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Genes Apr 2024Cellular senescence is an irreversible growth arrest that acts as a barrier to cancer initiation and progression. Histone alteration is one of the major events during...
Cellular senescence is an irreversible growth arrest that acts as a barrier to cancer initiation and progression. Histone alteration is one of the major events during replicative senescence. However, little is known about the function of H3.3 in cellular senescence. Here we found that the downregulation of H3.3 induced growth suppression with senescence-like phenotypes such as senescence-associated heterochromatin foci (SAHF) and β-galactosidase (SA-β-gal) activity. Furthermore, H3.3 depletion induced senescence-like phenotypes with the p53/p21-depedent pathway. In addition, we identified miR-22-3p, tumor suppressive miRNA, as an upstream regulator of the (H3 histone, family 3B) gene which is the histone variant H3.3 and replaces conventional H3 in active genes. Therefore, our results reveal for the first time the molecular mechanisms for cellular senescence which are regulated by H3.3 abundance. Taken together, our studies suggest that H3.3 exerts functional roles in regulating cellular senescence and is a promising target for cancer therapy.
Topics: Cellular Senescence; Humans; Histones; Tumor Suppressor Protein p53; Fibroblasts; MicroRNAs; Diploidy; Down-Regulation; Heterochromatin
PubMed: 38790171
DOI: 10.3390/genes15050543 -
Cancers Apr 2024Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, or...
Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, or amplification, 11q, histology, diploidy with or mutations, and aberrations. Anti-GD2 immunotherapy has significantly improved the outcome of high-risk (HR) NB and is mostly effective against osteomedullary minimal residual disease (MRD), but less so against soft tissue disease. The question is whether adding anti-GD2 monoclonal antibodies (mAbs) benefits patients with HR-NB compounded by only soft tissue. We reviewed 31 patients treated at SJD for HR-NB with no osteomedullary involvement at diagnosis. All tumors had molecular genetic features of HR-NB. The outcome after first-line treatment showed 25 (80.6%) patients achieving CR. Thirteen patients remain in continued CR, median follow-up 3.9 years. We analyzed whether adding anti-GD2 immunotherapy to first-line treatment had any prognostic significance. The EFS analysis using Cox models showed a HR of 0.20, = 0.0054, and an 80% decrease in the risk of relapse in patients treated with anti-GD2 immunotherapy in the first line. Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival.
PubMed: 38730688
DOI: 10.3390/cancers16091735 -
BMC Plant Biology Apr 2024Whole-genome doubling leads to cell reprogramming, upregulation of stress genes, and establishment of new pathways of drought stress responses in plants. This study...
Whole-genome doubling leads to cell reprogramming, upregulation of stress genes, and establishment of new pathways of drought stress responses in plants. This study investigated the molecular mechanisms of drought tolerance and cuticular wax characteristics in diploid and tetraploid-induced Erysimum cheiri. According to real-time PCR analysis, tetraploid induced wallflowers exhibited increased expression of several genes encoding transcription factors (TFs), including AREB1 and AREB3; the stress response genes RD29A and ERD1 under drought stress conditions. Furthermore, two cuticular wax biosynthetic pathway genes, CER1 and SHN1, were upregulated in tetraploid plants under drought conditions. Leaf morphological studies revealed that tetraploid leaves were covered with unique cuticular wax crystalloids, which produced a white fluffy appearance, while the diploid leaves were green and smooth. The greater content of epicuticular wax in tetraploid leaves than in diploid leaves can explain the decrease in cuticle permeability as well as the decrease in water loss and improvement in drought tolerance in wallflowers. GC‒MS analysis revealed that the wax components included alkanes, alcohols, aldehydes, and fatty acids. The most abundant wax compound in this plant was alkanes (50%), the most predominant of which was C29. The relative abundance of these compounds increased significantly in tetraploid plants under drought stress conditions. These findings revealed that tetraploid-induced wallflowers presented upregulation of multiple drought-related and wax biosynthesis genes; therefore, polyploidization has proved useful for improving plant drought tolerance.
