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1.
PLoS One ; 15(8): e0237808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866209

RESUMO

In this study, we performed an analysis of the impact of performance enhancing polymorphisms (PEPs) on gymnastic aptitude while considering epistatic effects. Seven PEPs (rs1815739, rs8192678, rs4253778, rs6265, rs5443, rs1076560, rs362584) were considered in a case (gymnasts)-control (sedentary individuals) setting. The study sample comprised of two athletes' sets: 27 elite (aged 24.8 ± 2.1 years) and 46 sub-elite (aged 19.7 ± 2.4 years) sportsmen as well as a control group of 245 sedentary individuals (aged 22.5 ± 2.1 years). The DNA was derived from saliva and PEP alleles were determined by PCR, RT-PCR. Following Multifactor Dimensionality Reduction, logistic regression models were built. The synergistic effect for rs1815739 x rs362584 reached 5.43%. The rs1815739 x rs362584 epistatic regression model exhibited a good fit to the data (Chi-squared = 33.758, p ≈ 0) achieving a significant improvement in sportsmen identification over naïve guessing. The area under the receiver operating characteristic curve was 0.715 (Z-score = 38.917, p ≈ 0). In contrast, the additive ACTN3 -SNAP-25 logistic regression model has been verified as non-significant. We demonstrate that a gene involved in the differentiation of muscle architecture-ACTN3 and a gene, which plays an important role in the nervous system-SNAP-25 interact. From the perspective originally established by the Berlin Academy of Science in 1751, the matter of communication between the brain and muscles via nerves adopts molecular manifestations. Further in-vitro investigations are required to explain the molecular details of the rs1815739 -rs362584 interaction.


Assuntos
Actinina/genética , Aptidão , Epistasia Genética , Ginástica/fisiologia , Proteína 25 Associada a Sinaptossoma/genética , Adulto , Alelos , Área Sob a Curva , Bases de Dados Genéticas , Entropia , Feminino , Marcadores Genéticos , Humanos , Modelos Logísticos , Masculino , Modelos Genéticos , Redução Dimensional com Múltiplos Fatores , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
2.
Nat Commun ; 11(1): 4013, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782250

RESUMO

Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by "translation bottlenecks": points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of "continuous epistasis" in bacterial physiology.


Assuntos
Antibacterianos/farmacologia , Modelos Teóricos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Interações Medicamentosas , Epistasia Genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Biossíntese de Proteínas/fisiologia , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo
3.
PLoS Comput Biol ; 16(8): e1008082, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790763

RESUMO

We study the genotype-phenotype maps of 80 quantitative phenotypes in the model plant Arabidopsis thaliana, by representing the genotypes affecting each phenotype as a genotype network. In such a network, each vertex or node corresponds to an individual's genotype at all those genomic loci that affect a given phenotype. Two vertices are connected by an edge if the associated genotypes differ in exactly one nucleotide. The 80 genotype networks we analyze are based on data from genome-wide association studies of 199 A. thaliana accessions. They form connected graphs whose topography differs substantially among phenotypes. We focus our analysis on the incidence of epistasis (non-additive interactions among mutations) because a high incidence of epistasis can reduce the accessibility of evolutionary paths towards high or low phenotypic values. We find epistatic interactions in 67 phenotypes, and in 51 phenotypes every pairwise mutant interaction is epistatic. Moreover, we find phenotype-specific differences in the fraction of accessible mutational paths to maximum phenotypic values. However, even though epistasis affects the accessibility of maximum phenotypic values, the relationships between genotypic and phenotypic change of our analyzed phenotypes are sufficiently smooth that some evolutionary paths remain accessible for most phenotypes, even where epistasis is pervasive. The genotype network representation we use can complement existing approaches to understand the genetic architecture of polygenic traits in many different organisms.


