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1.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063069

RESUMO

The nematode worm Caenorhabditis elegans has been used extensively to enhance our understanding of the human neuromuscular disorder Duchenne Muscular Dystrophy (DMD). With new arising clinically relevant models, technologies and treatments, there is a need to reconcile the literature and collate the key findings associated with this model.


Assuntos
Caenorhabditis elegans/fisiologia , Distrofia Muscular de Duchenne/patologia , Animais , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Epistasia Genética , Humanos , Distrofia Muscular de Duchenne/genética , Mutação/genética , Fenótipo
2.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062819

RESUMO

An oxidative burst is an early response of plants to various biotic/abiotic stresses. In plant-microbe interactions, the plant body can induce oxidative burst to activate various defense mechanisms to combat phytopathogens. A localized oxidative burst is also one of the typical behaviors during hypersensitive response (HR) caused by gene-for-gene interaction. In this study, the occurrence of oxidative burst and its signaling pathways was studied from different levels of disease severity (i.e., susceptible, intermediate, and resistant) in the B. napus-L. maculans pathosystem. Canola cotyledons with distinct levels of resistance exhibited differential regulation of the genes involved in reactive oxygen species (ROS) accumulation and responses. Histochemical assays were carried out to understand the patterns of H2O2 accumulation and cell death. Intermediate and resistant genotypes exhibited earlier accumulation of H2O2 and emergence of cell death around the inoculation origins. The observations also suggested that the cotyledons with stronger resistance were able to form a protective region of intensive oxidative bursts between the areas with and without hyphal intrusions to block further fungal advancement to the uninfected regions. The qPCR analysis suggested that different onset patterns of some marker genes in ROS accumulation/programmed cell death (PCD) such as RBOHD, MPK3 were associated with distinct levels of resistance from B. napus cultivars against L. maculans. The observations and datasets from this article indicated the distinct differences in ROS-related cellular behaviors and signaling between compatible and incompatible interactions.


Assuntos
Cotilédone/genética , Resistência à Doença/genética , Doenças das Plantas/genética , Explosão Respiratória/genética , Brassica napus/genética , Brassica napus/parasitologia , Morte Celular/genética , Cotilédone/parasitologia , Epistasia Genética , Genótipo , Peróxido de Hidrogênio/metabolismo , Leptosphaeria/genética , Leptosphaeria/patogenicidade , Doenças das Plantas/parasitologia , Proteínas de Plantas/genética , Transdução de Sinais/genética , Estresse Fisiológico/genética
3.
Nat Commun ; 12(1): 3867, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162839

RESUMO

Enzymes can evolve new catalytic activity when environmental changes present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct catalytic target can also impact adaptation. Here, we characterize the catalytic activity of a recently evolved bacterial methyl-parathion hydrolase for all possible combinations of the five functionally relevant mutations under eight different laboratory conditions (in which an alternative divalent metal is supplemented). The resultant adaptive landscapes across this historical evolutionary transition vary in terms of both the number of "fitness peaks" as well as the genotype(s) at which they are found as a result of genotype-by-environment interactions and environment-dependent epistasis. This suggests that adaptive landscapes may be fluid and molecular adaptation is highly contingent not only on obvious factors (such as catalytic targets), but also on less obvious secondary environmental factors that can direct it towards distinct outcomes.


Assuntos
Adaptação Fisiológica/genética , Bactérias/genética , Proteínas de Bactérias/genética , Epistasia Genética , Hidrolases/genética , Sequência de Aminoácidos , Bactérias/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Biocatálise , Evolução Molecular , Interação Gene-Ambiente , Genótipo , Hidrolases/química , Hidrolases/metabolismo , Cinética , Metais/química , Metais/metabolismo , Metil Paration/química , Metil Paration/metabolismo , Mutação , Domínios Proteicos , Homologia de Sequência de Aminoácidos
4.
Nat Commun ; 12(1): 3426, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103516