Topics: Waxes; Tetraploidy; Diploidy; Droughts; Gene Expression Regulation, Plant; Plant Leaves; Plant Epidermis; Gene Expression Profiling; Drought Resistance
PubMed: 38664602
DOI: 10.1186/s12870-024-05007-6 -
BioRxiv : the Preprint Server For... Apr 2024Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution. However, given the instability of newly-formed polyploid genomes,...
Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution. However, given the instability of newly-formed polyploid genomes, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE), we show that diploid snowflake yeast () under selection for larger multicellular size rapidly undergo spontaneous WGD. From its origin within the first 50 days of the experiment, tetraploids persist for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in ten replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modeling, and counter-selection experiments, we found that tetraploidy evolved because it confers immediate fitness benefits in this environment, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, playing a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection, and fuel long-term innovations by creating additional dimensions of heritable genetic variation.
PubMed: 38659912
DOI: 10.1101/2024.04.18.588554 -
Nature Communications Apr 2024Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their...
Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we perform multi-region, single-cell DNA sequencing to characterize the SCNA landscape across tumor-rich and normal tissue in two male patients with localized prostate cancer. We identify two distinct karyotypes: 'pseudo-diploid' cells harboring few SCNAs and highly aneuploid cells. Pseudo-diploid cells form numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones. In contrast, aneuploid cells do not form subclones and are detected throughout the prostate, including normal tissue regions. Highly localized pseudo-diploid subclones are confined within tumor-rich regions and carry deletions in multiple tumor-suppressor genes. Our study reveals that SCNAs are widespread in normal and tumor regions across the prostate in localized prostate cancer patients and suggests that a subset of pseudo-diploid cells drive tumorigenesis in the aging prostate.
Topics: Humans; Male; Prostatic Neoplasms; DNA Copy Number Variations; Single-Cell Analysis; Aneuploidy; Prostate; Clone Cells; Diploidy; Aged
PubMed: 38658552
DOI: 10.1038/s41467-024-47664-z -
Scientific Reports Apr 2024Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have...
Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.
Topics: Humans; Aneuploidy; Colorectal Neoplasms; Diploidy; Microsatellite Instability; Middle Aged; Female; Male; Adult; Mutation; ErbB Receptors; Age of Onset; Genomics
PubMed: 38654044
DOI: 10.1038/s41598-024-59398-5 -
Scientific Data Apr 2024Diploid wild oat Avena longiglumis has nutritional and adaptive traits which are valuable for common oat (A. sativa) breeding. The combination of Illumina, Nanopore and...
Diploid wild oat Avena longiglumis has nutritional and adaptive traits which are valuable for common oat (A. sativa) breeding. The combination of Illumina, Nanopore and Hi-C data allowed us to assemble a high-quality chromosome-level genome of A. longiglumis (ALO), evidenced by contig N50 of 12.68 Mb with 99% BUSCO completeness for the assembly size of 3,960.97 Mb. A total of 40,845 protein-coding genes were annotated. The assembled genome was composed of 87.04% repetitive DNA sequences. Dotplots of the genome assembly (PI657387) with two published ALO genomes were compared to indicate the conservation of gene order and equal expansion of all syntenic blocks among three genome assemblies. Two recent whole-genome duplication events were characterized in genomes of diploid Avena species. These findings provide new knowledge for the genomic features of A. longiglumis, give information about the species diversity, and will accelerate the functional genomics and breeding studies in oat and related cereal crops.
Topics: Avena; Genome, Plant; Diploidy; Chromosomes, Plant
PubMed: 38649380
DOI: 10.1038/s41597-024-03248-6 -
Cell Reports Methods May 2024Precision medicine's emphasis on individual genetic variants highlights the importance of haplotype-resolved assembly, a computational challenge in bioinformatics given...
