Alzheimer's disease(AD),a neurodegenera-tive disorder with complex etiologies,manifests through a cascade of pathological changes before clinical symptoms become apparent.Among these early changes,alterations in t...Alzheimer's disease(AD),a neurodegenera-tive disorder with complex etiologies,manifests through a cascade of pathological changes before clinical symptoms become apparent.Among these early changes,alterations in the expression of non-coding RNAs(ncRNAs)have emerged as pivotal events.In this study,we focused on the aber-rant expression of ncRNAs and revealed that Lamrl-ps1,a pseudogene of the laminin receptor,significantly exac-erbates early spatial learning and memory deficits in APP/PS1 mice.Through a combination of bioinformatics pre-diction and experimental validation,we identified the miR-29c/Bacel pathway as a potential regulatory mechanism by which Lamrl-ps1 influences AD pathology.Importantly,augmenting the miR-29c-3p levels in mice ameliorated memory deficits,underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention.This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for consid-ering miR-29c as a viable therapeutic target,offering a novel avenue for AD research and treatment strategies.展开更多
Novel pseudogenes homologous to the mitochondrial(mt) 16S rRNA gene were detected via different approaches. Eight pseudogenes were sequenced. Copynumber polymorphism of the mtDNA pseudogenes wasobserved among randomly...Novel pseudogenes homologous to the mitochondrial(mt) 16S rRNA gene were detected via different approaches. Eight pseudogenes were sequenced. Copynumber polymorphism of the mtDNA pseudogenes wasobserved among randomly chosen individuals, and evenamong siblings. A mtDNA pseudogene in the Ychromosome was observed in a YAC clone carrying onlyrepetitive sequence tag site (STS). PCR screening of human yeast artificial chromosome (YAC) libraries showedthat there were at least 5.7×105 hp of the mtDNA pseudogenes in each haploid nuclear genome. Possible involvement of the mtDNA pseudogenes in the variable part ofthe human nuclear genome is discussed.展开更多
Pseudogenes are genomic remnants of ancient protein-coding genes which have lost their coding potentials through evolution.Although broadly existed,pseudogenes used to be considered as junk or relics of genomes which ...Pseudogenes are genomic remnants of ancient protein-coding genes which have lost their coding potentials through evolution.Although broadly existed,pseudogenes used to be considered as junk or relics of genomes which have not drawn enough attentions of biologists until recent years.With the broad applications of high-throughput experimental techniques,growing lines of evidence have strongly suggested that some pseudogenes possess special functions,including regulating parental gene expression and participating in the regulation of many biological processes.In this review,we summarize some basic features of pseudogenes and their functions in regulating development and diseases.All of these observations indicate that pseudogenes are not purely dead fossils of genomes,but warrant further exploration in their distribution,expression regulation and functions.A new nomenclature is desirable for the currently called ＇pseudogenes＇ to better describe their functions.展开更多
Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudog...Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudogenes with cancer prognosis. We selected six potentially functional single nucleotide polymorphisms （SNPs） in cancerrelated pseudogenes, and performed a case-only study to assess the association between those SNPs and the prognosis of hepatocellular carcinoma （HCC） in 331 HBV-positive HCC patients without surgical treatment. Log-rank test and Cox proportional hazard models were used for survival analysis. We found that the A allele of rs9909601 in E2F3P1 was significantly associated with a better prognosis compared with the G allele [adjusted hazard ratio （HR） = 0.69, 95% confidence interval （CI） = 0.56-0.86, P = 0.001]. Additionally, this protective effect was more predominant for patients without chemotherapy and transcatheter hepatic arterial chemoembolization （TACE） treatment. Interestingly, we also detected a statistically significant multiplicative interaction between genotypes of rs9909601 and chemotherapy or TACE status on HCC survival （P for multiplicative interaction 〈 0.001）. These findings indicate that rs9909601 in the pseudogene E2F3P1 may be a genetic marker for HCC prognosis in Chinese.展开更多
More and more studies have demonstrated that pseudogenes possess coding ability,and the functions of their transcripts in the development of diseases have been partially revealed.However,the role of pseudogenes in mai...More and more studies have demonstrated that pseudogenes possess coding ability,and the functions of their transcripts in the development of diseases have been partially revealed.However,the role of pseudogenes in maintenance of normal physiological states and life activities has long been neglected.Here,we identify pseudogenes that are dynamically expressed during human early embryogenesis,showing different expression patterns from that of adult tissues.We explore the expression correlation between pseudogenes and the parent genes,partly due to their shared gene regulatory elements or the potential regulation network between them.The essential role of three pseudogenes,PI4KAP1,TMED10P1,and FBXW4P1,in maintaining self-renewal of human embryonic stem cells is demonstrated.We further find that the three pseudogenes might perform their regulatory functions by binding to proteins or microRNAs.The pseudogene-related single-nucleotide polymorphisms are significantly associated with human congenital disease,further illustrating their importance during early embryonic development.Overall,this study is an excavation and exploration of functional pseudogenes during early human embryonic development,suggesting that pseudogenes are not only capable of being specifically activated in pathological states,but also play crucial roles in the maintenance of normal physiological states.展开更多
