA constructs in germline-compatible vectors representing 331 of the top 500 genes. We assessed targeted ovaries for SC formation and maintenance, oocyte specification, cyst development, and double-strand break dynamics. Six uncharacterized genes exhibited early developmental defects. SC and developmental defects were observed for additional genes not well characterized in the early ovary. Interestingly, in some lines with developmental delays, meiotic events could still be completed once oocyte specificity occurred indicating plasticity in meiotic timing. These data indicate that a transcriptomics approach can be used to identify genes involved in functions in a specific cell type in the Drosophila ovary.
Topics: Animals; Female; Drosophila melanogaster; RNA Interference; Recombination, Genetic; Synaptonemal Complex; Meiosis; Drosophila; Drosophila Proteins; Oocytes; Gene Expression Profiling; Cysts
PubMed: 38333961
DOI: 10.1093/g3journal/jkae028