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Scientific Reports Jan 2024Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a...
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.
Topics: Humans; Infant; Female; Menkes Kinky Hair Syndrome; X Chromosome Inactivation; Copper; Chromosomes, Human, X; Mutation
PubMed: 38172222
DOI: 10.1038/s41598-023-50668-2 -
Genetics Mar 2024Accurate segregation of homologous chromosomes during meiosis depends on both the presence and the regulated placement of crossovers (COs). The centromere effect, or CO...
Accurate segregation of homologous chromosomes during meiosis depends on both the presence and the regulated placement of crossovers (COs). The centromere effect, or CO exclusion in pericentromeric regions of the chromosome, is a meiotic CO patterning phenomenon that helps prevent nondisjunction, thereby protecting against chromosomal disorders and other meiotic defects. Despite being identified nearly a century ago, the mechanisms behind this fundamental cellular process remain unknown, with most studies of the Drosophila centromere effect focusing on local influences of the centromere and pericentric heterochromatin. In this study, we sought to investigate whether dosage changes in centromere number and repetitive DNA content affect the strength of the centromere effect, using phenotypic recombination mapping. Additionally, we studied the effects of repetitive DNA function on centromere effect strength using satellite DNA-binding protein mutants displaying defective centromere-clustering in meiotic nuclei. Despite what previous studies suggest, our results show that the Drosophila centromere effect is robust to changes in centromere number, repetitive DNA content, as well as repetitive DNA function. Our study suggests that the centromere effect is unlikely to be spatially controlled, providing novel insight into the mechanisms behind the Drosophila centromere effect.
Topics: Animals; Drosophila; Centromere; Drosophila Proteins; Meiosis; DNA; Chromosome Segregation
PubMed: 38150397
DOI: 10.1093/genetics/iyad216 -
Proceedings of the National Academy of... Dec 2023Reciprocal exchanges of DNA between homologous chromosomes during meiosis, or crossovers (COs), shuffle genetic information in gametes and progeny. In many eukaryotes,...
Reciprocal exchanges of DNA between homologous chromosomes during meiosis, or crossovers (COs), shuffle genetic information in gametes and progeny. In many eukaryotes, the majority of COs (class I COs) are sensitive to a phenomenon called interference, which influences the occurrence of closely spaced double COs. Class I COs depend on a group of factors called ZMM (Zip, Msh, Mer) proteins including HEI10 (Human Enhancer of Invasion-10). However, how these proteins are recruited to class I CO sites is unclear. Here, we show that HEI10 forms foci on chromatin via a liquid-liquid phase separation (LLPS) mechanism that relies on residue Ser70. A HEI10 allele results in LLPS failure and a defect in class I CO formation. We further used immunoprecipitation-mass spectrometry to identify RPA1a (Replication Protein A 1) as a HEI10 interacting protein. Surprisingly, we find that RPA1a also undergoes phase separation and its ubiquitination and degradation are directly regulated by HEI10. We also show that HEI10 is required for the condensation of other class I CO factors. Thus, our results provide mechanistic insight into how meiotic class I CO formation is controlled by HEI10 coupling LLPS and ubiquitination.
Topics: Chromosomes; Crossing Over, Genetic; Meiosis; Phase Separation; Arabidopsis Proteins; Arabidopsis
PubMed: 38134200
DOI: 10.1073/pnas.2310542120 -
Annals of Botany Apr 2024Dogroses (Rosa sect. Caninae) are mostly pentaploid, bearing 2n = 5x = 35 chromosomes in somatic cells. They evolved a unique form of asymmetrical meiosis...
BACKGROUND AND AIMS
Dogroses (Rosa sect. Caninae) are mostly pentaploid, bearing 2n = 5x = 35 chromosomes in somatic cells. They evolved a unique form of asymmetrical meiosis characterized by two types of chromosomes: (1) chromosomes forming bivalents and distributed in the normal sexual way; and (2) chromosomes occurring as univalents and transferred by a female gamete only. In the mature pollen of pentaploid species, seven bivalent-derived chromosomes are transmitted to offspring, and 21 unpaired univalent chromosomes are eliminated during microsporogenesis. To discriminate between bivalent- and univalent-forming chromosomes, we studied histone H3 phosphorylation patterns regulating meiotic chromosome condensation and segregation.
