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The American Journal of Pathology May 2024A number of patients with colon cancer with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this...
A number of patients with colon cancer with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of mRNAs, long noncoding RNAs, snRNAs, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs, pseudogenes, and circular RNAs, as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and noncoding RNAs, differential expression analysis also uncovered transcripts that have not been implicated previously in colon cancer, such as RNA5SP149, RNU4-2, and SNORD3A. Moreover, there was a profound global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in more advanced tumors. A global down-regulation of circular RNAs in tumors relative to normal tissues was observed, although only a few were expressed differentially between tumor stages. Many previously undescribed transcripts, including RNU6-620P, RNU2-20P, VTRNA1-3, and RNA5SP60, indicated strong prognostic biomarker potential in receiver operating characteristics analyses. In summary, this study unveiled numerous differentially expressed RNAs across various classes between recurrent and nonrecurrent colon cancer. Notably, there was a significant global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in advanced tumors. Many of these newly discovered candidates demonstrate a strong prognostic potential for stage II colon cancer.
PubMed: 38704091
DOI: 10.1016/j.ajpath.2024.04.003 -
Proceedings of the National Academy of... May 2024Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated...
Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated glycolysis, yet effective strategies targeting cancer cell metabolic reprogramming to overcome therapeutic resistance in ovarian cancer remain elusive. Here, we revealed that epigenetic silencing of Otubain 2 () is a driving force for mitochondrial metabolic reprogramming in ovarian cancer, which promotes tumorigenesis and chemoresistance. Mechanistically, OTUB2 silencing destabilizes sorting nexin 29 pseudogene 2 (SNX29P2), which subsequently prevents hypoxia-inducible factor-1 alpha (HIF-1α) from von Hippel-Lindau tumor suppressor-mediated degradation. Elevated HIF-1α activates the transcription of carbonic anhydrase 9 () and drives ovarian cancer progression and chemoresistance by promoting glycolysis. Importantly, pharmacological inhibition of CA9 substantially suppressed tumor growth and synergized with carboplatin in the treatment of -silenced ovarian cancer. Thus, our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.
Topics: Female; Ovarian Neoplasms; Humans; Mitochondria; Carbonic Anhydrase IX; Cell Line, Tumor; Animals; Mice; Antigens, Neoplasm; Hypoxia-Inducible Factor 1, alpha Subunit; Glycolysis; Gene Silencing; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Metabolic Reprogramming
PubMed: 38701117
DOI: 10.1073/pnas.2315348121 -
MedRxiv : the Preprint Server For... Apr 2024Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements...
Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements (DNRTs) in birth defects and childhood cancers has not been well characterized due to the lack of adequate data and efficient computational tools. Here, we examine whole-genome sequencing data of 3,244 trios from 12 birth defect and childhood cancer cohorts in the Gabriella Miller Kids First Pediatric Research Program. Using an improved version of our tool xTea (x-Transposable element analyzer) that incorporates a deep-learning module, we identified 162 DNRTs, as well as 2 pseudogene insertions. Several variants are likely to be causal, such as a insertion that led to the ablation of a whole exon in the gene in a proband with brain tumor. We observe a high SVA insertion burden in both high-intolerance loss-of-function genes and exons as well as more frequent insertions of paternal origin. We also identify potential mosaic DNRTs from embryonic stages. Our study reveals the important roles of DNRTs in causing birth defects and predisposition to childhood cancers.
PubMed: 38699361
DOI: 10.1101/2024.04.15.24305733 -
Frontiers in Cellular and Infection... 2024Diagnosing poses challenges, and it's unclear if its rare isolation is due to infrequent occurrence or its fastidious nutritional requirements.
INTRODUCTION
Diagnosing poses challenges, and it's unclear if its rare isolation is due to infrequent occurrence or its fastidious nutritional requirements.
METHODS
This study analyzes the complete genome sequence of , obtained directly from the pus of a sternum infection in a lung transplant patient using metagenomic sequencing.
RESULTS
Genome analysis revealed limited therapeutic options for the infection, primarily susceptibility to tetracyclines. Three classes of mobile genetic elements were identified: two new insertion sequences, a new prophage (phiUMCG-1), and a species-specific variant of a mycoplasma integrative and conjugative element (MICE). Additionally, a Type I Restriction-Modification system was identified, featuring 5'-terminally truncated pseudogenes with overlapping repeats, indicating the potential for forming alternative variants through recombination.
CONCLUSION
This study represents the first-ever acquisition of a complete circularized bacterial genome directly from a patient sample obtained from invasive infection of a primary sterile site using culture-independent, PCR-free clinical metagenomics.