RESUMO

Adaptive plasticity in stress responses is a key element of plant survival strategies. For instance, moderate heat stress (HS) primes a plant to acquire thermotolerance, which allows subsequent survival of more severe HS conditions. Acquired thermotolerance is actively maintained over several days (HS memory) and involves the sustained induction of memory-related genes. Here we show that FORGETTER3/ HEAT SHOCK TRANSCRIPTION FACTOR A3 (FGT3/HSFA3) is specifically required for physiological HS memory and maintaining high memory-gene expression during the days following a HS exposure. HSFA3 mediates HS memory by direct transcriptional activation of memory-related genes after return to normal growth temperatures. HSFA3 binds HSFA2, and in vivo both proteins form heteromeric complexes with additional HSFs. Our results indicate that only complexes containing both HSFA2 and HSFA3 efficiently promote transcriptional memory by positively influencing histone H3 lysine 4 (H3K4) hyper-methylation. In summary, our work defines the major HSF complex controlling transcriptional memory and elucidates the in vivo dynamics of HSF complexes during somatic stress memory.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/fisiologia , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Complexos Multiproteicos/metabolismo , Transcrição Genética , Proteínas de Arabidopsis/genética , Epistasia Genética , Genes de Plantas , Loci Gênicos , Fatores de Transcrição de Choque Térmico/genética , Histonas/metabolismo , Cinética , Lisina/metabolismo , Metilação , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
BMC Ecol Evol ; 21(1): 99, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039270

RESUMO

BACKGROUND: The impact of genetic interaction networks on evolution is a fundamental issue. Previous studies have demonstrated that the topology of the network is determined by the properties of the cellular machinery. Functionally related genes frequently interact with one another, and they establish modules, e.g., modules of protein complexes and biochemical pathways. In this study, we experimentally tested the hypothesis that compensatory evolutionary modifications, such as mutations and transcriptional changes, occur frequently in genes from perturbed modules of interacting genes. RESULTS: Using Saccharomyces cerevisiae haploid deletion mutants as a model, we investigated two modules lacking COG7 or NUP133, which are evolutionarily conserved genes with many interactions. We performed laboratory evolution experiments with these strains in two genetic backgrounds (with or without additional deletion of MSH2), subjecting them to continuous culture in a non-limiting minimal medium. Next, the evolved yeast populations were characterized through whole-genome sequencing and transcriptome analyses. No obvious compensatory changes resulting from inactivation of genes already included in modules were identified. The supposedly compensatory inactivation of genes in the evolved strains was only rarely observed to be in accordance with the established fitness effect of the genetic interaction network. In fact, a substantial majority of the gene inactivations were predicted to be neutral in the experimental conditions used to determine the interaction network. Similarly, transcriptome changes during continuous culture mostly signified adaptation to growth conditions rather than compensation of the absence of the COG7, NUP133 or MSH2 genes. However, we noticed that for genes whose inactivation was deleterious an upregulation of transcription was more common than downregulation. CONCLUSIONS: Our findings demonstrate that the genetic interactions and the modular structure of the network described by others have very limited effects on the evolutionary trajectory following gene deletion of module elements in our experimental conditions and has no significant impact on short-term compensatory evolution. However, we observed likely compensatory evolution in functionally related (albeit non-interacting) genes.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Epistasia Genética , Deleção de Genes , Redes Reguladoras de Genes , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
6.
Mol Genet Genomics ; 296(4): 919-938, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33966103

RESUMO

The studies investigating gene-gene and gene-environment (or gene-behavior) interactions provide valuable insight into the pathomechanisms underlying obese phenotypes. The Pakistani population due to its unique characteristics offers numerous advantages for conducting such studies. In this view, the current study was undertaken to examine the effects of gene-gene and gene-environment/behavior interactions on the risk of obesity in a sample of Pakistani population. A total of 578 adult participants including 290 overweight/obese cases and 288 normal-weight controls were involved. The five key obesity-associated genetic variants namely MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752 were genotyped using the TaqMan allelic discrimination assays. The data related to behavioral factors, such as eating pattern, diet consciousness, the tendency toward fat-dense food (TFDF), sleep duration, sleep-wake cycle (SWC), shift work (SW), and physical activity levels were collected via a questionnaire. Gene-gene and gene-behavior interactions were analyzed by multifactor dimensionality reduction and linear regression, respectively. In our study, only TMEM18 rs7561317 was found to be significantly associated with anthropometric traits with no significant effect of gene-gene interactions were observed on obesity-related phenotypes. However, the genetic variants were found to interact with the behavioral factors to significantly influence various obesity-related anthropometric traits including BMI, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and percentage of body fat. In conclusion, the interaction between genetic architecture and behavior/environment determines the outcome of obesity-related anthropometric phenotypes. Thus, gene-environment/behavior interaction studies should be promoted to explore the risk of complex and multifactorial disorders, such as obesity.


