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Frontiers in Endocrinology 2021Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the... (Review)
Review
Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the molecular basis of a wide spectrum of disease. Multiallelic CNVs represent a considerable fraction of large CNVs and are strictly related to segmental duplications according to their prevalent duplicate alleles. RCCX CNV is a complex, multiallelic and tandem CNV located in the major histocompatibility complex (MHC) class III region. RCCX structure is typically defined by the copy number of a DNA segment containing a series of genes - the serine/threonine kinase 19 (), the complement 4 (), the steroid 21-hydroxylase (), and the tenascin-X () - lie close to each other. In the Caucasian population, the most common RCCX haplotype (69%) consists of two segments containing the genes , with a telomere-to-centromere orientation. Nonallelic homologous recombination (NAHR) plays a key role into the RCCX genetic diversity: unequal crossover facilitates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers. The results of these events increased the RCCX genetic diversity and are responsible of specific human diseases. This review provides an overview on RCCX complexity pointing out the molecular bases of Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 deficiency, CAH-X Syndrome and disorders related to CNV of complement component C4.
Topics: Adrenal Hyperplasia, Congenital; Complement C4; DNA Copy Number Variations; Genetic Variation; Humans; Nuclear Proteins; Protein Serine-Threonine Kinases; Pseudogenes; Steroid 21-Hydroxylase; Tenascin
PubMed: 34394006
DOI: 10.3389/fendo.2021.709758 -
BMC Evolutionary Biology Oct 2020Through its ability to open pores in cell membranes, perforin-1 plays a key role in the immune system. Consistent with this role, the gene encoding perforin shows...
BACKGROUND
Through its ability to open pores in cell membranes, perforin-1 plays a key role in the immune system. Consistent with this role, the gene encoding perforin shows hallmarks of complex evolutionary events, including amplification and pseudogenization, in multiple species. A large proportion of these events occurred in phyla for which scarce genomic data were available. However, recent large-scale genomics projects have added a wealth of information on those phyla. Using this input, we annotated perforin-1 homologs in more than eighty species including mammals, reptiles, birds, amphibians and fishes.
RESULTS
We have annotated more than 400 perforin genes in all groups studied. Most mammalian species only have one perforin locus, which may contain a related pseudogene. However, we found four independent small expansions in unrelated members of this class. We could reconstruct the full-length coding sequences of only a few avian perforin genes, although we found incomplete and truncated forms of these gene in other birds. In the rest of reptilia, perforin-like genes can be found in at least three different loci containing up to twelve copies. Notably, mammals, non-avian reptiles, amphibians, and possibly teleosts share at least one perforin-1 locus as assessed by flanking genes. Finally, fish genomes contain multiple perforin loci with varying copy numbers and diverse exon/intron patterns. We have also found evidence for shorter genes with high similarity to the C2 domain of perforin in several teleosts. A preliminary analysis suggests that these genes arose at least twice during evolution from perforin-1 homologs.
CONCLUSIONS
The assisted annotation of new genomic assemblies shows complex patterns of birth-and-death events in the evolution of perforin. These events include duplication/pseudogenization in mammals, multiple amplifications and losses in reptiles and fishes and at least one case of partial duplication with a novel start codon in fishes.
Topics: Amphibians; Animals; Birds; Evolution, Molecular; Fishes; Genome; Mammals; Perforin; Phylogeny; Reptiles
PubMed: 33076840
DOI: 10.1186/s12862-020-01698-1 -
BMC Medical Genomics Apr 2020Given the vast range of molecular mechanisms giving rise to breast cancer, it is unlikely universal cures exist. However, by providing a more precise prognosis for...
