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1.
Virology ; 562: 149-157, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34339929

RESUMO

Six candidate overlapping genes have been detected in SARS-CoV-2, yet current methods struggle to detect overlapping genes that recently originated. However, such genes might encode proteins beneficial to the virus, and provide a model system to understand gene birth. To complement existing detection methods, I first demonstrated that selection pressure to avoid stop codons in alternative reading frames is a driving force in the origin and retention of overlapping genes. I then built a detection method, CodScr, based on this selection pressure. Finally, I combined CodScr with methods that detect other properties of overlapping genes, such as a biased nucleotide and amino acid composition. I detected two novel ORFs (ORF-Sh and ORF-Mh), overlapping the spike and membrane genes respectively, which are under selection pressure and may be beneficial to SARS-CoV-2. ORF-Sh and ORF-Mh are present, as ORF uninterrupted by stop codons, in 100% and 95% of the SARS-CoV-2 genomes, respectively.


Assuntos
Uso do Códon , Homologia de Genes , Fases de Leitura Aberta , SARS-CoV-2/genética , Evolução Molecular , Genoma Viral , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Estatística como Assunto
2.
Methods Mol Biol ; 2348: 243-253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34160812

RESUMO

Viruses, like their metazoan hosts, have evolved to utilize intricate transcriptional mechanisms to generate a vast array of both coding and noncoding RNA transcripts. The resolution of specific noncoding RNA transcripts produced by viruses, particularly herpesviruses, presents a particularly difficult challenge due to their highly dense dsDNA genomes and their complex, overlapping, and context-dependent network of transcripts. While new long read sequencing platforms have facilitated the resolution of some noncoding transcripts from virus genomes, empirical molecular validation of transcripts from individual regions is essential. Herein, we demonstrate that the use of strand specific northern blots is essential for true validation of specific viral noncoding RNAs, and provide here a detailed molecular method for such an approach.


Assuntos
Northern Blotting , Homologia de Genes , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Viral/genética , Northern Blotting/métodos , Eletroforese em Gel de Poliacrilamida , Regulação Viral da Expressão Gênica , Genoma Viral , Herpesviridae/genética , Fases de Leitura Aberta , Vírus/genética
3.
PLoS Pathog ; 17(3): e1009376, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33720976

RESUMO

Hypervirulent K. pneumoniae (hvKp) is a distinct pathotype that causes invasive community-acquired infections in healthy individuals. Hypermucoviscosity (hmv) is a major phenotype associated with hvKp characterized by copious capsule production and poor sedimentation. Dissecting the individual functions of CPS production and hmv in hvKp has been hindered by the conflation of these two properties. Although hmv requires capsular polysaccharide (CPS) biosynthesis, other cellular factors may also be required and some fitness phenotypes ascribed to CPS may be distinctly attributed to hmv. To address this challenge, we systematically identified genes that impact capsule and hmv. We generated a condensed, ordered transposon library in hypervirulent strain KPPR1, then evaluated the CPS production and hmv phenotypes of the 3,733 transposon mutants, representing 72% of all open reading frames in the genome. We employed forward and reverse genetic screens to evaluate effects of novel and known genes on CPS biosynthesis and hmv. These screens expand our understanding of core genes that coordinate CPS biosynthesis and hmv, as well as identify central metabolism genes that distinctly impact CPS biosynthesis or hmv, specifically those related to purine metabolism, pyruvate metabolism and the TCA cycle. Six representative mutants, with varying effect on CPS biosynthesis and hmv, were evaluated for their impact on CPS thickness, serum resistance, host cell association, and fitness in a murine model of disseminating pneumonia. Altogether, these data demonstrate that hmv requires both CPS biosynthesis and other cellular factors, and that hmv and CPS may serve distinct functions during pathogenesis. The integration of hmv and CPS to the metabolic status of the cell suggests that hvKp may require certain nutrients to specifically cause deep tissue infections.