Assuntos
Interação Gene-Ambiente , Comportamentos Relacionados com a Saúde/fisiologia , Obesidade/etiologia , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Índice de Massa Corporal , Peso Corporal/genética , Estudos de Casos e Controles , Epistasia Genética/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Preferências Alimentares/fisiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Sobrepeso/genética , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
7.
Am J Hum Genet ; 108(5): 786-798, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811805

RESUMO

Non-additive genetic variance for complex traits is traditionally estimated from data on relatives. It is notoriously difficult to estimate without bias in non-laboratory species, including humans, because of possible confounding with environmental covariance among relatives. In principle, non-additive variance attributable to common DNA variants can be estimated from a random sample of unrelated individuals with genome-wide SNP data. Here, we jointly estimate the proportion of variance explained by additive (hSNP2), dominance (δSNP2) and additive-by-additive (ηSNP2) genetic variance in a single analysis model. We first show by simulations that our model leads to unbiased estimates and provide a new theory to predict standard errors estimated using either least-squares or maximum likelihood. We then apply the model to 70 complex traits using 254,679 unrelated individuals from the UK Biobank and 1.1 M genotyped and imputed SNPs. We found strong evidence for additive variance (average across traits h¯SNP2=0.208). In contrast, the average estimate of δ¯SNP2 across traits was 0.001, implying negligible dominance variance at causal variants tagged by common SNPs. The average epistatic variance η¯SNP2 across the traits was 0.055, not significantly different from zero because of the large sampling variance. Our results provide new evidence that genetic variance for complex traits is predominantly additive and that sample sizes of many millions of unrelated individuals are needed to estimate epistatic variance with sufficient precision.


Assuntos
Conjuntos de Dados como Assunto , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Bancos de Espécimes Biológicos , Epistasia Genética , Feminino , Genótipo , Humanos , Masculino , Modelos Genéticos , Fenótipo , Reprodutibilidade dos Testes , Reino Unido
8.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919775

RESUMO

Histone chaperones regulate the flow and dynamics of histone variants and ensure their assembly into nucleosomal structures, thereby contributing to the repertoire of histone variants in specialized cells or tissues. To date, not much is known on the distribution of histone variants and their modifications in the dry seed embryo. Here, we bring evidence that genes encoding the replacement histone variant H3.3 are expressed in Arabidopsis dry seeds and that embryo chromatin is characterized by a low H3.1/H3.3 ratio. Loss of HISTONE REGULATOR A (HIRA), a histone chaperone responsible for H3.3 deposition, reduces cellular H3 levels and increases chromatin accessibility in dry seeds. These molecular differences are accompanied by increased seed dormancy in hira-1 mutant seeds. The loss of HIRA negatively affects seed germination even in the absence of HISTONE MONOUBIQUITINATION 1 or TRANSCRIPTION ELONGATION FACTOR II S, known to be required for seed dormancy. Finally, hira-1 mutant seeds show lower germination efficiency when aged under controlled deterioration conditions or when facing unfavorable environmental conditions such as high salinity. Altogether, our results reveal a dependency of dry seed chromatin organization on the replication-independent histone deposition pathway and show that HIRA contributes to modulating seed dormancy and vigor.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Germinação , Chaperonas de Histonas/metabolismo , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Cromatina/metabolismo , Epistasia Genética/efeitos dos fármacos , Temperatura Alta , Umidade , Vigor Híbrido , Mutação/genética , Dormência de Plantas , Reguladores de Crescimento de Plantas/farmacologia , Estresse Salino , Fatores de Elongação da Transcrição/metabolismo
9.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919724