Objective: To clone cytochrome P450 from Aedes aegypti(Ae. aegypti) and determine the characteristics using bioinformatics tools. Methods: Cytochrome P450 of Ae. aegypti was amplified using polymerase chain reaction, ...Objective: To clone cytochrome P450 from Aedes aegypti(Ae. aegypti) and determine the characteristics using bioinformatics tools. Methods: Cytochrome P450 of Ae. aegypti was amplified using polymerase chain reaction, cloned and sequenced. Evolutionary relationship of the sequence was inferred and bioinformatics tools were used to predict subcellular localisation, signal peptide, transmembrane helix, phosphorylation, O-glycosylation, secondary and tertiary structures of the deduced protein. Results: Polymerase chain reaction rather amplified a cytochrome P450 pseudogene which was named CYP4H44P(Gen Bank accession number KF779932). The pseudogene has 1537 nucleotides and an open reading frame of 335 amino acids containing cytochrome P450 motifs except the Wxxx R motif. It is highly homologous to CYP4H28 and CYP4H28v2. Phylogenetic analysis and evolutionary divergence showed strong clustering with CYP4H28 alleles and least divergence from the alleles respectively. The deduced protein was predicted to be found in the cytoplasm and likely to be phosphorylated but devoid of signal peptide, transmembrane helix and O-glycosylated sites. The secondary and tertiary structures were also generated. Conclusions: A cytochrome P450 pseudogene, CYP4H44 P was cloned from Ae. aegypti. The pseudogene is homologous with CYP4H28 alleles and seems to have recently diverged from this group. Isolating this pseudogene is an important step for evaluating its biological role in the mosquito and for the evolutionary analysis of Ae. aegypti CYPs.展开更多
Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies and occasionally associated with orofacial, limb and musculoskeletal malform...Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves Ⅴ through Ⅻ underlines the disease pathogenesis. Although a genetic etiology for Moebius syndrome was proposed, molecular genetic studies to identify the causative gene（s） are scarce. In this study, we selected two candidate genes. One is BASP1 residing in a human chromosome 5p15.1-p15.2, syntenic to mouse chromosome 15qA2-qB2, to which a mouse model with facial nerve anomalies was mapped. The other is transcribed processed pseudogene TPψg-BASP1, which is located on chromosome 13q flanking the putative locus for Moebius syndrome and might be involved in the regulation of the transcripts encoded by BASP1. Mutation analyses in nineteen patients excluded these genes as being candidates for Moebius syndrome.展开更多
Olfactory receptors（ORs）,the first dedicated molecules with which odorants physically interact to arouse an olfactory sensation,constitute the largest gene family in vertebrates.Dogs and wolves,like many other mamma...Olfactory receptors（ORs）,the first dedicated molecules with which odorants physically interact to arouse an olfactory sensation,constitute the largest gene family in vertebrates.Dogs and wolves,like many other mammals,have a highly developed capability to detect and identify odorant molecules,even at minimum concentrations.In this study,the olfactory receptor repertoire from domestic dog and its closest relative,the wolf,were sequenced to estimate the fraction of pseudogenes in each subspecies.The fraction of disrupted olfactory receptor genes in dog was 17.78%,whereas,that in wolf was 12.08%.As expected the dog was less dependent on olfaction than the wolf,and the dog had more olfactory receptor pseudogenes.However,the observed difference between the two subspecies was not at the significant level（χ2 = 1.388,p = 0.239 0.05）.The values indicated that although domestication might play a role in the reduction of OR genes,it could not be concluded that the living environment provided by domestication lead to a significant reduction of the functional olfactory receptor repertoire.Furthermore,the purpose of domestication may also have influence on the ratio of functional olfactory receptor genes reduction.展开更多
Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue.For this reason,their presence is often considered troublesome in molecular diagnostics.In p...Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue.For this reason,their presence is often considered troublesome in molecular diagnostics.In pseudoxanthoma elasticum(PXE),a disease predominantly caused by mutations in ATPbinding cassette family C member 6(ABCC6),the presence of two pseudogenes complicates the analysis of sequence data.With whole-exome sequencing(WES)becoming the standard of care in molecular diagnostics,we wanted to evaluate whether this technique is as reliable as gene-specific targeted enrichment analysis for the analysis of ABCC6.We established a PCR-based targeted enrichment and next-generation sequencing testing approach and demonstrated that the ABCC6-specific enrichment combined with the applied mapping algorithm overcomes the complication of ABCC6 pseudogene aspecificities,contrary to WES.We propose a time-and cost-efficient diagnostic strategy for comprehensive and accurate molecular genetic testing of PXE,which is highly automatable.展开更多