Assuntos
Cápsulas Bacterianas/fisiologia , Aptidão Genética/fisiologia , Infecções por Klebsiella , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/patogenicidade , Animais , Homologia de Genes , Humanos , Camundongos , Virulência/genética , Viscosidade
4.
Plant Physiol Biochem ; 161: 248-258, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33652257

RESUMO

Co-occurrence of abiotic stresses, especially drought and salinity, is a natural phenomenon in field conditions and is worse for crop production than any single stress. Nowadays, rigorous methods of meta-analysis and systems biology have made it possible to perform cross-study comparisons of single stress experiments, which can uncover main overlapping mechanisms underlying tolerance to combined stress. In this study, a meta-analysis of RNA-Seq data was conducted to obtain the overlapping gene network of drought and salinity stresses in barley (Hordeum vulgare L.), which identified Rubisco activase A (RcaA) as a hub gene in the dual-stress response. Thereafter, a greenhouse experiment was carried out using two barley genotypes with different abiotic stress tolerance and evaluated several physiochemical properties as well as the expression profile and protein activity of RcaA. Finally, machine learning analysis was applied to uncover relationships among combined stress tolerance and evaluated properties. We identified 441 genes which were differentially expressed under both drought and salinity stress. Results revealed that the photosynthesis pathway and, in particular, the RcaA gene are major components of the dual-stress responsive transcriptome. Comparative physiochemical and molecular evaluations further confirmed that enhanced photosynthesis capability, mainly through regulation of RcaA expression and activity as well as accumulation of proline content, have a significant association with combined drought and salinity stress tolerance in barley. Overall, our results clarify the importance of RcaA in combined stress tolerance and may provide new insights for future investigations.


Assuntos
Secas , Hordeum , Homologia de Genes , Hordeum/genética , Ribulose-Bifosfato Carboxilase , Salinidade , Estresse Fisiológico/genética , Ativador de Plasminogênio Tecidual
5.
Elife ; 92020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001029

RESUMO

Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/virologia , Evolução Molecular , Homologia de Genes , Genes Virais , Especificidade de Hospedeiro/genética , Fases de Leitura Aberta/genética , Pandemias , Pneumonia Viral/virologia , Proteínas Virais/genética , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Antígenos Virais/biossíntese , Antígenos Virais/genética , Antígenos Virais/imunologia , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , COVID-19 , China/epidemiologia , Quirópteros/virologia , Coronavirus/genética , Infecções por Coronavirus/epidemiologia , Epitopos/genética , Epitopos/imunologia , Europa (Continente)/epidemiologia , Eutérios/virologia , Regulação Viral da Expressão Gênica , Variação Genética , Haplótipos/genética , Humanos , Modelos Moleculares , Mutação , Filogenia , Pneumonia Viral/epidemiologia , Biossíntese de Proteínas , Conformação Proteica , RNA Viral/genética , SARS-CoV-2 , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Proteínas Virais/imunologia
6.
Nat Commun ; 11(1): 4016, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782260

RESUMO

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Tronco Encefálico/anatomia & histologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/metabolismo , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Homologia de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Herança Multifatorial , Tamanho do Órgão/genética
7.
J Gen Virol ; 101(10): 1085-1089, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32667280

RESUMO

Identification of the full complement of genes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a crucial step towards gaining a fuller understanding of its molecular biology. However, short and/or overlapping genes can be difficult to detect using conventional computational approaches, whereas high-throughput experimental approaches - such as ribosome profiling - cannot distinguish translation of functional peptides from regulatory translation or translational noise. By studying regions showing enhanced conservation at synonymous sites in alignments of SARS-CoV-2 and related viruses (subgenus Sarbecovirus) and correlating the results with the conserved presence of an open reading frame (ORF) and a plausible translation mechanism, a putative new gene - ORF3c - was identified. ORF3c overlaps ORF3a in an alternative reading frame. A recently published ribosome profiling study confirmed that ORF3c is indeed translated during infection. ORF3c is conserved across the subgenus Sarbecovirus, and encodes a 40-41 amino acid predicted transmembrane protein.