RESUMO

Esters constitute a broad family of volatile compounds impacting the organoleptic properties of many beverages, including wine and beer. They can be classified according to their chemical structure. Higher alcohol acetates differ from fatty acid ethyl esters, whereas a third group, substituted ethyl esters, contributes to the fruitiness of red wines. Derived from yeast metabolism, the biosynthesis of higher alcohol acetates and fatty acid ethyl esters has been widely investigated at the enzymatic and genetic levels. As previously reported, two pairs of esterases, respectively encoded by the paralogue genes ATF1 and ATF2, and EEB1 and EHT1, are mostly involved in the biosynthesis of higher alcohol acetates and fatty acid ethyl esters. These esterases have a moderate effect on the biosynthesis of substituted ethyl esters, which depend on mono-acyl lipases encoded by MGL2 and YJU3. The functional characterization of such genes helps to improve our understanding of substituted ester metabolism in the context of wine alcohol fermentation. In order to evaluate the overall sensorial impact of esters, we attempted to produce young red wines without esters by generating a multiple esterase-free strain (Δatf1, Δatf2, Δeeb1, and Δeht1). Surprisingly, it was not possible to obtain the deletion of MGL2 in the Δatf1/Δatf2/Δeeb1/Δeht1 background, highlighting unsuspected genetic incompatibilities between ATF1 and MGL2. A preliminary RNA-seq analysis depicted the overall effect of the Δatf1/Δatf2/Δeeb1/Δeht1 genotype that triggers the expression shift of 1124 genes involved in nitrogen and lipid metabolism, but also chromatin organization and histone acetylation. These findings reveal unsuspected regulatory roles of ester metabolism in genome expression for the first time.


Assuntos
Ésteres/metabolismo , Genes Fúngicos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sensação , Transcriptoma/genética , Acetiltransferases/metabolismo , Adulto , Epistasia Genética , Esterases/metabolismo , Ésteres/análise , Feminino , Fermentação , Haplótipos/genética , Histonas/metabolismo , Humanos , Lipase/metabolismo , Masculino , Mutação/genética , Mapeamento de Interação de Proteínas , Reprodutibilidade dos Testes , Proteínas de Saccharomyces cerevisiae/metabolismo , Volatilização , Vinho/microbiologia
10.
Mol Genet Genomics ; 296(4): 799-808, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33856550

RESUMO

Myocardial infarction (MI) is a frequent outcome of coronary artery disease (CAD) and the key factor contributing to worldwide disability and death. Genetic factors contribute to the pathogenesis of CAD/MI, and SNP rs6903956 in the ADTRP gene was first found associated with CAD/MI in the Chinese Han population, which was successfully replicated in other cohorts. However, whether rs6903956 is a functional SNP and its risk mechanism to CAD/MI remains unknown. The ADTRP gene-encoded androgen-dependent TFPI regulating protein regulates vascular endothelial cell function, endothelial-monocyte adhesion, and thrombosis. The allele A of rs6903956, in particular, is associated with lower ADTRP mRNA levels in lymphocytes. In the current study, we found that SNP rs6903956 exhibits allelic differences in transcriptional activity by interacting with GATA2. Also, the A allele conferred a greater risk of CAD and MI, lowered transcriptional activity, and GATA2 binding ability as compared to the G allele. Our findings provide details on how rs6903956 regulates the expression of ADTRP and may provide novel insights into CAD pathology and susceptibility.