Assuntos
Arabidopsis/genética , Epistasia Genética/genética , Redes Reguladoras de Genes/genética , Genes de Plantas/genética , Evolução Molecular , Estudo de Associação Genômica Ampla , Genótipo , Fenótipo
4.
PLoS One ; 15(8): e0237662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822370

RESUMO

The larvae of Drosophila melanogaster grow rapidly through use of a highly truncated cell cycle in which mitosis is entirely eliminated. The Drosophila homolog of the protooncogene transcription factor Myc plays a major role in promoting this endopolyploid (EP) growth. We have previously determined that the gene jim lovell (lov), which encodes a member of the BTB/POZ (Bric-a-brac, Tramtrack, Broad/Pox virus zinc finger) domain family of transcription factors, is also required for EP growth in one larval tissue, the trachea. Here we show that lov promotes EP growth in three further tissues indicating a fundamental role in this process. However, epistasis experiments revealed heterogeneity in lov's action in these tissues. Whereas in the tracheae and salivary glands lov acts downstream of Myc, in the fat body, reduced expression of lov does not impede the action of Myc, indicating an upstream action for the gene. We show here that lov's regulation of the gene uninflatable (uif) in the tracheae is a component of this difference. uif is required for tracheal EP growth downstream of Myc and lov but has no equivalent role in the fat body. Although Uif is a transmembrane component of the plasma membrane in the tracheae, its action downstream of Myc suggests an intracellular role for the protein in the tracheae. In addition to regulating uif expression in some tissues we also show that lov locates to the nucleolus, indicating it can function in both polymerase I and polymerase II transcriptional events. Our major finding is that tissue-specific mechanisms can interact with universal growth promotion by Myc to generate the individual endopolyploid organs of the larvae.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Drosophila/análise , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Epistasia Genética , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Proteínas de Membrana/análise , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Poliploidia , Fatores de Transcrição/análise , Fatores de Transcrição/genética
5.
J Toxicol Sci ; 45(8): 449-473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741897

RESUMO

Although peroxisome proliferator-activated receptor α (PPARα) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPARα acts as a part of the transcription factor complex, but its precise mechanism is still unknown. Using the data of Toxicogenomics Database, reliable genes responsive to PPARα agonists, clofibrate, fenofibrate and WY-14,643, in rat liver, were extracted from both in vivo and in vitro data, and sorted by their fold increase. It was found that there were many genes responding to fibrates exclusively in vivo. Most of the in vivo specific genes appear to be unrelated to lipid metabolism and are not upregulated in the kidney. Fifty-seven genes directly related to cell proliferation were extracted from in vivo data, but they were not induced in vitro at all. Analysis of PPAR-responsive elements could not explain the observed difference in induction. To evaluate possible interaction between neighboring genes in gene expression, the correlation of the fold changes of neighboring genes for 22 drugs with various PPARα agonistic potencies were calculated for the genes showing more than 2.5 fold induction by 3 fibrates in vivo, and their genomic location was compared with that of the human orthologue. In the present study, many candidates of genes other than lipid metabolism were selected, and these could be good starting points to elucidate the mechanism of PPARα agonist-induced rodent-specific toxicity.


Assuntos
Bases de Dados Genéticas , Fenofibrato/toxicidade , Loci Gênicos/genética , Armazenamento e Recuperação da Informação/métodos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , PPAR alfa/agonistas , Pirimidinas/toxicidade , Animais , Epistasia Genética , Expressão Gênica , Estudos de Associação Genética , Masculino , Ratos Sprague-Dawley , Especificidade da Espécie
6.
PLoS Genet ; 16(8): e1008906, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804949

RESUMO

The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.


Assuntos
Epistasia Genética , Antígenos HLA/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Alelos , Aminopeptidases/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único
7.
PLoS Genet ; 16(7): e1008812, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658893