Precision medicine's emphasis on individual genetic variants highlights the importance of haplotype-resolved assembly, a computational challenge in bioinformatics given its combinatorial nature. While classical algorithms have made strides in addressing this issue, the potential of quantum computing remains largely untapped. Here, we present the vehicle routing problem (VRP) assembler: an approach that transforms this task into a vehicle routing problem, an optimization formulation solvable on a quantum computer. We demonstrate its potential and feasibility through a proof of concept on short synthetic diploid and triploid genomes using a D-Wave quantum annealer. To tackle larger-scale assembly problems, we integrate the VRP assembler with Google's OR-Tools, achieving a haplotype-resolved local assembly across the human major histocompatibility complex (MHC) region. Our results show encouraging performance compared to Hifiasm with phasing accuracy approaching the theoretical limit, underscoring the promising future of quantum computing in bioinformatics.
Topics: Humans; Haplotypes; Diploidy; Polyploidy; Computational Biology; Algorithms; Quantum Theory; Genome, Human; Major Histocompatibility Complex
PubMed: 38614089
DOI: 10.1016/j.crmeth.2024.100754 -
Nature Communications Apr 2024The high sequencing error rate has impeded the application of long noisy reads for diploid genome assembly. Most existing assemblers failed to generate high-quality...
The high sequencing error rate has impeded the application of long noisy reads for diploid genome assembly. Most existing assemblers failed to generate high-quality phased assemblies using long noisy reads. Here, we present PECAT, a Phased Error Correction and Assembly Tool, for reconstructing diploid genomes from long noisy reads. We design a haplotype-aware error correction method that can retain heterozygote alleles while correcting sequencing errors. We combine a corrected read SNP caller and a raw read SNP caller to further improve the identification of inconsistent overlaps in the string graph. We use a grouping method to assign reads to different haplotype groups. PECAT efficiently assembles diploid genomes using Nanopore R9, PacBio CLR or Nanopore R10 reads only. PECAT generates more contiguous haplotype-specific contigs compared to other assemblers. Especially, PECAT achieves nearly haplotype-resolved assembly on B. taurus (Bison×Simmental) using Nanopore R9 reads and phase block NG50 with 59.4/58.0 Mb for HG002 using Nanopore R10 reads.
Topics: Diploidy; Nanopores; Alleles; Haplotypes; Heterozygote; Sequence Analysis, DNA; High-Throughput Nucleotide Sequencing
PubMed: 38580638
DOI: 10.1038/s41467-024-47349-7 -
Journal of Insect Science (Online) Mar 2024Declines in bumble bee species range and abundances are documented across multiple continents and have prompted the need for research to aid species recovery and...
Range-wide genetic analysis of an endangered bumble bee (Bombus affinis, Hymenoptera: Apidae) reveals population structure, isolation by distance, and low colony abundance.
Declines in bumble bee species range and abundances are documented across multiple continents and have prompted the need for research to aid species recovery and conservation. The rusty patched bumble bee (Bombus affinis) is the first federally listed bumble bee species in North America. We conducted a range-wide population genetics study of B. affinis from across all extant conservation units to inform conservation efforts. To understand the species' vulnerability and help establish recovery targets, we examined population structure, patterns of genetic diversity, and population differentiation. Additionally, we conducted a site-level analysis of colony abundance to inform prioritizing areas for conservation, translocation, and other recovery actions. We find substantial evidence of population structuring along an east-to-west gradient. Putative populations show evidence of isolation by distance, high inbreeding coefficients, and a range-wide male diploidy rate of ~15%. Our results suggest the Appalachians represent a genetically distinct cluster with high levels of private alleles and substantial differentiation from the rest of the extant range. Site-level analyses suggest low colony abundance estimates for B. affinis compared to similar datasets of stable, co-occurring species. These results lend genetic support to trends from observational studies, suggesting that B. affinis has undergone a recent decline and exhibit substantial spatial structure. The low colony abundances observed here suggest caution in overinterpreting the stability of populations even where B. affinis is reliably detected interannually. These results help delineate informed management units, provide context for the potential risks of translocation programs, and help set clear recovery targets for this and other threatened bumble bee species.
Topics: Bees; Male; Animals; Hymenoptera; Endangered Species
PubMed: 38569059
DOI: 10.1093/jisesa/ieae041