Assuntos
Doença da Artéria Coronariana/genética , Fator de Transcrição GATA2/genética , Proteínas de Membrana/genética , Alelos , Células Cultivadas , Doença da Artéria Coronariana/epidemiologia , Epistasia Genética , Fator de Transcrição GATA2/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas de Membrana/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Risco
11.
BMC Bioinformatics ; 22(1): 180, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827420

RESUMO

BACKGROUND: Permutation testing is often considered the "gold standard" for multi-test significance analysis, as it is an exact test requiring few assumptions about the distribution being computed. However, it can be computationally very expensive, particularly in its naive form in which the full analysis pipeline is re-run after permuting the phenotype labels. This can become intractable in multi-locus genome-wide association studies (GWAS), in which the number of potential interactions to be tested is combinatorially large. RESULTS: In this paper, we develop an approach for permutation testing in multi-locus GWAS, specifically focusing on SNP-SNP-phenotype interactions using multivariable measures that can be computed from frequency count tables, such as those based in Information Theory. We find that the computational bottleneck in this process is the construction of the count tables themselves, and that this step can be eliminated at each iteration of the permutation testing by transforming the count tables directly. This leads to a speed-up by a factor of over 103 for a typical permutation test compared to the naive approach. Additionally, this approach is insensitive to the number of samples making it suitable for datasets with large number of samples. CONCLUSIONS: The proliferation of large-scale datasets with genotype data for hundreds of thousands of individuals enables new and more powerful approaches for the detection of multi-locus genotype-phenotype interactions. Our approach significantly improves the computational tractability of permutation testing for these studies. Moreover, our approach is insensitive to the large number of samples in these modern datasets. The code for performing these computations and replicating the figures in this paper is freely available at https://github.com/kunert/permute-counts .


Assuntos
Epistasia Genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Genótipo , Humanos , Fenótipo
12.
Front Immunol ; 12: 608723, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643312

RESUMO

Objective: Posner-Schlossman syndrome (PSS), also known as glaucomatocyclitic crisis, is an ocular condition characterized by recurrent attacks of anterior uveitis and raised intraocular pressure. Previous studies by our team and others have identified the genetic association of complement pathway genes with uveitis and glaucoma. This study aimed to investigate the complement genes in PSS patients with the view of elucidating the genetic background of the disease. Methods: A total of 331 subjects (56 PSS patients and 275 controls) were recruited for this study. We selected 27 variants in six complement pathway genes (SERPING1, C2, CFB, CFH, C3, and C5) and detected them using TaqMan single nucleotide polymorphism (SNP) Genotyping Assays. Univariate SNP association analysis, haplotype-based association analysis, gene-gene interaction analysis among complement genes, and genotype-phenotype correlation analysis were performed. Results: Among the 27 variants of six complement pathway genes, the functional variant I62V (rs800292) at the CFH gene was found to be significantly associated with PSS; there was a significant increase in the frequency of A allele and AA homozygosity in PSS patients than in controls (P = 1.79 × 10-4; odds ratio (OR) 2.18, 95% CI: 1.44-3.29; P = 4.65 × 10-4; OR 3.66, 95% CI: 1.70-7.85, respectively). The additive effect of CFH-rs800292 and SERPING1-rs3824988 was identified with an OR of 12.50 (95% CI: 2.16-72.28). Genotype-phenotype analysis indicated that the rs800292 AA genotype was associated with a higher intraocular pressure and higher frequency of recurrence. Unlike a high proportion of human leukocyte antigen (HLA)-B27 positivity in anterior uveitis, only 3 in 56 (5.36%) PSS patients were HLA-B27 positive. In addition, one haplotype block (GC) in the SERPING1 gene showed a nominal association with PSS with an increased risk of 2.04 (P = 0.01; 95% CI: 1.18-3.53), but the P-value could not withstand the Bonferroni correction (P corr > 0.05). Conclusion: This study revealed a genetic association of a CFH variant with PSS as well as its clinical parameters, implying that the alternative complement pathway might play an important role in the pathogenesis of PSS. Further studies to enrich the understanding of the genetic background of PSS and the role of the complement system in ocular inflammation are warranted.