RESUMO

In Arabidopsis, CONSTANS (CO) integrates light and circadian clock signals to promote flowering under long days (LD). In the grasses, a duplication generated two paralogs designated as CONSTANS1 (CO1) and CONSTANS2 (CO2). Here we show that in tetraploid wheat plants grown under LD, combined loss-of-function mutations in the A and B-genome homeologs of CO1 and CO2 (co1 co2) result in a small (3 d) but significant (P<0.0001) acceleration of heading time both in PHOTOPERIOD1 (PPD1) sensitive (Ppd-A1b, functional ancestral allele) and insensitive (Ppd-A1a, functional dominant allele) backgrounds. Under short days (SD), co1 co2 mutants headed 13 d earlier than the wild type (P<0.0001) in the presence of Ppd-A1a. However, in the presence of Ppd-A1b, spikes from both genotypes failed to emerge by 180 d. These results indicate that CO1 and CO2 operate mainly as weak heading time repressors in both LD and SD. By contrast, in ppd1 mutants with loss-of-function mutations in both PPD1 homeologs, the wild type Co1 allele accelerated heading time >60 d relative to the co1 mutant allele under LD. We detected significant genetic interactions among CO1, CO2 and PPD1 genes on heading time, which were reflected in complex interactions at the transcriptional and protein levels. Loss-of-function mutations in PPD1 delayed heading more than combined co1 co2 mutations and, more importantly, PPD1 was able to perceive and respond to differences in photoperiod in the absence of functional CO1 and CO2 genes. Similarly, CO1 was able to accelerate heading time in response to LD in the absence of a functional PPD1. Taken together, these results indicate that PPD1 and CO1 are able to respond to photoperiod in the absence of each other, and that interactions between these two photoperiod pathways at the transcriptional and protein levels are important to fine-tune the flowering response in wheat.


Assuntos
Epistasia Genética/genética , Fotoperíodo , Proteínas de Plantas/genética , Triticum/genética , Alelos , Arabidopsis , Relógios Circadianos/genética , Ritmo Circadiano/genética , Flores/genética , Flores/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/genética , Genótipo , Fatores de Transcrição/genética , Triticum/crescimento & desenvolvimento
8.
Proc Natl Acad Sci U S A ; 117(32): 19367-19375, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719112

RESUMO

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene × gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Herança Multifatorial , Sequenciamento Completo do Exoma/métodos , Craniossinostoses/genética , Epistasia Genética , Exoma/genética , Ligação Genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos
9.
Nat Commun ; 11(1): 2789, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493961

RESUMO

RNA-binding proteins play key roles in regulation of gene expression via recognition of structural features in RNA molecules. Here we apply a quantitative RNA pull-down approach to 186 evolutionary conserved RNA structures and report 162 interacting proteins. Unlike global RNA interactome capture, we associate individual RNA structures within messenger RNA with their interacting proteins. Of our binders 69% are known RNA-binding proteins, whereas some are previously unrelated to RNA binding and do not harbor canonical RNA-binding domains. While current knowledge about RNA-binding proteins relates to their functions at 5' or 3'-UTRs, we report a significant number of them binding to RNA folds in the coding regions of mRNAs. Using an in vivo reporter screen and pulsed SILAC, we characterize a subset of mRNA-RBP pairs and thus connect structural RNA features to functionality. Ultimately, we here present a generic, scalable approach to interrogate the increasing number of RNA structural motifs.


Assuntos
Sequência Conservada , Evolução Molecular , Conformação de Ácido Nucleico , RNA Fúngico/química , Saccharomyces cerevisiae/genética , Regiões 3' não Traduzidas/genética , Regiões 5' não Traduzidas/genética , Sequência de Bases , Sequência Conservada/genética , Epistasia Genética , Genes Reporter , Genoma Fúngico , Proteínas de Fluorescência Verde/metabolismo , Motivos de Nucleotídeos/genética , Biossíntese de Proteínas , Proteoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Reprodutibilidade dos Testes , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
10.
Nat Commun ; 11(1): 3105, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561723

RESUMO

Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics.