Topics: Humans; Metagenomics; Genome, Bacterial; High-Throughput Nucleotide Sequencing; Mycoplasma; Mycoplasma Infections; Whole Genome Sequencing; Lung Transplantation; Prophages; Interspersed Repetitive Sequences; Anti-Bacterial Agents
PubMed: 38694516
DOI: 10.3389/fcimb.2024.1368923 -
BMC Biology May 2024Sex-limited chromosomes Y and W share some characteristics, including the degeneration of protein-coding genes, enrichment of repetitive elements, and heterochromatin....
BACKGROUND
Sex-limited chromosomes Y and W share some characteristics, including the degeneration of protein-coding genes, enrichment of repetitive elements, and heterochromatin. However, although many studies have suggested that Y chromosomes retain genes related to male function, far less is known about W chromosomes and whether they retain genes related to female-specific function.
RESULTS
Here, we built a chromosome-level genome assembly of the Asian corn borer, Ostrinia furnacalis Guenée (Lepidoptera: Crambidae, Pyraloidea), an economically important pest in corn, from a female, including both the Z and W chromosome. Despite deep conservation of the Z chromosome across Lepidoptera, our chromosome-level W assembly reveals little conservation with available W chromosome sequence in related species or with the Z chromosome, consistent with a non-canonical origin of the W chromosome. The W chromosome has accumulated significant repetitive elements and experienced rapid gene gain from the remainder of the genome, with most genes exhibiting pseudogenization after duplication to the W. The genes that retain significant expression are largely enriched for functions in DNA recombination, the nucleosome, chromatin, and DNA binding, likely related to meiotic and mitotic processes within the female gonad.
CONCLUSIONS
Overall, our chromosome-level genome assembly supports the non-canonical origin of the W chromosome in O. furnacalis, which experienced rapid gene gain and loss, with the retention of genes related to female-specific function.
Topics: Animals; Moths; Female; Sex Chromosomes; Chromosomes, Insect; Male; Evolution, Molecular; Genome, Insect
PubMed: 38693535
DOI: 10.1186/s12915-024-01902-4 -
Proceedings of the National Academy of... May 2024Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these...
Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the genus. Comparative genomic analyses of species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist . CRISPR-Cas9 knockouts of the three main UGT gene clusters of revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist species, , which specializes on plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in . Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.
Topics: Animals; Spodoptera; Glycosyltransferases; Host Specificity; Uridine Diphosphate; Insect Proteins; Phylogeny
PubMed: 38683998
DOI: 10.1073/pnas.2402045121 -
G3 (Bethesda, Md.) Apr 2024Salmon lice, Lepeophtheirus salmonis (family Caligidae), are ectoparasites that have negatively impacted the salmon aquaculture industry and vulnerable wild salmon...
Salmon lice, Lepeophtheirus salmonis (family Caligidae), are ectoparasites that have negatively impacted the salmon aquaculture industry and vulnerable wild salmon populations. Researchers have studied salmon lice to better understand their biology to develop effective control strategies. In this study, we updated the chromosome-level reference genome assembly of the Pacific subspecies of L. salmonis using Hi-C data. The previous version placed contigs/scaffolds using an Atlantic salmon louse genetic map. By utilizing Hi-C data from Pacific salmon lice, we were able to properly assign locations to contigs/scaffolds previously unplaced or misplaced. This resulted in a more accurate genome assembly and a more comprehensive characterization of the sex-chromosome unique to females (W). We found evidence that the same ZW-ZZ mechanism is common in both Atlantic and Pacific subspecies of salmon lice using PCR assays. The W-chromosome was approximately 800 kbp in size, which is ∼30 times smaller than the Z-chromosome (24 Mbp). The W-chromosome contained 61 annotated genes, including 32 protein-coding genes, 27 long non-coding RNA (lncRNA) genes, and 2 pseudogenes. Among these 61 genes, 39 genes shared homology to genes found on other chromosomes, while 20 were unique to the W-chromosome. Two genes of interest on the W-chromosome, prohibitin-2 and kinase suppressor of ras-2, were previously identified as potential sex-linked markers in the salmon louse. However, we prioritized the 20 unique genes on the W-chromosome as sex-determining candidates. This information furthers our understanding of the biology of this ectoparasite and may help in the development of more effective management strategies.
PubMed: 38683737
DOI: 10.1093/g3journal/jkae087 -
Journal of Molecular Evolution Jun 2024Ascorbic acid functions as an antioxidant and facilitates other biochemical processes such as collagen triple helix formation, and iron uptake by cells. Animals which...