The outcomes of ovarian cancer are complicated and usually unfavorable due to their diagnoses at a late stage.Identifying the efficient prognostic biomarkers to improve the survival of ovarian cancer is urgently warra...The outcomes of ovarian cancer are complicated and usually unfavorable due to their diagnoses at a late stage.Identifying the efficient prognostic biomarkers to improve the survival of ovarian cancer is urgently warranted.The survival-related pseudogenes retrieved from the Cancer Genome Atlas database were screened by univariate Cox regression analysis and further assessed by least absolute shrinkage and selection operator(LASSO)method.A risk score model based on the prognostic pseudogenes was also constructed.The pseudogene-mRNA regulatory networks were established using correlation analysis,and their potent roles in the ovarian cancer progression were uncovered by functional enrichment analysis.Lastly,ssGSEA and ESTIMATE algorithms was used to evaluate the levels of immune cell infiltrations in cancer tissues and explore their relationship with risk signature.A prediction model of 10-pseudogenes including RPL10P6,AC026688.1,FAR2P4,AL391840.2,AC068647.2,FAM35BP,GBP1P1,ARL4AP5,RPS3AP2,and AMD1P1 was established.The 10-pseudogenes signature was demonstrated to be an independent prognostic factor in patient with ovarian cancer in the random set(hazard ratio[HR]=2.512,95%confidence interval[CI]=2.03–3.11,P<0.001)and total set(HR=1.71,95%CI=1.472–1.988,P<0.001).When models integrating with age,grade,stage,and risk signature,the Area Under Curve(AUC)of the 1-year,3-year,5-year and 10-year Receiver Operating Characteristic curve in the random set and total set were 0.854,0.824,0.855,0.805 and 0.679,0.697,0.739,0.790,respectively.The results of functional enrichment analysis indicated that the underlying mechanisms by which these pseudogenes influence cancer prognosis may involve the immune-related biological processes and signaling pathways.Correlation analysis showed that risk signature was significantly correlated with immune cell infiltration and immune score.We identified a novel 10-pseudogenes signature to predict the survival of patients with ovarian cancer,and that may serve as novel possible prognostic biomarkers and therapeutic targets for ovarian cancer.展开更多
HMGN2 have functions in inflammatory response.However,the role of HMGN2 in severe acute pancreatitis(SAP)remains unclear.Here,our study was to discuss the role and regulatory mechanism ofHMGN2 in SAP.In this study,the...HMGN2 have functions in inflammatory response.However,the role of HMGN2 in severe acute pancreatitis(SAP)remains unclear.Here,our study was to discuss the role and regulatory mechanism ofHMGN2 in SAP.In this study,the SAP cell model of AR42J was used to study the function and mechanism of HMGN2 in SAP.The protein expression in cells and serums were examined by western blot and ELISA assay.qPCR was used to test the transcriptional RNA level.Cell viability were examined by MTT assay.Luciferase assay was used to evaluate the interaction between gene and gene.Our results showed that HMGN2 was significantly upregulated in SAP patients.The database predicted and luciferase assay data indicated the HMGN2 was directly binding with miR-590-3p.ELISA,MTT and western blot experiments showed that the HMGN2 were promoted the cell proliferation,reduced the inflammation,and repressed the cell autophagy.Mechanism studies showed that the pseudogene HMGN2P46 level was positively correlated with HMGN2 and upregulated HMGN2 expression by competing for miR-590-3p in SAP.Taken together,all over these results showed upregulation of HMGN2 alleviates SAP,this process was regulated by HMGN2P46 competitively binding with miR-590-3p,which may provide a new insight for the treatment and intervention in SAP.Pseudogene HMGN2P46 was a miRNA sponge to regulate HMGN2 level by competing for miR-590-3p to alleviate the process of SAP.It provided a novel strategy for the diagnosis and treatment of severe acute pancreatitis.展开更多
Objective Pseudogenes are initially regarded as nonfunctional genomic sequences,but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activiti...Objective Pseudogenes are initially regarded as nonfunctional genomic sequences,but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities.Olfactory receptor family 7 subfamily E member 47 pseudogene(OR7E47P)is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment(TME)of lung adenocarcinoma(LUAD).This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma(LUSC).Methods Clinical and molecular information from The Cancer Genome Atlas(TCGA)LUSC cohort was used to identify OR7E47P-related immune genes(ORIGs)by weighted gene correlation network analysis(WGCNA).Based on the ORIGs,2 OR7E47P clusters were identified using non-negative matrix factorization(NMF)clustering,and the stability of the clustering was tested by an extreme gradient boosting classifier(XGBoost).LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model(ORPScore)for immunotherapy.The Botling cohorts and 8 immunotherapy cohorts(the Samstein,Braun,Jung,Gide,IMvigor210,Lauss,Van Allen,and Cho cohorts)were included as independent validation cohorts.Results OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC.A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters(Cluster 1 and Cluster 2)with distinct immune,mutation,and stromal programs.Compared to Cluster 1,Cluster 2 had more infiltration by immune and stromal cells,lower mutation rates of driver genes,and higher expression of immune-related proteins.The clustering performed well in the internal and 5 external validation cohorts.Based on the 7 ORIGs(HOPX,STX2,WFS,DUSP22,SLFN13,GGCT,and CCSER2),the ORPScore was constructed to predict the prognosis and the treatment response.In addition,the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients.The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts.Conclusion Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC.ORIGs can be applied to molecularly stratify patients,and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.展开更多