Assuntos
Antibacterianos/farmacologia , Evolução Molecular Direcionada/métodos , Resistência Microbiana a Medicamentos/genética , Epistasia Genética , Escherichia coli K12/genética , Escherichia coli K12/efeitos dos fármacos , Deleção de Genes , Genes Bacterianos/genética , Seleção Genética/efeitos dos fármacos
12.
Mol Genet Genomics ; 295(5): 1187-1195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32476049

RESUMO

Cowpea (Vigna unguiculate (L.) Walp.) is a worldwide important multifunctional legume crop for food grain, vegetable, fodder, and cover crop. Nevertheless, only limited research has been conducted on agronomic traits. Here, we report quantitative trait locus (QTL) analysis of the days to flowering (DTF) and plant height (PH) using a dense SNP linkage map recently developed from a recombinant inbred line (RIL) population derived from a cross between Golden Eye Cream and IT98K-476-8. The population was phenotyped for DTF and PH through field and greenhouse trials under two environments. The QTLs controlling these traits were mapped using multiple-environment combined and individual trial phenotypic data. The combined data analysis identified one major QTL (qDTF9.1) for DTF, and one major QTL (qPH9.1) and a minor QTL (qPH4.1) for PH. qDTF9.1 and qPH9.1 were adjacent to each other on Chromosome 9 and each explained 29.3% and 29.5% of the phenotypic variation (PVE), respectively. The individual trial data analysis identified a minor QTL (qDTF2.1) on Chromosome 2 for DTF and two minor QTLs (qPH4.1 and qPH4.2) on Chromosome 4 for PH, while the major QTLs, qDTF9.1 and qPH9.1, were consistently identified in all trials conducted. Epistasis analysis revealed that qDTF9.1 interacted with one locus on Chromosome 4, contributed 50% of the PVE, and qPH9.1 interacted with one locus on each of Chromosomes 4 and 6, contributing 30% and 23% of the PVE, respectively, suggesting that epistasis plays an important role in the trait performance. These results, therefore, provide a deeper understanding of the genetic architecture of plant DTF and PH, and molecular tools necessary for cloning the genes and for enhanced cowpea breeding.


Assuntos
Mapeamento Cromossômico/métodos , Locos de Características Quantitativas , Vigna/fisiologia , Cromossomos de Plantas/genética , Cruzamentos Genéticos , Epistasia Genética , Flores/genética , Flores/crescimento & desenvolvimento , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigna/anatomia & histologia , Vigna/genética
13.
Proc Biol Sci ; 287(1928): 20200057, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32517624

RESUMO

Social interactions can influence the expression and underlying genetic basis of many traits. Yet, empirical investigations of indirect genetic effects (IGEs) and genotype-by-genotype epistasis-quantitative genetics parameters representing the role of genetic variation in a focal individual and its interacting partners in producing the observed trait values-are still scarce. While it is commonly observed that an individual's traits are influenced by the traits of interacting conspecifics, representing social plasticity, studying this social plasticity and its quantitative-genetic basis is notoriously challenging. These challenges are compounded when individuals interact in groups, rather than (simpler) dyads. Here, we investigate the genetic architecture of social plasticity for exploratory behaviour, one of the most intensively studied behaviours in recent decades. Using genotypes of Drosophila simulans, we measured genotypes both alone, and in social groups representing a mix of two genotypes. We found that females adjusted their exploratory behaviour based on the behaviour of others in the group, representing social plasticity. However, the direction of this plasticity depended on the identity of group members: focal individuals were more likely to emerge from a refuge if group members who were the same genotype as the focal remained inside for longer. By contrast, focal individuals were less likely to emerge from a refuge if partner-genotype group members remained inside for longer. Exploratory behaviour also depended on the identities of both genotypes that composed the group. Together, these findings demonstrate genotype-by-genotype epistasis for exploratory behaviour both within and among groups.


Assuntos
Drosophila simulans/genética , Comportamento Exploratório/fisiologia , Genótipo , Animais , Epistasia Genética , Relações Interpessoais , Fenótipo , Comportamento Social
14.
J Vis Exp ; (160)2020 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568253