METHODS
We analysed histone modification patterns during male canina meiosis in two representative dogrose species, 5x Rosa canina and 5x Rosa rubiginosa, by immunohistochemical and molecular cytogenetics approaches. Immunostaining of meiotic cells included α-tubulin, histone H3 phosphorylation (H3S10p, H3S28p and H3T3p) and methylation (H3K4me3 and H3K27me3) marks. In addition, fluorescent in situ hybridization was carried out with an 18S rDNA probe.
KEY RESULTS
In the first meiotic division, univalent chromosomes underwent equational division into chromatids, while homologues in bivalents were segregated as regular dyads. In diakinesis, bivalent chromosomes displayed strong H3 phosphorylation signals in proximal regions, spreading to the rest of the chromosome. In contrast, in univalents, the H3 phosphorylation signals were weaker, occurring mostly outside proximal regions largely overlapping with the H3K4me3 signals. Reduced phosphorylation was associated with relative under-condensation of the univalent chromosomes, particularly at early diakinesis.
CONCLUSIONS
We hypothesize that the absence of pairing and/or recombination in univalent chromosomes negatively affects the histone H3 phosphorylation of their chromatin and perhaps the loading of meiotic-specific cohesins. This apparently destabilizes cohesion of sister chromatids, leading to their premature split in the first meiotic division.
Topics: Histones; Phosphorylation; In Situ Hybridization, Fluorescence; Meiosis; Chromosomes; Epigenesis, Genetic
PubMed: 38127060
DOI: 10.1093/aob/mcad198 -
Microbiology Spectrum Jan 2024Sexual reproduction allows eukaryotic organisms to produce genetically diverse progeny. This process relies on meiosis, a reductional division that enables ploidy...
Sexual reproduction allows eukaryotic organisms to produce genetically diverse progeny. This process relies on meiosis, a reductional division that enables ploidy maintenance and genetic recombination. Meiotic differentiation also involves the renewal of cell functioning to promote offspring rejuvenation. Research in the model fungus has shown that this process involves a complex regulation of the function and dynamics of different organelles, including peroxisomes. These organelles are critical for meiosis induction and play further significant roles in meiotic development. Here we show that PEX13-a key constituent of the protein conduit through which the proteins defining peroxisome function reach into the organelle-is subject to a developmental regulation that almost certainly involves its selective ubiquitination-dependent removal and that modulates its abundance throughout meiotic development and at different sexual differentiation processes. Our results show that meiotic development involves a complex developmental regulation of the peroxisome protein translocation system.
Topics: Peroxisomes; Podospora; Fungal Proteins; Protein Transport; Meiosis
PubMed: 38088545
DOI: 10.1128/spectrum.02139-23 -
Frontiers in Cell and Developmental... 2023Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these... (Review)
Review
Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these processes, actin's role in respect to its structure, complex mechanical, and protein-binding properties has been studied primarily in the cytoplasmic and cellular membrane compartments. However, its role in somatic cell nuclei has recently become evident where it participates in transcription, chromatin remodeling, and DNA damage repair. What remains enigmatic is the involvement of nuclear actin in physiological processes that lead to the generation of germ cells, in general, and primary spermatocytes, in particular. Here, we will discuss the possible role and nuclear localization of actin during meiotic prophase I and its interaction with chromatin remodeling complexes, the latter being essential for the control of pairing of homologous chromosomes, cross-over formation, and recombination. It is our hope that this perspective article will extend the scope of actin's nuclear function in germ cells undergoing meiotic division.
PubMed: 38078006
DOI: 10.3389/fcell.2023.1295452 -
BioRxiv : the Preprint Server For... Nov 2023Programmed DNA double-strand break (DSB) formation is a unique meiotic feature that initiates recombination-mediated linking of homologous chromosomes, thereby enabling...
Programmed DNA double-strand break (DSB) formation is a unique meiotic feature that initiates recombination-mediated linking of homologous chromosomes, thereby enabling chromosome number halving 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 discovered in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms, which are based on a DBF4-dependent kinase (DDK)-modulated 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.
PubMed: 38077023
DOI: 10.1101/2023.11.27.568863 -
Genome Research Feb 2024Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by...
Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring recombination landscapes rely either on population genetic patterns of linkage disequilibrium (LD)-capturing a time-averaged view-or on direct detection of crossovers in gametes or multigeneration pedigrees, which limits data set scale and availability. Here, we introduce an approach for inferring sex-specific recombination landscapes using data from preimplantation genetic testing for aneuploidy (PGT-A). This method relies on low-coverage (<0.05×) whole-genome sequencing of in vitro fertilized (IVF) embryo biopsies. To overcome the data sparsity, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, and the frequent occurrence of monosomies in embryos, whereby the remaining chromosome is phased by default. Extensive simulations show our method's high accuracy, even at coverages as low as 0.02×. Applying this method to PGT-A data from 18,967 embryos, we mapped 70,660 recombination events with ∼150 kbp resolution, replicating established sex-specific recombination patterns. We observed a reduced total length of the female genetic map in trisomies compared with disomies, as well as chromosome-specific alterations in crossover distributions. Based on haplotype configurations in pericentromeric regions, our data indicate chromosome-specific propensities for different mechanisms of meiotic error. Our results provide a comprehensive view of the role of aberrant meiotic recombination in the origins of human aneuploidies and offer a versatile tool for mapping crossovers in low-coverage sequencing data from multiple siblings.
Topics: Male; Humans; Female; Genetic Testing; Aneuploidy; Chromosome Aberrations; Linkage Disequilibrium; Pedigree
PubMed: 38071472
DOI: 10.1101/gr.278168.123 -
Animals : An Open Access Journal From... Nov 2023Meiotic recombination is an important source of genetic diversity. Using immunolocalization of several meiotic proteins at the spreads of male pachytene cells, we...
Meiotic recombination is an important source of genetic diversity. Using immunolocalization of several meiotic proteins at the spreads of male pachytene cells, we estimated the number of recombination nodules per cell and their distribution along the macrochromosome 1 of the , , , and . The macrochromosomes of the two former species have metapolycentromeres, composed of several centromeric domains. We detected significant interspecies differences in the mean numbers of recombination nodules per genome: 52.9 ± 2.8 in the , 49.5 ± 3.5 in the , 61.5 ± 6.3 in the and 52.2 ± 2.7 in the . Recombination patterns on macrochromosome 1 were similar across species, with more nodules localized near chromosome ends and fewer around centromeres. The distance from the proximal nodule to the centromere depended on the nodule count per chromosome arm, with more events leading to a closer location. However, species with different centromere types showed no difference in this regard. We propose that the deficiency of recombination sites near centromeres could be due to the sequential occurrence of crossovers starting from the chromosome ends and may not be attributed to any suppressive effect of the centromere itself.
PubMed: 38066976
DOI: 10.3390/ani13233624 -
Genome Biology Dec 2023The dikaryotic stage dominates most of the life cycle in basidiomycetes, and each cell carries two different haploid nuclei. Accurate phasing of these two nuclear... (Review)
Review
BACKGROUND
The dikaryotic stage dominates most of the life cycle in basidiomycetes, and each cell carries two different haploid nuclei. Accurate phasing of these two nuclear genomes and their interactions have long been of interest.
RESULTS
We combine PacBio HiFi reads, Nanopore ultra-long reads, and Hi-C data to generate a complete, high-quality asymmetric dikaryotic genome of Tremella fuciformis Tr01, including Haplotypes A and B genomes. We assemble a meiotic haploid DBZ04 genome and detect three recombination events in these two haplotypes. We identify several chromosomal rearrangements that lead to differences in chromosome number, length, content, and sequence arrangement between these two haplotypes. Each nucleus contains a two-speed genome, harboring three accessory chromosomes and two accessory compartments that affect horizontal chromatin transfer between nuclei. We find few basidiospores are ejected from fruiting bodies of Tr01. Most monospore isolates sequenced belong to Tr01-Haplotype A genome architecture. More than one-third of monospore isolates carry one or two extra chromosomes including Chr12B and two new chromosomes ChrN1 and ChrN2. We hypothesize that homologous regions of seven sister chromatids pair into a large complex during meiosis, followed by inter-chromosomal recombination at physical contact sites and formation of new chromosomes.
CONCLUSION
We assemble two haplotype genomes of T. fuciformis Tr01 and provide the first overview of basidiomycetous genomes with discrete genomic architecture. Meiotic activities of asymmetric dikaryotic genomes result in formation of new chromosomes, aneuploidy of some daughter cells, and inviability of most other daughter cells. We propose a new approach for breeding of sporeless mushroom.
Topics: Basidiomycota; Chromatin; Chromosomes; Meiosis
PubMed: 38053144
DOI: 10.1186/s13059-023-03093-7