GAPDH is a conserved enzyme that binds diverse proteins, such as Siah during apoptotic nuclear translocation. There is one somatic GAPDH gene, but over 60 pseudogenes, the expression of which is nebulous. A single nuc...GAPDH is a conserved enzyme that binds diverse proteins, such as Siah during apoptotic nuclear translocation. There is one somatic GAPDH gene, but over 60 pseudogenes, the expression of which is nebulous. A single nucleotide polymorphism (SNP) in the GAPDHP44 pseudogene exhibits a beneficial allele in AD. The objective of this study was to examine the P44 gene and to propose a mechanism for the putative protein and its impact on AD. We examined the sequences in the putative coding region of the human GAPDHP44 gene and the upstream genetic elements usinga bioinformatics approach. We compared the amino acid sequences of the putative gene product with that of the parent GAPDH protein. There is a TATA box 24 nt upstream from, and a Kozak sequence at, putative transcription and translation start sites, respecttively. The upstream region also has sequences (7 - 16 nt) paralogous to those in parent gene introns;one shows homology to a known enhancer element. The resulting protein would contain 139 aa due to a stop codon, roughly the same size as the dinucleotide domain (151 aa) of the parent protein. The SNP is in a region (residues 80 - 120) that binds to the protein GOSPEL. We propose that the beneficial SNP may cause a glutamine to glutamate substitution. NMDA-stmulated neurons undergo GAPDH nitrosylation, Siah translocation, but can be rescued by GOSPEL binding to GAPDH. Our model suggests that the putative P44 protein may regulate GAPDH-GO-SPEL interaction and the beneficial SNPmay ameliorate AD.展开更多
The p53 tumor suppressor gene is either non- functional or highly and frequently mutated in majority of cancers. In our study towards understanding cellular adaptations to stress using a rat histiocytic tumor model, w...The p53 tumor suppressor gene is either non- functional or highly and frequently mutated in majority of cancers. In our study towards understanding cellular adaptations to stress using a rat histiocytic tumor model, we have identified mis-sense mutation in p53 that led to premature termination of translation at the carboxyl-termi- nus. Further, the cDNA isolated from heat stre- ssed cells producing two amplicons with cDNA specific primers (N-terminus) suggested occurrence of possible pseudogene(s). A comparative analysis between different tumor cell lines of rat origin and rat genomic DNA using p53 gene specific primers resulted in the amplification of a processed pseudogene and its positive interaction with wild type p53 probe on Southern blot analysis. The genomic DNA sequence analysis, and sequence comparison with cDNA discovered that the processed pseudogene lacks DNA binding domain and nuclear localization signal, however, contains the ribosomal entry and stop signals. Rat genome BLAST analysis of the pesudogene suggested chromosome-18 localization which was in addition to 14, 13, 10, 9 localization of the cDNA. In the interest of unraveling hidden dimensions of p53 tumor suppressor gene, our study explores the probability of p53 functional pseudogenes in rat histiocytoma.展开更多
Olfactory receptors(ORs),the largest vertebrate multigene family,exhibit wide copy number variation among taxa,ranging from~100 to 4000.The ecological importance of smell has been suggested to positively correlate wit...Olfactory receptors(ORs),the largest vertebrate multigene family,exhibit wide copy number variation among taxa,ranging from~100 to 4000.The ecological importance of smell has been suggested to positively correlate with OR gene number,though debate exists on whether the number of total ORs,functional ORs,or the percentage of pseudogenes matters most.While olfaction has been poorly studied in most birds,Turkey Vultures(Cathartes aura)demonstrate keen olfactory ability,capable of foraging using smell alone.In contrast,Black Vultures(Coragyps atratus)have been thought to primarily use vision to locate food.Comparison of the OR genes in these two New World vultures presents an opportunity to examine the dynamics of OR evolution in related avian species that may differ in olfactory abilities.Using a PCR and cloning approach with degenerate primers,we sampled the OR subgenome in Turkey and Black Vultures,as well as Red-tailed Hawks(Buteo jamaicensis)and the distantly related Chicken(Gallus gallus),neither of which are thought to use olfaction extensively.Our results indicate that Turkey Vultures have many more OR genes than Red-tailed Hawks or chickens.Surprisingly,Black Vultures had an intermediate number of OR genes.The number of OR genes we estimated in the Turkey Vulture was much greater than previously reported in studies that used short-read sequencing.Additionally,we found that OR genes from New World vultures and Red-tailed Hawks form clades that were distinct from the clade that included most chicken OR genes,indicating that chickens share few OR orthologs with New World vultures or hawks.As previously observed in other animal groups,pseudogenes appeared throughout all clades and their percentage varied among taxa.These findings suggest the OR gene family is highly dynamic,changing rapidly over evolutionary time,and that taxa may have distinct suites of ORs in their genomes.展开更多
基金supported by a Cooperation Project of Nanchong Science and Technology(22SXZRKX0016)the Research Development Fund of North Sichuan Medical College(CBY21-QD24)+2 种基金the Sichuan Science and Technology Program(2022NSFSC1472)the National Natural Science Foundation of China(32200795)the Natural Science Foundation of Hubei Province(2022CFB608).