RESUMO

Correct folding and assembly of proteins and protein complexes are essential for cellular function. Cells employ quality control pathways that correct, sequester or eliminate damaged proteins to maintain a healthy proteome, thus ensuring cellular proteostasis and preventing further protein damage. Because of redundant functions within the proteostasis network, screening for detectable phenotypes using knockdown or mutations in chaperone-encoding genes in the multicellular organism Caenorhabditis elegans results in the detection of minor or no phenotypes in most cases. We have developed a targeted screening strategy to identify chaperones required for a specific function and thus bridge the gap between phenotype and function. Specifically, we monitor novel chaperone interactions using RNAi synthetic interaction screens, knocking-down chaperone expression, one chaperone at a time, in animals carrying a mutation in a chaperone-encoding gene or over-expressing a chaperone of interest. By disrupting two chaperones that individually present no gross phenotype, we can identify chaperones that aggravate or expose a specific phenotype when both perturbed. We demonstrate that this approach can identify specific sets of chaperones that function together to modulate the folding of a protein or protein complexes associated with a given phenotype.


Assuntos
Caenorhabditis elegans/metabolismo , Programas de Rastreamento , Chaperonas Moleculares/metabolismo , Especificidade de Órgãos , Animais , Bioensaio , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Embrião não Mamífero/metabolismo , Epistasia Genética , Mitocôndrias/metabolismo , Óvulo/metabolismo , Fenótipo , Ligação Proteica , Dobramento de Proteína , Proteoma/metabolismo , Interferência de RNA , Reprodutibilidade dos Testes
15.
Proc Natl Acad Sci U S A ; 117(20): 11038-11047, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32366663

RESUMO

Dengue virus (DENV) is a global health threat, causing repeated epidemics throughout the tropical world. While low herd immunity levels to any one of the four antigenic types of DENV predispose populations to outbreaks, viral genetic determinants that confer greater fitness for epidemic spread is an important but poorly understood contributor of dengue outbreaks. Here we report that positive epistasis between the coding and noncoding regions of the viral genome combined to elicit an epidemiologic fitness phenotype associated with the 1994 DENV2 outbreak in Puerto Rico. We found that five amino acid substitutions in the NS5 protein reduced viral genomic RNA (gRNA) replication rate to achieve a more favorable and relatively more abundant subgenomic flavivirus RNA (sfRNA), a byproduct of host 5'-3' exoribonuclease activity. The resulting increase in sfRNA relative to gRNA levels not only inhibited type I interferon (IFN) expression in infected cells through a previously described mechanism, but also enabled sfRNA to compete with gRNA for packaging into infectious particles. We suggest that delivery of sfRNA to new susceptible cells to inhibit type I IFN induction before gRNA replication and without the need for further de novo sfRNA synthesis could form a "preemptive strike" strategy against DENV.


Assuntos
Regiões 3' não Traduzidas/genética , Vírus da Dengue/genética , Dengue/virologia , Proteínas não Estruturais Virais/genética , Células A549 , Dengue/epidemiologia , Epistasia Genética , Exorribonucleases , Técnicas de Inativação de Genes , Genoma Viral , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Interferon Tipo I/metabolismo , Proteínas Associadas aos Microtúbulos , Mutação , Porto Rico/epidemiologia , RNA Guia/metabolismo , Replicação Viral
16.
PLoS Genet ; 16(5): e1008801, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392218

RESUMO

Cryptic genetic variation could arise from, for example, Gene-by-Gene (G-by-G) or Gene-by-Environment (G-by-E) interactions. The underlying molecular mechanisms and how they influence allelic effects and the genetic variance of complex traits is largely unclear. Here, we empirically explored the role of environmentally influenced epistasis on the suppression and release of cryptic variation by reanalysing a dataset of 4,390 haploid yeast segregants phenotyped on 20 different media. The focus was on 130 epistatic loci, each contributing to segregant growth in at least one environment and that together explained most (69-100%) of the narrow sense heritability of growth in the individual environments. We revealed that the epistatic growth network reorganised upon environmental changes to alter the estimated marginal (additive) effects of the individual loci, how multi-locus interactions contributed to individual segregant growth and the level of expressed genetic variance in growth. The estimated additive effects varied most across environments for loci that were highly interactive network hubs in some environments but had few or no interactors in other environments, resulting in changes in total genetic variance across environments. This environmentally dependent epistasis was thus an important mechanism for the suppression and release of cryptic variation in this population. Our findings increase the understanding of the complex genetic mechanisms leading to cryptic variation in populations, providing a basis for future studies on the genetic maintenance of trait robustness and development of genetic models for studying and predicting selection responses for quantitative traits in breeding and evolution.