BACKGROUND
Given the vast range of molecular mechanisms giving rise to breast cancer, it is unlikely universal cures exist. However, by providing a more precise prognosis for breast cancer patients through integrative models, treatments can become more individualized, resulting in more successful outcomes. Specifically, we combine gene expression, pseudogene expression, miRNA expression, clinical factors, and pseudogene-gene functional networks to generate these models for breast cancer prognostics. Establishing a LASSO-generated molecular gene signature revealed that the increased expression of genes STXBP5, GALP and LOC387646 indicate a poor prognosis for a breast cancer patient. We also found that increased CTSLP8 and RPS10P20 and decreased HLA-K pseudogene expression indicate poor prognosis for a patient. Perhaps most importantly we identified a pseudogene-gene interaction, GPS2-GPS2P1 (improved prognosis) that is prognostic where neither the gene nor pseudogene alone is prognostic of survival. Besides, miR-3923 was predicted to target GPS2 using miRanda, PicTar, and TargetScan, which imply modules of gene-pseudogene-miRNAs that are potentially functionally related to patient survival.
RESULTS
In our LASSO-based model, we take into account features including pseudogenes, genes and candidate pseudogene-gene interactions. Key biomarkers were identified from the features. The identification of key biomarkers in combination with significant clinical factors (such as stage and radiation therapy status) should be considered as well, enabling a specific prognostic prediction and future treatment plan for an individual patient. Here we used our PseudoFuN web application to identify the candidate pseudogene-gene interactions as candidate features in our integrative models. We further identified potential miRNAs targeting those features in our models using PseudoFuN as well. From this study, we present an interpretable survival model based on LASSO and decision trees, we also provide a novel feature set which includes pseudogene-gene interaction terms that have been ignored by previous prognostic models. We find that some interaction terms for pseudogenes and genes are significantly prognostic of survival. These interactions are cross-over interactions, where the impact of the gene expression on survival changes with pseudogene expression and vice versa. These may imply more complicated regulation mechanisms than previously understood.
CONCLUSIONS
We recommend these novel feature sets be considered when training other types of prognostic models as well, which may provide more comprehensive insights into personalized treatment decisions.
Topics: Biomarkers, Tumor; Breast Neoplasms; Computational Biology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Prognosis; Pseudogenes; Survival Rate
PubMed: 32241256
DOI: 10.1186/s12920-020-0687-0 -
International Journal of Molecular... Dec 2020Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that... (Review)
Review
Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases.
Topics: Animals; Biomarkers; Cell-Free Nucleic Acids; Gene Regulatory Networks; Humans; Neurodegenerative Diseases
PubMed: 33339180
DOI: 10.3390/ijms21249582 -
Genome Biology Nov 2022Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic...
BACKGROUND
Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic functional characterization and evolution of pseudogenes remain largely unexplored.
RESULTS
To systematically characterize pseudogenes, we date the origin of human and mouse pseudogenes across vertebrates and observe a burst of pseudogene gain in these two lineages. Based on a hybrid sequencing dataset combining full-length PacBio sequencing, sample-matched Illumina sequencing, and public time-course transcriptome data, we observe that abundant mammalian pseudogenes could be transcribed, which contribute to the establishment of organ identity. Our analyses reveal that developmentally dynamic pseudogenes are evolutionarily conserved and show an increasing weight during development. Besides, they are involved in complex transcriptional and post-transcriptional modulation, exhibiting the signatures of functional enrichment. Coding potential evaluation suggests that 19% of human pseudogenes could be translated, thus serving as a new way for protein innovation. Moreover, pseudogenes carry disease-associated SNPs and conduce to cancer transcriptome perturbation.
CONCLUSIONS
Our discovery reveals an unexpectedly high abundance of mammalian pseudogenes that can be transcribed and translated, and these pseudogenes represent a novel regulatory layer. Our study also prioritizes developmentally dynamic pseudogenes with signatures of functional enrichment and provides a hybrid sequencing dataset for further unraveling their biological mechanisms in organ development and carcinogenesis in the future.