文摘Alzheimer's disease(AD),a neurodegenera-tive disorder with complex etiologies,manifests through a cascade of pathological changes before clinical symptoms become apparent.Among these early changes,alterations in the expression of non-coding RNAs(ncRNAs)have emerged as pivotal events.In this study,we focused on the aber-rant expression of ncRNAs and revealed that Lamrl-ps1,a pseudogene of the laminin receptor,significantly exac-erbates early spatial learning and memory deficits in APP/PS1 mice.Through a combination of bioinformatics pre-diction and experimental validation,we identified the miR-29c/Bacel pathway as a potential regulatory mechanism by which Lamrl-ps1 influences AD pathology.Importantly,augmenting the miR-29c-3p levels in mice ameliorated memory deficits,underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention.This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for consid-ering miR-29c as a viable therapeutic target,offering a novel avenue for AD research and treatment strategies.
文摘Novel pseudogenes homologous to the mitochondrial(mt) 16S rRNA gene were detected via different approaches. Eight pseudogenes were sequenced. Copynumber polymorphism of the mtDNA pseudogenes wasobserved among randomly chosen individuals, and evenamong siblings. A mtDNA pseudogene in the Ychromosome was observed in a YAC clone carrying onlyrepetitive sequence tag site (STS). PCR screening of human yeast artificial chromosome (YAC) libraries showedthat there were at least 5.7×105 hp of the mtDNA pseudogenes in each haploid nuclear genome. Possible involvement of the mtDNA pseudogenes in the variable part ofthe human nuclear genome is discussed.
基金supported by the grants from the Ministry of Science and Technology of China(No.2011CBA01101) to X.-J.W.from the Chinese Academy of Sciences(Nos. XDA01020105,KSCX2-EW-R-01-03 and 2010-Biols-CAS0303) to X.-J.W.
文摘Pseudogenes are genomic remnants of ancient protein-coding genes which have lost their coding potentials through evolution.Although broadly existed,pseudogenes used to be considered as junk or relics of genomes which have not drawn enough attentions of biologists until recent years.With the broad applications of high-throughput experimental techniques,growing lines of evidence have strongly suggested that some pseudogenes possess special functions,including regulating parental gene expression and participating in the regulation of many biological processes.In this review,we summarize some basic features of pseudogenes and their functions in regulating development and diseases.All of these observations indicate that pseudogenes are not purely dead fossils of genomes,but warrant further exploration in their distribution,expression regulation and functions.A new nomenclature is desirable for the currently called ＇pseudogenes＇ to better describe their functions.
基金funded by the National Natural Science Foundation of China(81372606 and 81072344)supported by the National Key Basic Research Program Grant(2013CB911400)+6 种基金the project supportedby the National Science Foundation for Distinguished Young Scholarsof China(81225020)Foundation of Jiangsu Province for Distinguished Young Scholars(BK2012042)Foundation for the Program for NewCentury Excellent Talents in University(NCET-10-0178)the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions(122031)Young Tip-top Talents Support Program by the Organization Department of the CPC Central Committee,the Author of National Excellent Doctoral Dissertation(201081)Jiangsu Province Clinical Science and Technology Projects(BL2012008)the Priority Academic Program for the Development of Jiangsu Higher Education Institutions(Public Health and PreventiveMedicine)
文摘Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudogenes with cancer prognosis. We selected six potentially functional single nucleotide polymorphisms （SNPs） in cancerrelated pseudogenes, and performed a case-only study to assess the association between those SNPs and the prognosis of hepatocellular carcinoma （HCC） in 331 HBV-positive HCC patients without surgical treatment. Log-rank test and Cox proportional hazard models were used for survival analysis. We found that the A allele of rs9909601 in E2F3P1 was significantly associated with a better prognosis compared with the G allele [adjusted hazard ratio （HR） = 0.69, 95% confidence interval （CI） = 0.56-0.86, P = 0.001]. Additionally, this protective effect was more predominant for patients without chemotherapy and transcatheter hepatic arterial chemoembolization （TACE） treatment. Interestingly, we also detected a statistically significant multiplicative interaction between genotypes of rs9909601 and chemotherapy or TACE status on HCC survival （P for multiplicative interaction 〈 0.001）. These findings indicate that rs9909601 in the pseudogene E2F3P1 may be a genetic marker for HCC prognosis in Chinese.
基金supported by the National Key Research and Development Program of China(2021YFA0805703,2019YFA0801800,and 2019YFA0802600)the National Natural Science Foundation of China(82330007,82122005,92268205 and 81970101)+1 种基金CAMS Innovation Fund for Medical Sciences(2021-I2M1-019)Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00027)。
文摘More and more studies have demonstrated that pseudogenes possess coding ability,and the functions of their transcripts in the development of diseases have been partially revealed.However,the role of pseudogenes in maintenance of normal physiological states and life activities has long been neglected.Here,we identify pseudogenes that are dynamically expressed during human early embryogenesis,showing different expression patterns from that of adult tissues.We explore the expression correlation between pseudogenes and the parent genes,partly due to their shared gene regulatory elements or the potential regulation network between them.The essential role of three pseudogenes,PI4KAP1,TMED10P1,and FBXW4P1,in maintaining self-renewal of human embryonic stem cells is demonstrated.We further find that the three pseudogenes might perform their regulatory functions by binding to proteins or microRNAs.The pseudogene-related single-nucleotide polymorphisms are significantly associated with human congenital disease,further illustrating their importance during early embryonic development.Overall,this study is an excavation and exploration of functional pseudogenes during early human embryonic development,suggesting that pseudogenes are not only capable of being specifically activated in pathological states,but also play crucial roles in the maintenance of normal physiological states.