Assuntos
Biologia Computacional/métodos , Epistasia Genética , Variação Genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Regulação Fúngica da Expressão Gênica , Interação Gene-Ambiente , Genes Fúngicos , Modelos Genéticos , Fenótipo , Locos de Características Quantitativas , Saccharomyces cerevisiae/genética
17.
PLoS One ; 15(5): e0232719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392228

RESUMO

BACKGROUND: Atrial fibrillation (AF) is predicted to affect around 17.9 million individuals in Europe by 2060. The disease is associated with severe electrical and structural remodelling of the heart, and increased the risk of stroke and heart failure. In order to improve treatment and find new drug targets, the field needs to better comprehend the exact molecular mechanisms in these remodelling processes. OBJECTIVES: This study aims to identify gene and miRNA networks involved in the remodelling of AF hearts in AF patients with mitral valve regurgitation (MVR). METHODS: Total RNA was extracted from right atrial biopsies from patients undergoing surgery for mitral valve replacement or repair with AF and without history of AF to test for differentially expressed genes and miRNAs using RNA-sequencing and miRNA microarray. In silico predictions were used to construct a mRNA-miRNA network including differentially expressed mRNAs and miRNAs. Gene and chromosome enrichment analysis were used to identify molecular pathways and high-density AF loci. RESULTS: We found 644 genes and 43 miRNAs differentially expressed in AF patients compared to controls. From these lists, we identified 905 pairs of putative miRNA-mRNA interactions, including 37 miRNAs and 295 genes. Of particular note, AF-associated miR-130b-3p, miR-338-5p and miR-208a-3p were differentially expressed in our AF tissue samples. These miRNAs are predicted regulators of several differentially expressed genes associated with cardiac conduction and fibrosis. We identified two high-density AF loci in chromosomes 14q11.2 and 6p21.3. CONCLUSIONS: AF in MVR patients is associated with down-regulation of ion channel genes and up-regulation of extracellular matrix genes. Other AF related genes are dysregulated and several are predicted to be targeted by miRNAs. Our novel miRNA-mRNA regulatory network provides new insights into the mechanisms of AF.


Assuntos
Fibrilação Atrial/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Insuficiência da Valva Mitral/genética , Fibrilação Atrial/complicações , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Biópsia , Estudos de Casos e Controles , Cromossomos Humanos/genética , Epistasia Genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Genoma Humano , Átrios do Coração/fisiopatologia , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/fisiopatologia , Análise de Componente Principal , Remodelação Vascular
18.
Mol Genet Genomics ; 295(4): 855-870, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32361785

RESUMO

MicroRNAs (miRNAs) play crucial roles in all aspects of plant growth and development, but the genetic interactions of miRNAs and their target genes in woody plants are largely unknown. Here, we integrated association genetics and expression profiling to decipher the allelic variations and interactions of the Pto-MIR319 family of miRNAs and 12 putative Pto-miR319 target genes related to wood formation in 435 unrelated individuals of Populus tomentosa Carrière (Chinese white poplar). Expression pattern analysis showed that among all pairings between expressions of pre-miRNA of Pto-MIR319 members and targets, 70.0% showed negative correlation of expression levels (r = - 0.944 to 0.674, P < 0.01) in eight tissues and organs of poplar, suggesting that Pto-miR319 may participate in the regulatory network of wood formation. Single SNP-based association studies identified 137 significant associations (P < 0.01, Q < 0.1), representing 126 unique SNPs from Pto-MIR319 members and their targets, with 10 tree growth traits, revealing that these genetic factors have common roles related to wood formation. Epistasis analysis uncovered 105 significant SNP-SNP associations (P < 0.01) influencing the 10 traits, demonstrating the close genetic interactions between Pto-MIR319 family members and the 12 Pto-miR319 target genes. Notably, one common SNP, in the precursor region of Pto-MIR319e, affected the stability of Pto-MIR319e's secondary structure by altering the stem-loop structure and minimum free energy, contributing to variations in the expression of Pto-MIR319e and Pto-miR319e target genes. This study enriches the understanding of the functions of miR319 family miRNAs in poplar and exemplifies a feasible approach to exploring the genetic effects underlying miRNA-mRNA interactions related to complex traits in trees.