Assuntos
Betacoronavirus/genética , Homologia de Genes/genética , Fases de Leitura/genética , Sequência de Aminoácidos/genética , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Pandemias , Filogenia , Pneumonia Viral/virologia , SARS-CoV-2 , Alinhamento de Sequência , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Viroporinas
8.
Nucleic Acids Res ; 48(W1): W558-W565, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32374885

RESUMO

Overlapping genes are commonplace in viruses and play an important role in their function and evolution. For these genes, molecular coevolution may be seen as a mechanism to decrease the evolutionary constraints of amino acid positions in the overlapping regions and to tolerate or compensate unfavorable mutations. Tracing these mutational sites, could help to gain insight on the direct or indirect effect of the mutations in the corresponding overlapping proteins. In the past, coevolution analysis has been used to identify residue pairs and coevolutionary signatures within or between proteins that served as markers of physical interactions and/or functional relationships. Coevolution in OVerlapped sequences by Tree analysis (COVTree) is a web server providing the online analysis of coevolving amino-acid pairs in overlapping genes, where residues might be located inside or outside the overlapping region. COVTree is designed to handle protein families with various characteristics, among which those that typically display a small number of highly conserved sequences. It is based on BIS2, a fast version of the coevolution analysis tool Blocks in Sequences (BIS). COVTree provides a rich and interactive graphical interface to ease biological interpretation of the results and it is openly accessible at http://www.lcqb.upmc.fr/COVTree/.


Assuntos
Evolução Molecular , Homologia de Genes , Software , Genes Virais , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Alinhamento de Sequência
9.
Virology ; 546: 51-66, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452417

RESUMO

Overlapping genes originate by a mechanism of overprinting, in which nucleotide substitutions in a pre-existing frame induce the expression of a de novo protein from an alternative frame. In this study, I assembled a dataset of 319 viral overlapping genes, which included 82 overlaps whose expression is experimentally known and the respective 237 homologs. Principal component analysis revealed that overlapping genes have a common pattern of nucleotide and amino acid composition. Discriminant analysis separated overlapping from non-overlapping genes with an accuracy of 97%. When applied to overlapping genes with known genealogy, it separated ancestral from de novo frames with an accuracy close to 100%. This high discriminant power was crucial to computationally design variants of de novo viral proteins known to possess selective anticancer toxicity (apoptin) or protection against neurodegeneration (X protein), as well as to detect two new potential overlapping genes in the genome of the new coronavirus SARS-CoV-2.


Assuntos
Betacoronavirus/genética , Evolução Molecular , Homologia de Genes , Genes Virais , Algoritmos , Sequência de Aminoácidos , Sequência de Bases , Biologia Computacional , Simulação por Computador , Análise Discriminante , Análise dos Mínimos Quadrados , Análise de Componente Principal , SARS-CoV-2
10.
Mol Biol Evol ; 37(8): 2440-2449, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32243542

RESUMO

Purifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbing dN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false-positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1's putative antisense protein gene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available at https://github.com/chasewnelson/OLGenie (last accessed April 10, 2020).


Assuntos
Homologia de Genes , Técnicas Genéticas , Seleção Genética , Mutação Silenciosa , Software , HIV-1/genética
11.
Psychol Med ; 50(10): 1695-1705, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31328717

RESUMO

BACKGROUND: Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders. METHODS: We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls. RESULTS: We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex. CONCLUSIONS: We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders.


Assuntos
Alelos , Homologia de Genes , Heterogeneidade Genética , Testes Genéticos , Transtornos Mentais/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Fatores de Risco , Esquizofrenia/genética
12.
Sci Rep ; 9(1): 13377, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527706