基金funded by the Malaysian Ministry of Education(ERGS 203/PJJAUH/6730097)Universiti Sains Malaysia(RU grant 1001/PJJAUH/815095)
文摘Objective: To clone cytochrome P450 from Aedes aegypti(Ae. aegypti) and determine the characteristics using bioinformatics tools. Methods: Cytochrome P450 of Ae. aegypti was amplified using polymerase chain reaction, cloned and sequenced. Evolutionary relationship of the sequence was inferred and bioinformatics tools were used to predict subcellular localisation, signal peptide, transmembrane helix, phosphorylation, O-glycosylation, secondary and tertiary structures of the deduced protein. Results: Polymerase chain reaction rather amplified a cytochrome P450 pseudogene which was named CYP4H44P(Gen Bank accession number KF779932). The pseudogene has 1537 nucleotides and an open reading frame of 335 amino acids containing cytochrome P450 motifs except the Wxxx R motif. It is highly homologous to CYP4H28 and CYP4H28v2. Phylogenetic analysis and evolutionary divergence showed strong clustering with CYP4H28 alleles and least divergence from the alleles respectively. The deduced protein was predicted to be found in the cytoplasm and likely to be phosphorylated but devoid of signal peptide, transmembrane helix and O-glycosylated sites. The secondary and tertiary structures were also generated. Conclusions: A cytochrome P450 pseudogene, CYP4H44 P was cloned from Ae. aegypti. The pseudogene is homologous with CYP4H28 alleles and seems to have recently diverged from this group. Isolating this pseudogene is an important step for evaluating its biological role in the mosquito and for the evolutionary analysis of Ae. aegypti CYPs.
基金supported by the Research Fund of the Istanbul University, Turkey (No. 480 [2359/2006])
文摘Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves Ⅴ through Ⅻ underlines the disease pathogenesis. Although a genetic etiology for Moebius syndrome was proposed, molecular genetic studies to identify the causative gene（s） are scarce. In this study, we selected two candidate genes. One is BASP1 residing in a human chromosome 5p15.1-p15.2, syntenic to mouse chromosome 15qA2-qB2, to which a mouse model with facial nerve anomalies was mapped. The other is transcribed processed pseudogene TPψg-BASP1, which is located on chromosome 13q flanking the putative locus for Moebius syndrome and might be involved in the regulation of the transcripts encoded by BASP1. Mutation analyses in nineteen patients excluded these genes as being candidates for Moebius syndrome.
基金supported by Program for New Century Excellent Talents (NCET-07-0507)National Natural Science Foundation of China (30370218)+1 种基金Natural Science Foundation of Shandong Province (Z2008D01)Project of Science and Technology Development Plan of Shandong Province (2007GG2009011)
文摘Olfactory receptors（ORs）,the first dedicated molecules with which odorants physically interact to arouse an olfactory sensation,constitute the largest gene family in vertebrates.Dogs and wolves,like many other mammals,have a highly developed capability to detect and identify odorant molecules,even at minimum concentrations.In this study,the olfactory receptor repertoire from domestic dog and its closest relative,the wolf,were sequenced to estimate the fraction of pseudogenes in each subspecies.The fraction of disrupted olfactory receptor genes in dog was 17.78%,whereas,that in wolf was 12.08%.As expected the dog was less dependent on olfaction than the wolf,and the dog had more olfactory receptor pseudogenes.However,the observed difference between the two subspecies was not at the significant level（χ2 = 1.388,p = 0.239 0.05）.The values indicated that although domestication might play a role in the reduction of OR genes,it could not be concluded that the living environment provided by domestication lead to a significant reduction of the functional olfactory receptor repertoire.Furthermore,the purpose of domestication may also have influence on the ratio of functional olfactory receptor genes reduction.
基金supported by a Methusalem grant(BOF08/01M01108)from Ghent Universityfunded by Ghent University+1 种基金FWOthe Flemish Government-department EWI。
文摘Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue.For this reason,their presence is often considered troublesome in molecular diagnostics.In pseudoxanthoma elasticum(PXE),a disease predominantly caused by mutations in ATPbinding cassette family C member 6(ABCC6),the presence of two pseudogenes complicates the analysis of sequence data.With whole-exome sequencing(WES)becoming the standard of care in molecular diagnostics,we wanted to evaluate whether this technique is as reliable as gene-specific targeted enrichment analysis for the analysis of ABCC6.We established a PCR-based targeted enrichment and next-generation sequencing testing approach and demonstrated that the ABCC6-specific enrichment combined with the applied mapping algorithm overcomes the complication of ABCC6 pseudogene aspecificities,contrary to WES.We propose a time-and cost-efficient diagnostic strategy for comprehensive and accurate molecular genetic testing of PXE,which is highly automatable.