Ascorbic acid functions as an antioxidant and facilitates other biochemical processes such as collagen triple helix formation, and iron uptake by cells. Animals which endogenously produce ascorbic acid have a functional gulonolactone oxidase gene (GULO); however, humans have a GULO pseudogene (GULOP) and depend on dietary ascorbic acid. In this study, the conservation of GULOP sequences in the primate haplorhini suborder were investigated and compared to the GULO sequences belonging to the primates strepsirrhini suborder. Phylogenetic analysis suggested that the conserved GULOP exons in the haplorhini primates experienced a high rate of mutations following the haplorhini/strepsirrhini divergence. This high mutation rate has decreased during the evolution of the haplorhini primates. Additionally, indels of the haplorhini GULOP sequences were conserved across the suborder. A separate analysis for GULO sequences and well-conserved GULOP sequences focusing on placental mammals identified an in-frame GULO sequence in the Brazilian guinea pig, and a potential GULOP sequence in the pika. Similar to haplorhini primates, the guinea pig and lagomorph species have experienced a high substitution rate when compared to the mammals used in this study. A shared synteny to examine the conservation of local genes near GULO/GULOP identified a conserved inversion around the GULO/GULOP locus between the haplorhini and strepsirrhini primates. Fischer's exact test did not support an association between GULOP and the chromosomal inversion. Mauve alignment showed that the inversion of the length of the syntenic block that the GULO/GULOP genes belonged to was variable. However, there were frequent rearrangements around ~ 2 million base pairs adjacent to GULOP involving the KIF13B and MSRA genes. These data may suggest that genes acquiring deleterious mutations in the coding sequence may respond to these deleterious mutations with rapid substitution rates.
Topics: Animals; Evolution, Molecular; Exons; Phylogeny; Primates; Mutation; Humans; L-Gulonolactone Oxidase; Chromosome Inversion; Pseudogenes; Conserved Sequence
PubMed: 38683367
DOI: 10.1007/s00239-024-10165-0 -
Genes Mar 2024There are about 14,000 pseudogenes that are mutated or truncated sequences resembling functional parent genes. About two-thirds of pseudogenes are processed, while...
There are about 14,000 pseudogenes that are mutated or truncated sequences resembling functional parent genes. About two-thirds of pseudogenes are processed, while others are duplicated. Although initially thought dead, emerging studies indicate they have functional and regulatory roles. We study 14-3-3ζ, an adaptor protein that regulates cytokine signaling and inflammatory diseases, including rheumatoid arthritis, cancer, and neurological disorders. To understand how 14-3-3ζ (gene symbol YWHAZ) performs diverse functions, we examined the human genome and identified nine YWHAZ pseudogenes spread across many chromosomes. Unlike the 32 kb exon-to-exon sequence in YWHAZ, all pseudogenes are much shorter and lack introns. Out of six, four YWHAZ exons are highly conserved, but the untranslated region (UTR) shows significant diversity. The putative amino acid sequence of pseudogenes is 78-97% homologous, resulting in striking structural similarities with the parent protein. The OMIM and Decipher database searches revealed chromosomal loci containing pseudogenes are associated with human diseases that overlap with the parent gene. To the best of our knowledge, this is the first report on pseudogenes of the 14-3-3 family protein and their implications for human health. This bioinformatics-based study introduces a new insight into the complexity of 14-3-3ζ's functions in biology.
Topics: Humans; 14-3-3 Proteins; Exons; Genome, Human; Pseudogenes
PubMed: 38674334
DOI: 10.3390/genes15040399 -
The ISME Journal Jan 2024Dinoflagellates in the family Symbiodiniaceae are taxonomically diverse, predominantly symbiotic lineages that are well-known for their association with corals. The...
Dinoflagellates in the family Symbiodiniaceae are taxonomically diverse, predominantly symbiotic lineages that are well-known for their association with corals. The ancestor of these taxa is believed to have been free-living. The establishment of symbiosis (i.e. symbiogenesis) is hypothesized to have occurred multiple times during Symbiodiniaceae evolution, but its impact on genome evolution of these taxa is largely unknown. Among Symbiodiniaceae, the genus Effrenium is a free-living lineage that is phylogenetically positioned between two robustly supported groups of genera within which symbiotic taxa have emerged. The apparent lack of symbiogenesis in Effrenium suggests that the ancestral features of Symbiodiniaceae may have been retained in this lineage. Here, we present de novo assembled genomes (1.2-1.9 Gbp in size) and transcriptome data from three isolates of Effrenium voratum and conduct a comparative analysis that includes 16 Symbiodiniaceae taxa and the other dinoflagellates. Surprisingly, we find that genome reduction, which is often associated with a symbiotic lifestyle, predates the origin of Symbiodiniaceae. The free-living lifestyle distinguishes Effrenium from symbiotic Symbiodiniaceae vis-à-vis their longer introns, more-extensive mRNA editing, fewer (~30%) lineage-specific gene sets, and lower (~10%) level of pseudogenization. These results demonstrate how genome reduction and the adaptation to distinct lifestyles intersect to drive diversification and genome evolution of Symbiodiniaceae.
Topics: Dinoflagellida; Symbiosis; Phylogeny; Evolution, Molecular; Transcriptome; Genome, Protozoan
PubMed: 38655774
DOI: 10.1093/ismejo/wrae059