Topics: Humans; Mice; Animals; Pseudogenes; Genome; Mammals; Sequence Analysis, DNA; Neoplasms
PubMed: 36348461
DOI: 10.1186/s13059-022-02802-y -
Genome Biology May 2021Pseudogenes are gene copies presumed to mainly be functionless relics of evolution due to acquired deleterious mutations or transcriptional silencing. Using deep...
Pseudogenes are gene copies presumed to mainly be functionless relics of evolution due to acquired deleterious mutations or transcriptional silencing. Using deep full-length PacBio cDNA sequencing of normal human tissues and cancer cell lines, we identify here hundreds of novel transcribed pseudogenes expressed in tissue-specific patterns. Some pseudogene transcripts have intact open reading frames and are translated in cultured cells, representing unannotated protein-coding genes. To assess the biological impact of noncoding pseudogenes, we CRISPR-Cas9 delete the nucleus-enriched pseudogene PDCL3P4 and observe hundreds of perturbed genes. This study highlights pseudogenes as a complex and dynamic component of the human transcriptional landscape.
Topics: Cell Line; DNA, Complementary; Gene Deletion; Haploidy; Humans; Promoter Regions, Genetic; Pseudogenes; Sequence Analysis, DNA; Transcriptome
PubMed: 33971925
DOI: 10.1186/s13059-021-02369-0 -
Cancer Cell International Jan 2022HPV as the main cause of cervical cancer has long been revealed, but the detailed mechanism has not yet been elucidated. The role of testis/cancer antigen in cervical...
BACKGROUND
HPV as the main cause of cervical cancer has long been revealed, but the detailed mechanism has not yet been elucidated. The role of testis/cancer antigen in cervical cancer has been revealed. However, there are no reports about the statement of testis/cancer-specific non-coding RNA. In this study, we first proposed TCAM1P as a testis/cancer-specific pseudogene, and used a series of experimental data to verify its relationship with HPV, and analyzed its diagnosis value of high-grade cervical lesions and the mechanism of their high expression in cervical cancer. This provides a new direction for the prevention and treatment of cervical cancer.
METHODS
The specific expression of pseudogenes in each tissue was calculated by "TAU" formula. ROC curve was used to judge the diagnosed value of TCAM1P for high-grade lesions. The proliferation ability of cells was measured by CCK8. The expression of TCAM1P, HPV E6/E7 were detected by qRT-PCR. The binding for RBPs on TCAM1P was predicted by starbase v2.0 database, then RIP assay was used to verify. Besides, Gene Ontology (GO) and KEGG enrichment analysis were performed with "clusterprofiler" R package.
RESULTS
TCAM1P was specifically high-expressed in normal testicular tissue and cervical cancer. Interesting, with the severity of cervical lesions increased, the expression of TCAM1P increased, and TCAM1P could effectively diagnose high-grade cervical lesions. Besides, the expression of TCAM1P was HPV dependent, with highest expression in HPV-positive cervical cancer tissues. Furthermore, RIP assay showed that EIF4A3 regulated the expression of TCAM1P through binding with it. CCK8 assay showed that TCAM1P promoted the proliferation and the Gene ontology (GO) and KEGG Pathway enrichment analysis same suggested that TCAM1P is involved in multiple ways in cell proliferation including Cell cycle, DNA replication and etc. CONCLUSIONS: In this study, we firstly proposed that TCAM1P is cancer/testis pseudogene and is regulated by HPV E6/E7 and EIF4A3. TCAM1P promotes the proliferation of cervical cancer cells and acts as promoter in cervical cancer. Otherwise, TCAM1P promote proliferation through regulating cell cycle and DNA replication, but more evidence needs to be provided to reveal the mechanism by which TCAM1P plays a role in cervical cancer.
PubMed: 35016697
DOI: 10.1186/s12935-021-02440-7 -
International Journal of Molecular... Nov 2019Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, gene is in linkage disequilibrium with gene... (Review)
Review
Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, gene is in linkage disequilibrium with gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and-not last-to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene , stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.