基金supported by the National Natural Science Foundation of China Grants 81872127,81602289(FQ)81872694,81673267,81473040(JL)+3 种基金81402753,81672303,81871876(LY)Guangzhou Science Research Program General Project Grant 201707010123(FQ)Guangzhou Municipal Scientific Research Project Grant 1201630073(FQ)Guangdong High School Young Innovative Talents Project Grant 2015KQNCX136(FQ).
文摘The outcomes of ovarian cancer are complicated and usually unfavorable due to their diagnoses at a late stage.Identifying the efficient prognostic biomarkers to improve the survival of ovarian cancer is urgently warranted.The survival-related pseudogenes retrieved from the Cancer Genome Atlas database were screened by univariate Cox regression analysis and further assessed by least absolute shrinkage and selection operator(LASSO)method.A risk score model based on the prognostic pseudogenes was also constructed.The pseudogene-mRNA regulatory networks were established using correlation analysis,and their potent roles in the ovarian cancer progression were uncovered by functional enrichment analysis.Lastly,ssGSEA and ESTIMATE algorithms was used to evaluate the levels of immune cell infiltrations in cancer tissues and explore their relationship with risk signature.A prediction model of 10-pseudogenes including RPL10P6,AC026688.1,FAR2P4,AL391840.2,AC068647.2,FAM35BP,GBP1P1,ARL4AP5,RPS3AP2,and AMD1P1 was established.The 10-pseudogenes signature was demonstrated to be an independent prognostic factor in patient with ovarian cancer in the random set(hazard ratio[HR]=2.512,95%confidence interval[CI]=2.03–3.11,P<0.001)and total set(HR=1.71,95%CI=1.472–1.988,P<0.001).When models integrating with age,grade,stage,and risk signature,the Area Under Curve(AUC)of the 1-year,3-year,5-year and 10-year Receiver Operating Characteristic curve in the random set and total set were 0.854,0.824,0.855,0.805 and 0.679,0.697,0.739,0.790,respectively.The results of functional enrichment analysis indicated that the underlying mechanisms by which these pseudogenes influence cancer prognosis may involve the immune-related biological processes and signaling pathways.Correlation analysis showed that risk signature was significantly correlated with immune cell infiltration and immune score.We identified a novel 10-pseudogenes signature to predict the survival of patients with ovarian cancer,and that may serve as novel possible prognostic biomarkers and therapeutic targets for ovarian cancer.
基金This work was supported by National Natural Science Foundation of China[81901957]China Postdoctoral Science Foundation[2018M633723].
文摘HMGN2 have functions in inflammatory response.However,the role of HMGN2 in severe acute pancreatitis(SAP)remains unclear.Here,our study was to discuss the role and regulatory mechanism ofHMGN2 in SAP.In this study,the SAP cell model of AR42J was used to study the function and mechanism of HMGN2 in SAP.The protein expression in cells and serums were examined by western blot and ELISA assay.qPCR was used to test the transcriptional RNA level.Cell viability were examined by MTT assay.Luciferase assay was used to evaluate the interaction between gene and gene.Our results showed that HMGN2 was significantly upregulated in SAP patients.The database predicted and luciferase assay data indicated the HMGN2 was directly binding with miR-590-3p.ELISA,MTT and western blot experiments showed that the HMGN2 were promoted the cell proliferation,reduced the inflammation,and repressed the cell autophagy.Mechanism studies showed that the pseudogene HMGN2P46 level was positively correlated with HMGN2 and upregulated HMGN2 expression by competing for miR-590-3p in SAP.Taken together,all over these results showed upregulation of HMGN2 alleviates SAP,this process was regulated by HMGN2P46 competitively binding with miR-590-3p,which may provide a new insight for the treatment and intervention in SAP.Pseudogene HMGN2P46 was a miRNA sponge to regulate HMGN2 level by competing for miR-590-3p to alleviate the process of SAP.It provided a novel strategy for the diagnosis and treatment of severe acute pancreatitis.
基金the Wuhan University Medical Faculty Innovation Seed Fund Cultivation Project(No.TFZZ2018025)the Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province(No.CXPJJH12000001-2020313)the National Natural Science Foundation of China(No.81670123 and No.81670144).