Assuntos
Estudos de Associação Genética , MicroRNAs/genética , Populus/genética , Madeira/genética , Alelos , Arabidopsis , Epistasia Genética/genética , Regulação da Expressão Gênica de Plantas/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Populus/crescimento & desenvolvimento , RNA Mensageiro/genética
19.
BMC Bioinformatics ; 21(1): 190, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414319

RESUMO

BACKGROUND: Most organisms cannot be cultivated, as they live in unique ecological conditions that cannot be mimicked in the lab. Understanding the functionality of those organisms' genes and their interactions by performing large-scale measurements of transcription levels, protein-protein interactions or metabolism, is extremely difficult and, in some cases, impossible. Thus, efficient algorithms for deciphering genome functionality based only on the genomic sequences with no other experimental measurements are needed. RESULTS: In this study, we describe a novel algorithm that infers gene networks that we name Common Substring Network (CSN). The algorithm enables inferring novel regulatory relations among genes based only on the genomic sequence of a given organism and partial homolog/ortholog-based functional annotation. It can specifically infer the functional annotation of genes with unknown homology. This approach is based on the assumption that related genes, not necessarily homologs, tend to share sub-sequences, which may be related to common regulatory mechanisms, similar functionality of encoded proteins, common evolutionary history, and more. We demonstrate that CSNs, which are based on S. cerevisiae and E. coli genomes, have properties similar to 'traditional' biological networks inferred from experiments. Highly expressed genes tend to have higher degree nodes in the CSN, genes with similar protein functionality tend to be closer, and the CSN graph exhibits a power-law degree distribution. Also, we show how the CSN can be used for predicting gene interactions and functions. CONCLUSIONS: The reported results suggest that 'silent' code inside the transcript can help to predict central features of biological networks and gene function. This approach can help researchers to understand the genome of novel microorganisms, analyze metagenomic data, and can help to decipher new gene functions. AVAILABILITY: Our MATLAB implementation of CSN is available at https://www.cs.tau.ac.il/~tamirtul/CSN-Autogen.


Assuntos
Redes Reguladoras de Genes , Genoma , Algoritmos , Epistasia Genética , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
20.
BMC Evol Biol ; 20(1): 49, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349663

RESUMO

BACKGROUND: Sympatric sister species provide an opportunity to investigate the genetic mechanisms and evolutionary forces that maintain species boundaries. The persistence of morphologically and genetically distinct populations in sympatry can only occur if some degree of reproductive isolation exists. A pair of sympatric sister species of Primulina (P. depressa and P. danxiaensis) was used to explore the genetic architecture of hybrid male sterility. RESULTS: We mapped one major- and seven minor-effect quantitative trait loci (QTLs) that underlie pollen fertility rate (PFR). These loci jointly explained 55.4% of the phenotypic variation in the F2 population. A Bateson-Dobzhansky-Muller (BDM) model involving three loci was observed in this system. We found genotypic correlations between hybrid male sterility and flower morphology, consistent with the weak but significant phenotypic correlations between PFR and floral traits. CONCLUSIONS: Hybrid male sterility in Primulina is controlled by a polygenic genetic basis with a complex pattern. The genetic incompatibility involves a three-locus BDM model. Hybrid male sterility is genetically correlated with floral morphology and divergence hitchhiking may occur between them.


Assuntos
Hibridização Genética , Lamiales/genética , Infertilidade das Plantas/genética , Simpatria/genética , Análise de Variância , Epistasia Genética , Flores/anatomia & histologia , Flores/genética , Genética Populacional , Genoma de Planta , Genótipo , Vigor Híbrido/genética , Fenótipo , Pólen/genética , Análise de Componente Principal , Locos de Características Quantitativas/genética
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