RESUMO

The completion of human genome sequences and the advancement of next-generation sequencing technologies have engendered a clear understanding of all human genes. Overlapping genes are usually observed in compact genomes, such as those of bacteria and viruses. Notably, overlapping protein-coding genes do exist in human genome sequences. Accordingly, we used the current Ensembl gene annotations to identify overlapping human protein-coding genes. We analysed 19,200 well-annotated protein-coding genes and determined that 4,951 protein-coding genes overlapped with their adjacent genes. Approximately a quarter of all human protein-coding genes were overlapping genes. We observed different clusters of overlapping protein-coding genes, ranging from two genes (paired overlapping genes) to 22 genes. We also divided the paired overlapping protein-coding gene groups into four subtypes. We found that the divergent overlapping gene subtype had a stronger expression association than did the subtypes of 5'-tandem overlapping and 3'-tandem overlapping genes. The majority of paired overlapping genes exhibited comparable coincidental tissue expression profiles; however, a few overlapping gene pairs displayed distinctive tissue expression association patterns. In summary, we have carefully examined the genomic features and distributions about human overlapping protein-coding genes and found coincidental expression in tissues for most overlapping protein-coding genes.


Assuntos
Homologia de Genes/genética , Genoma Humano/genética , Bases de Dados Genéticas , Genômica , Humanos , Fases de Leitura Aberta , Filogenia
13.
Nat Commun ; 10(1): 4006, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488843

RESUMO

The genomes of many prokaryotes contain substantial fractions of gene pairs with overlapping stop and start codons (ATGA or TGATG). A potential benefit of overlapping gene pairs is translational coupling. In 720 genomes of archaea and bacteria representing all major phyla, we identify substantial, albeit highly variable, fractions of co-directed overlapping gene pairs. Various patterns are observed for the utilization of the SD motif for de novo initiation at upstream genes versus reinitiation at overlapping gene pairs. We experimentally test the predicted coupling in 9 gene pairs from the archaeon Haloferax volcanii and 5 gene pairs from the bacterium Escherichia coli. In 13 of 14 cases, translation of both genes is strictly coupled. Mutational analysis of SD motifs located upstream of the downstream genes indicate that the contribution of the SD to translational coupling widely varies from gene to gene. The nearly universal, abundant occurrence of overlapping gene pairs suggests that tight translational coupling is widespread in archaea and bacteria.


Assuntos
Archaea/genética , Bactérias/genética , Genes Arqueais/genética , Genes Bacterianos/genética , Iniciação Traducional da Cadeia Peptídica/fisiologia , Terminação Traducional da Cadeia Peptídica/fisiologia , Biossíntese de Proteínas/fisiologia , Archaea/metabolismo , Bactérias/metabolismo , Sequência de Bases , Códon de Iniciação , Escherichia coli/genética , Homologia de Genes , Genes Reporter , Fases de Leitura Aberta/genética , RNA Mensageiro , Regiões Terminadoras Genéticas
14.
Science ; 365(6453): 595-598, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395784

RESUMO

In synthetic biology, methods for stabilizing genetically engineered functions and confining recombinant DNA to intended hosts are necessary to cope with natural mutation accumulation and pervasive lateral gene flow. We present a generalizable strategy to preserve and constrain genetic information through the computational design of overlapping genes. Overlapping a sequence with an essential gene altered its fitness landscape and produced a constrained evolutionary path, even for synonymous mutations. Embedding a toxin gene in a gene of interest restricted its horizontal propagation. We further demonstrated a multiplex and scalable approach to build and test >7500 overlapping sequence designs, yielding functional yet highly divergent variants from natural homologs. This work enables deeper exploration of natural and engineered overlapping genes and facilitates enhanced genetic stability and biocontainment in emerging applications.


Assuntos
Genes Essenciais , Homologia de Genes , Engenharia Genética/métodos , Aptidão Genética , Instabilidade Genômica , Proteínas de Bactérias/genética , DNA Recombinante , Mutagênese , Mutação Silenciosa , Biologia Sintética , Treonina Desidratase/genética
15.
Genes (Basel) ; 10(7)2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269762