文摘Objective Pseudogenes are initially regarded as nonfunctional genomic sequences,but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities.Olfactory receptor family 7 subfamily E member 47 pseudogene(OR7E47P)is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment(TME)of lung adenocarcinoma(LUAD).This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma(LUSC).Methods Clinical and molecular information from The Cancer Genome Atlas(TCGA)LUSC cohort was used to identify OR7E47P-related immune genes(ORIGs)by weighted gene correlation network analysis(WGCNA).Based on the ORIGs,2 OR7E47P clusters were identified using non-negative matrix factorization(NMF)clustering,and the stability of the clustering was tested by an extreme gradient boosting classifier(XGBoost).LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model(ORPScore)for immunotherapy.The Botling cohorts and 8 immunotherapy cohorts(the Samstein,Braun,Jung,Gide,IMvigor210,Lauss,Van Allen,and Cho cohorts)were included as independent validation cohorts.Results OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC.A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters(Cluster 1 and Cluster 2)with distinct immune,mutation,and stromal programs.Compared to Cluster 1,Cluster 2 had more infiltration by immune and stromal cells,lower mutation rates of driver genes,and higher expression of immune-related proteins.The clustering performed well in the internal and 5 external validation cohorts.Based on the 7 ORIGs(HOPX,STX2,WFS,DUSP22,SLFN13,GGCT,and CCSER2),the ORPScore was constructed to predict the prognosis and the treatment response.In addition,the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients.The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts.Conclusion Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC.ORIGs can be applied to molecularly stratify patients,and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.
文摘GAPDH is a conserved enzyme that binds diverse proteins, such as Siah during apoptotic nuclear translocation. There is one somatic GAPDH gene, but over 60 pseudogenes, the expression of which is nebulous. A single nucleotide polymorphism (SNP) in the GAPDHP44 pseudogene exhibits a beneficial allele in AD. The objective of this study was to examine the P44 gene and to propose a mechanism for the putative protein and its impact on AD. We examined the sequences in the putative coding region of the human GAPDHP44 gene and the upstream genetic elements usinga bioinformatics approach. We compared the amino acid sequences of the putative gene product with that of the parent GAPDH protein. There is a TATA box 24 nt upstream from, and a Kozak sequence at, putative transcription and translation start sites, respecttively. The upstream region also has sequences (7 - 16 nt) paralogous to those in parent gene introns;one shows homology to a known enhancer element. The resulting protein would contain 139 aa due to a stop codon, roughly the same size as the dinucleotide domain (151 aa) of the parent protein. The SNP is in a region (residues 80 - 120) that binds to the protein GOSPEL. We propose that the beneficial SNP may cause a glutamine to glutamate substitution. NMDA-stmulated neurons undergo GAPDH nitrosylation, Siah translocation, but can be rescued by GOSPEL binding to GAPDH. Our model suggests that the putative P44 protein may regulate GAPDH-GO-SPEL interaction and the beneficial SNPmay ameliorate AD.
文摘The p53 tumor suppressor gene is either non- functional or highly and frequently mutated in majority of cancers. In our study towards understanding cellular adaptations to stress using a rat histiocytic tumor model, we have identified mis-sense mutation in p53 that led to premature termination of translation at the carboxyl-termi- nus. Further, the cDNA isolated from heat stre- ssed cells producing two amplicons with cDNA specific primers (N-terminus) suggested occurrence of possible pseudogene(s). A comparative analysis between different tumor cell lines of rat origin and rat genomic DNA using p53 gene specific primers resulted in the amplification of a processed pseudogene and its positive interaction with wild type p53 probe on Southern blot analysis. The genomic DNA sequence analysis, and sequence comparison with cDNA discovered that the processed pseudogene lacks DNA binding domain and nuclear localization signal, however, contains the ribosomal entry and stop signals. Rat genome BLAST analysis of the pesudogene suggested chromosome-18 localization which was in addition to 14, 13, 10, 9 localization of the cDNA. In the interest of unraveling hidden dimensions of p53 tumor suppressor gene, our study explores the probability of p53 functional pseudogenes in rat histiocytoma.
基金supported by a grant from the Singer Biology Fund at the University of Florida。
文摘Olfactory receptors(ORs),the largest vertebrate multigene family,exhibit wide copy number variation among taxa,ranging from~100 to 4000.The ecological importance of smell has been suggested to positively correlate with OR gene number,though debate exists on whether the number of total ORs,functional ORs,or the percentage of pseudogenes matters most.While olfaction has been poorly studied in most birds,Turkey Vultures(Cathartes aura)demonstrate keen olfactory ability,capable of foraging using smell alone.In contrast,Black Vultures(Coragyps atratus)have been thought to primarily use vision to locate food.Comparison of the OR genes in these two New World vultures presents an opportunity to examine the dynamics of OR evolution in related avian species that may differ in olfactory abilities.Using a PCR and cloning approach with degenerate primers,we sampled the OR subgenome in Turkey and Black Vultures,as well as Red-tailed Hawks(Buteo jamaicensis)and the distantly related Chicken(Gallus gallus),neither of which are thought to use olfaction extensively.Our results indicate that Turkey Vultures have many more OR genes than Red-tailed Hawks or chickens.Surprisingly,Black Vultures had an intermediate number of OR genes.The number of OR genes we estimated in the Turkey Vulture was much greater than previously reported in studies that used short-read sequencing.Additionally,we found that OR genes from New World vultures and Red-tailed Hawks form clades that were distinct from the clade that included most chicken OR genes,indicating that chickens share few OR orthologs with New World vultures or hawks.As previously observed in other animal groups,pseudogenes appeared throughout all clades and their percentage varied among taxa.These findings suggest the OR gene family is highly dynamic,changing rapidly over evolutionary time,and that taxa may have distinct suites of ORs in their genomes.