Assuntos
Alelos , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Marcadores Genéticos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Fator H do Complemento/genética , Epistasia Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo
13.
Alzheimers Res Ther ; 13(1): 55, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663605

RESUMO

BACKGROUND: Single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies only explain part of the heritability of Alzheimer's disease (AD). Epistasis has been considered as one of the main causes of "missing heritability" in AD. METHODS: We performed genome-wide epistasis screening (N = 10,389) for the clinical diagnosis of AD using three popularly adopted methods. Subsequent analyses were performed to eliminate spurious associations caused by possible confounding factors. Then, candidate genetic interactions were examined for their co-expression in the brains of AD patients and analyzed for their association with intermediate AD phenotypes. Moreover, a new approach was developed to compile the epistasis risk factors into an epistasis risk score (ERS) based on multifactor dimensional reduction. Two independent datasets were used to evaluate the feasibility of ERSs in AD risk prediction. RESULTS: We identified 2 candidate genetic interactions with PFDR <  0.05 (RAMP3-SEMA3A and NSMCE1-DGKE/C17orf67) and another 5 genetic interactions with PFDR <  0.1. Co-expression between the identified interactions supported the existence of possible biological interactions underlying the observed statistical significance. Further association of candidate interactions with intermediate phenotypes helps explain the mechanisms of neuropathological alterations involved in AD. Importantly, we found that ERSs can identify high-risk individuals showing earlier onset of AD. Combined risk scores of SNPs and SNP-SNP interactions showed slightly but steadily increased AUC in predicting the clinical status of AD. CONCLUSIONS: In summary, we performed a genome-wide epistasis analysis to identify novel genetic interactions potentially implicated in AD. We found that ERS can serve as an indicator of the genetic risk of AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
14.
Methods Mol Biol ; 2212: 1-15, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733346

RESUMO

A mass-based protein phylogeny method, known as phylonumerics, is described to build phylogenetic-like trees using a purpose-built MassTree algorithm. These trees are constructed from sets of numerical mass map data for each protein without the need for gene or protein sequences. Such trees have been shown to be highly congruent with conventional sequence-based trees and provide a reliable means to study the evolutionary history of organisms. Mutations determined from the differences in the mass of peptide pairs across different mass sets are computed by the algorithm and displayed at branch nodes across the tree. By definition, since the trees display a phylogeny representing expressed proteins, all mutations are non-synonymous. The frequency of these mutations and a mutation score based on a sum of these frequencies weighted based upon their position to the root of the tree are output. The algorithm also outputs lists of pairs of mutations separated along interconnected branches of the tree. Those which co-occur or which occur consecutively, or near consecutively, and that are separated by a distance less than the average distance for all mutation pairs, are putatively assigned to be epistatic pairs. These pairs are examined further with a focus on non-conservative substitutions given their importance in driving structural and functional change and protein and organismal evolution. The application of the method is demonstrated for the H3 hemagglutinin protein of type A human H3N2 strains of the influenza virus. The most frequent ancestral mutations within epistatic pairs occur within antigenic site domains while the descendant mutations occur either at other antigenic sites or elsewhere in the protein. Both predominate at reported glycosylation sites. The results for this protein further support a "small steps" evolutionary model for the influenza virus where non-conservative mutations that involve the least structural change are favored over those involving substantive change, which may risk the virus's own extinction.


Assuntos
Epistasia Genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/virologia , Algoritmos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/patologia , Mutação , Filogenia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
15.
Methods Mol Biol ; 2212: 17-35, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733347

RESUMO

We present SNPInt-GPU, a software providing several methods for statistical epistasis testing. SNPInt-GPU supports GPU acceleration using the Nvidia CUDA framework, but can also be used without GPU hardware. The software implements logistic regression (as in PLINK epistasis testing), BOOST, log-linear regression, mutual information (MI), and information gain (IG) for pairwise testing as well as mutual information and information gain for third-order tests. Optionally, r2 scores for testing for linkage disequilibrium (LD) can be calculated on-the-fly. SNPInt-GPU is publicly available at GitHub. The software requires a Linux-based operating system and CUDA libraries. This chapter describes detailed installation and usage instructions as well as examples for basic preliminary quality control and analysis of results.