RESUMO

Increasing evidence suggests that overlapping genes are much more common in eukaryotic genomes than previously thought. These different-strand overlapping genes are potential sense-antisense (SAS) pairs, which might have regulatory effects on each other. In the present study, we identified the SAS loci in the equine genome using previously generated stranded, paired-end RNA sequencing data from the equine chorioallantois. We identified a total of 1261 overlapping loci. The ratio of the number of overlapping regions to chromosomal length was numerically higher on chromosome 11 followed by chromosomes 13 and 12. These results show that overlapping transcription is distributed throughout the equine genome, but that distributions differ for each chromosome. Next, we evaluated the expression patterns of SAS pairs during the course of gestation. The sense and antisense genes showed an overall positive correlation between the sense and antisense pairs. We further provide a list of SAS pairs with both positive and negative correlation in their expression patterns throughout gestation. This study characterizes the landscape of sense and antisense gene expression in the placenta for the first time and provides a resource that will enable researchers to elucidate the mechanisms of sense/antisense regulation during pregnancy.


Assuntos
Homologia de Genes , Cavalos/genética , Placenta/metabolismo , Animais , Feminino , Loci Gênicos , Gravidez , Transcriptoma
17.
Genet Test Mol Biomarkers ; 23(4): 235-240, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30986097

RESUMO

AIMS: Evaluation of nucleic acids in plasma exosomes is a noninvasive method that can be used to detect different types of cancer. The aim of this study was to determine the value of exosomal long noncoding RNAs (lncRNAs) in detecting lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A total of 75 LSCC patients and 79 negative control subjects were enrolled in the study. Twenty differentially expressed lncRNAs were evaluated as potential candidates. Exosomes were isolated by ultracentrifugation, and lncRNA levels in exosomes were determined using real-time polymerase chain reaction. Receiver Operating Characteristic (ROC) curves were used to determine specificity and sensitivity. RESULTS: Exosomal SOX2-OT was significantly upregulated in LSCC patients and showed the strongest power in detecting LSCC. The area under the ROC curve was 0.815, and the sensitivity and specificity were 76% and 73.17%, respectively. Moreover, exosomal SOX2-OT levels were significantly correlated with tumor size, TNM stage, and lymph node metastasis. Exosomal SOX2-OT levels were significantly decreased in the postoperative plasma of LSCC patients. CONCLUSION: SOX2-OT may serve as a promising noninvasive plasma-based tumor biomarker for LSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Fatores de Transcrição SOXB1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Complexo Multienzimático de Ribonucleases do Exossomo/sangue , Exossomos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Homologia de Genes/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/análise , RNA Longo não Codificante/genética , Curva ROC , Sensibilidade e Especificidade
18.
Virology ; 532: 39-47, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31004987

RESUMO

Overlapping genes represent an intriguing puzzle, as they encode two proteins whose ability to evolve is constrained by each other. Overlapping genes can undergo "symmetric evolution" (similar selection pressures on the two proteins) or "asymmetric evolution" (significantly different selection pressures on the two proteins). By sequence analysis of 75 pairs of homologous viral overlapping genes, I evaluated their accordance with one or the other model. Analysis of nucleotide and amino acid sequences revealed that half of overlaps undergo asymmetric evolution, as the protein from one frame shows a number of substitutions significantly higher than that of the protein from the other frame. Interestingly, the most variable protein (often known to interact with the host proteins) appeared to be encoded by the de novo frame in all cases examined. These findings suggest that overlapping genes, besides to increase the coding ability of viruses, are also a source of selective protein adaptation.


Assuntos
Evolução Molecular , Homologia de Genes , Genes Virais , Proteínas Virais/genética , Vírus/genética , Sequência de Aminoácidos , Sequência de Bases , Variação Genética , Modelos Genéticos , Fases de Leitura Aberta , Filogenia , Seleção Genética , Vírus/classificação
19.
BMC Pulm Med ; 19(1): 58, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845926

RESUMO

BACKGROUND: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development. CONCLUSIONS: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.


Assuntos
Fator de Ligação a CCAAT/genética , Proteína 7 de Ligação a Ácidos Graxos/genética , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Homologia de Genes/genética , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fumar/efeitos adversos , Espirometria , Capacidade Vital , Adulto Jovem
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