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Methods in Molecular Biology (Clifton,... 2021Pseudogenes have long been considered nonfunctional elements. The influx of large-scale sequencing projects over the last decade have provided rich sources of evidence...
Pseudogenes have long been considered nonfunctional elements. The influx of large-scale sequencing projects over the last decade have provided rich sources of evidence that pseudogenes can play key evolutionary and regulatory roles, highlighting the need for high quality annotation for both human and key model organisms. To date, GENCODE has completed the manual annotation of pseudogenes in human and has undertaken the task to curate and characterize pseudogenes in the mouse reference genome. Capitalizing on available high-quality annotations as well as on the functional-genomics, evolutionary, and phenotypical data, we were able to create a comprehensive picture of both the human and mouse pseudogene complements' creation, development, and activity. Thus, we found that while human pseudogenes were created through a single burst of retrotransposition events, the active transposable element content in mouse allows for a continuous renewal of the pseudogene pool. Despite their differences, the two organisms share a number of similarities in terms of pseudogene activity, with ~10% of pseudogenes being transcribed. Finally, we highlight a variety of resources developed based on the available GENCODE annotations that help shed light on pseudogene biology.
Topics: Animals; Computational Biology; Databases, Genetic; Evolution, Molecular; Genomics; Humans; Mice; Molecular Sequence Annotation; Pseudogenes; Retroelements; Sequence Analysis, DNA; Transcription, Genetic
PubMed: 34165709
DOI: 10.1007/978-1-0716-1503-4_5 -
Nature Communications Mar 2020Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms...
Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cellular Reprogramming; Esophageal Squamous Cell Carcinoma; Female; Gene Knockout Techniques; Glycolysis; Humans; Mice, Inbred BALB C; Mice, Nude; Phosphofructokinase-2; Pseudogenes; RNA, Long Noncoding; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 32198345
DOI: 10.1038/s41467-020-15112-3 -
Nucleic Acids Research Jan 2023Ferroptosis is a mode of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation. It is closely linked to the pathophysiological...
Ferroptosis is a mode of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation. It is closely linked to the pathophysiological processes in many diseases. Since our publication of the first ferroptosis database in 2020 (FerrDb V1), many new findings have been published. To keep up with the rapid progress in ferroptosis research and to provide timely and high-quality data, here we present the successor, FerrDb V2. It contains 1001 ferroptosis regulators and 143 ferroptosis-disease associations manually curated from 3288 articles. Specifically, there are 621 gene regulators, of which 264 are drivers, 238 are suppressors, 9 are markers, and 110 are unclassified genes; and there are 380 substance regulators, with 201 inducers and 179 inhibitors. Compared to FerrDb V1, curated articles increase by >300%, ferroptosis regulators increase by 175%, and ferroptosis-disease associations increase by 50.5%. Circular RNA and pseudogene are novel regulators in FerrDb V2, and the percentage of non-coding RNA increases from 7.3% to 13.6%. External gene-related data were integrated, enabling thought-provoking and gene-oriented analysis in FerrDb V2. In conclusion, FerrDb V2 will help to acquire deeper insights into ferroptosis. FerrDb V2 is freely accessible at http://www.zhounan.org/ferrdb/.
Topics: Ferroptosis; Data Accuracy; Databases, Factual; Lipid Peroxidation; Pseudogenes
PubMed: 36305834
DOI: 10.1093/nar/gkac935 -
Nature Methods Apr 2015HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an...
HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an indexing scheme based on the Burrows-Wheeler transform and the Ferragina-Manzini (FM) index, employing two types of indexes for alignment: a whole-genome FM index to anchor each alignment and numerous local FM indexes for very rapid extensions of these alignments. HISAT's hierarchical index for the human genome contains 48,000 local FM indexes, each representing a genomic region of ∼64,000 bp. Tests on real and simulated data sets showed that HISAT is the fastest system currently available, with equal or better accuracy than any other method. Despite its large number of indexes, HISAT requires only 4.3 gigabytes of memory. HISAT supports genomes of any size, including those larger than 4 billion bases.
Topics: Humans; Limit of Detection; Pseudogenes; Sequence Alignment; Sequence Analysis, DNA; Sequence Analysis, RNA
PubMed: 25751142
DOI: 10.1038/nmeth.3317 -
Methods in Molecular Biology (Clifton,... 2021Although long thought of as "gene relics," pseudogenes have recently gained research and medical interests because of their potential impacts on cellular pathways and of... (Review)
Review
Although long thought of as "gene relics," pseudogenes have recently gained research and medical interests because of their potential impacts on cellular pathways and of their clinical relevance. Studies have profiled pseudogenes at both DNA and RNA levels in cancers. Differences in pseudogene expression (RNA) or occurrence (DNA) help cancer subtype classification, which in turn can contribute to improving treatment selection in precision medicine. Such differences are also associated with clinical outcomes, such as patient survival.Here we review the existing methods on pseudogene profiling and discuss the application scenarios, as well as their relevant issues and challenges.