Topics: Amino Acid Motifs; Apolipoprotein C-I; Apolipoproteins E; Chromosome Mapping; Gene Expression Regulation; Humans; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, VLDL; Protein Binding; Pseudogenes; Receptors, Lipoprotein
PubMed: 31779116
DOI: 10.3390/ijms20235939 -
World Journal of Surgical Oncology Apr 2021BLCA is a common cancer worldwide, and it is both aggressive and fatal. Immunotherapy (ICT) has achieved an excellent curative effect in BLCA; however, only some BLCA...
BACKGROUND
BLCA is a common cancer worldwide, and it is both aggressive and fatal. Immunotherapy (ICT) has achieved an excellent curative effect in BLCA; however, only some BLCA patients can benefit from ICT. MT1L is a pseudogene, and a previous study suggested that MT1L can be used as an indicator of prognosis in colorectal cancer. However, the role of MT1L in BLCA has not yet been determined.
METHODS
Data were collected from TCGA, and logistic regression, Kaplan-Meier plotter, and multivariate Cox analysis were performed to demonstrate the correlation between the pseudogene MT1L and the prognosis of BLCA. To identify the association of MT1L with tumor-infiltrating immune cells, TIMER and TISIDB were utilized. Additionally, GSEA was performed to elucidate the potential biological function.
RESULTS
The expression of MT1L was decreased in BLCA. Additionally, MT1L was positively correlated with immune cells, such as Tregs (ρ = 0.708) and MDSCs (ρ = 0.664). We also confirmed that MT1L is related to typical markers of immune cells, such as PD-1 and CTLA-4. In addition, a high MT1L expression level was associated with the advanced T and N and high grade in BLCA. Increased expression of MT1L was significantly associated with shorter OS times of BLCA patients (p < 0.05). Multivariate Cox analysis revealed that MT1L expression could be an independent prognostic factor in BLCA.
CONCLUSION
Collectively, our findings demonstrated that the pseudogene MT1L regulates the immune microenvironment, correlates with poor survival, and is an independent prognostic biomarker in BLCA.
Topics: Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Prognosis; Pseudogenes; Tumor Microenvironment; Urinary Bladder Neoplasms
PubMed: 33888142
DOI: 10.1186/s12957-021-02231-4 -
Reports of Practical Oncology and... 2023Skin melanoma is one of the deadliest types of skin cancer and develops from melanocytes. The genetic aberrations in protein-coding genes are well characterized, but...
BACKGROUND
Skin melanoma is one of the deadliest types of skin cancer and develops from melanocytes. The genetic aberrations in protein-coding genes are well characterized, but little is known about changes in non-coding RNAs (ncRNAs) such as pseudogenes. Ribosomal protein pseudogenes (RPPs) have been described as the largest group of pseudogenes which are dispersed in the human genome.
MATERIALS AND METHIDS
We looked deeply at the role of one of them, ribosomal protein L23a pseudogene 53 (), and its potential diagnostic use. The expression level of was profiled in melanoma cell lines using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and analyzed based on the Cancer Genome Atlas (TCGA) data depending on status and clinicopathological parameters. Cellular phenotype, which was associated with levels, was described based on the REACTOME pathway browser, Gene Set Enrichment Analysis (GSEA) analysis as well as Immune and ESTIMATE Scores.
RESULTS
We indicted changes in level depending on a cell line, and based on analysis of TCGA samples demonstrated significant differences in expression between primary and metastatic melanoma, as well as correlation between and overall survival. No differences depending on status were observed. is associated with several signaling pathways and cellular processes.
CONCLUSIONS
This study showed that patients with higher expression of displayed changed infiltration of lymphocytes, macrophages, and neutrophils compared to groups with lower expression of . pseudogene is differently expressed in melanoma compared with normal tissue and its expression is associated with cellular proliferation. Thus, it may be considered as an indicator of patients' survival and a marker for the immune profile assessment.
PubMed: 37456695
DOI: 10.5603/RPOR.a2023.0030