Topics: DNA, Neoplasm; Datasets as Topic; Gene Expression Regulation, Neoplastic; Humans; Molecular Sequence Annotation; Multigene Family; Neoplasm Proteins; Neoplasms; Patients; Prognosis; Pseudogenes; RNA, Messenger; RNA, Neoplasm
PubMed: 34165723
DOI: 10.1007/978-1-0716-1503-4_19 -
Nature Nov 2016Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes. Although certain...
Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes. Although certain pseudogene-derived RNAs have regulatory roles, and some pseudogene fragments are translated, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid-a chemical cue important for locating fermenting food found only at trace levels in Morinda fruit-D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such 'pseudo-pseudogenes' could represent a widespread phenomenon.
Topics: Acetic Acid; Animals; Base Sequence; Codon, Terminator; Drosophila; Drosophila melanogaster; Ligands; Molecular Sequence Annotation; Neurons; Organ Specificity; Peptide Chain Elongation, Translational; Pseudogenes; Receptors, Odorant; Reproducibility of Results
PubMed: 27776356
DOI: 10.1038/nature19824 -
Methods in Molecular Biology (Clifton,... 2021A pseudogene is defined as a genomic DNA sequence that looks like a mutated or truncated version of a known functional gene. Nearly four decades since their first...
A pseudogene is defined as a genomic DNA sequence that looks like a mutated or truncated version of a known functional gene. Nearly four decades since their first discovery it has been estimated that between ~12,000 and ~20,000 pseudogenes exist in the human genome. Early efforts to characterize functions for pseudogenes were unsuccessful, thus they were considered functionless relics of evolutionary selection, junk DNA or genetic fossils. Remarkably, an increasing number of pseudogenes have been reported to be expressed as RNA transcripts above and beyond levels considered accidental or spurious transcription. There is emerging evidence that some expressed pseudogene transcripts have biological functions and should be defined as a subclass of functional long noncoding RNAs (lncRNA). In this introductory chapter, I briefly summarize the history and the current knowledge of pseudogenes, and highlight the emerging functions of some pseudogenes in human biology and disease. This second iteration of Pseudogenes in Methods in Molecular Biology highlights new methodological approaches to investigate this intriguing family of lncRNAs and the extent of their biological function.
Topics: Animals; Epigenesis, Genetic; Evolution, Molecular; Gene Duplication; Humans; MicroRNAs; Mutagenesis, Insertional; Mutation; Pseudogenes; RNA, Long Noncoding; RNA, Messenger; RNA, Small Interfering; Transcription, Genetic
PubMed: 34165705
DOI: 10.1007/978-1-0716-1503-4_1 -
Critical Reviews in Biotechnology Nov 2021Pseudogenes, the debilitated parts of ancient genes, were previously scrapped off as junk or discarded genes with no functional significance. Pseudogenes have come under... (Review)
Review
Pseudogenes, the debilitated parts of ancient genes, were previously scrapped off as junk or discarded genes with no functional significance. Pseudogenes have come under scrutiny for their functionality, since recent studies have unveiled their importance in the regulation of their corresponding parent genes and various biological mechanisms. Despite the enormous occurrence of pseudogenes in plants, the lack of experimental validation has contributed toward their unresolved roles in gene regulation. Contrarily, most of the studies associated with gene regulation have been mainly reported for humans, mice, and other mammalian genomes. Consequently, in order to present a cumulative report on plant-based pseudogenes research, an attempt has been made to assemble multiple studies presenting the pseudogene classification, the prediction and the determination of comparative accuracies of various computational pipelines, and recent trends in analyzing their biological functions, and regulatory mechanisms. This review represents the classical, as well as the recent advances on pseudogene identification and their potential roles in transcriptional regulation, which could possibly invigorate the quality of genome annotation, evolutionary analysis, and complexity surrounding the regulatory pathways in plants. Thus, when the ambiguous boundary girdling the pseudogenes eventually recedes on account of their explicit orchestration role, research in flora would no longer saunter compared to that on fauna.
Topics: Animals; Biological Evolution; Gene Expression Regulation; Genome; Mice; Pseudogenes
PubMed: 33993808
DOI: 10.1080/07388551.2021.1901648 -
Oncotarget May 2016Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their... (Review)
Review
Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
Topics: Disease Progression; Gene Expression Regulation, Neoplastic; HMGA1a Protein; HMGA1b Protein; Humans; Models, Genetic; Mutation; Neoplasms; Pseudogenes; RNA, Messenger
PubMed: 26895108
DOI: 10.18632/oncotarget.7427 -
Cell Research Jun 2016
Topics: Animals; High-Throughput Nucleotide Sequencing; Humans; Mice; Nucleic Acid Conformation; Primates; Pseudogenes; RNA; Rats; Retroelements; Sequence Analysis, RNA
PubMed: 27021280
DOI: 10.1038/cr.2016.42