Assuntos
Algoritmos , Curadoria de Dados/estatística & dados numéricos , Epistasia Genética , Software , Entropia , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Controle de Qualidade
16.
Methods Mol Biol ; 2212: 37-44, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733348

RESUMO

Variable selection is an important procedure to select relevant features from large datasets in optimization problems. The use of epistasis concepts becomes an alternative to assess the gene (variable) interdependence and select the most significative variables. This chapter describes the Epistasis-based Feature Selection Algorithm (EbFSA). Such implementation was recently proposed in a doctorate thesis from Computer Science. It has been applied to solve multivariate calibration problems with multiple linear regression and demonstrated superiority over traditional techniques by selecting the smallest number of variables as well as obtaining the best model predictive ability.


Assuntos
Algoritmos , Epistasia Genética , Proteínas de Plantas/genética , Sementes/genética , Triticum/genética , Conjuntos de Dados como Assunto , Expressão Gênica , Modelos Estatísticos , Análise Multivariada , Proteínas de Plantas/metabolismo , Sementes/metabolismo , Espectrofotometria Infravermelho , Triticum/metabolismo
17.
Methods Mol Biol ; 2212: 45-53, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733349

RESUMO

The genetic epistasis effect has been widely acknowledged as an essential contributor to genetic variation in complex diseases. In this chapter, we introduce a powerful and efficient statistical method, called W-test, for genetic epistasis testing. A wtest R package is developed for the implementation of the W-test method, which provides various functions to measure the main effect, pairwise interaction, higher-order interaction, and cis-regulation of SNP-CpG pairs in genetic and epigenetic data. It allows flexible stagewise and exhaustive association testing as well as diagnostic checking on the probability distributions in a user-friendly interface. The wtest package is available in CRAN at https://CRAN.R-project.org/package=wtest .


Assuntos
Algoritmos , Ilhas de CpG , Diabetes Mellitus/genética , Epistasia Genética , Polimorfismo de Nucleotídeo Único , Software , Biologia Computacional/métodos , Metilação de DNA , Conjuntos de Dados como Assunto , Diabetes Mellitus/diagnóstico , Testes Genéticos , Genótipo , Humanos , Probabilidade , Tamanho da Amostra
18.
Methods Mol Biol ; 2212: 55-67, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733350

RESUMO

Epistasis, or gene-gene interaction, contributes substantially to trait variation in organisms ranging from yeast to humans, and modeling epistasis directly is critical to understanding the genotype-phenotype map. However, inference of genetic interactions is challenging compared to inference of individual allele effects due to low statistical power. Furthermore, genetic interactions can appear inconsistent across different quantitative traits, presenting a challenge for the interpretation of detected interactions. Here we present a method called the Combined Analysis of Pleiotropy and Epistasis (CAPE) that combines information across multiple quantitative traits to infer directed epistatic interactions. By combining information across multiple traits, CAPE not only increases power to detect genetic interactions but also interprets these interactions across traits to identify a single interaction that is consistent across all observed data. This method generates informative, interpretable interaction networks that explain how variants interact with each other to influence groups of related traits. This method could potentially be used to link genetic variants to gene expression, physiological endophenotypes, and higher-level disease traits.


Assuntos
Epistasia Genética , Pleiotropia Genética , Modelos Genéticos , Característica Quantitativa Herdável , Software , Redes Reguladoras de Genes , Estudos de Associação Genética , Genótipo , Humanos , Fenótipo , Locos de Características Quantitativas
19.
Methods Mol Biol ; 2212: 69-92, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733351

RESUMO

Undiscovered gene-to-gene interaction (epistasis) is a possible explanation for the "missing heritability" of complex traits and diseases. On a genome-wide scale, screening for epistatic effects among all possible pairs of genetic markers faces two main complications. Firstly, the classical statistical methods for modeling epistasis are computationally very expensive, which makes them impractical on such large scale. Secondly, straightforward corrections for multiple testing using the classical methods tend to be too coarse and inefficient at discovering the epistatic effects in such a large scale application. In this chapter, we describe both the underlying framework and practical examples of two-stage statistical testing methods that alleviate both of the aforementioned complications.


Assuntos
Epistasia Genética , Testes Genéticos/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Software , Estudos de Associação Genética , Genoma Humano , Genótipo , Humanos , Padrões de Herança , Fenótipo , Locos de Características Quantitativas
20.
Methods Mol Biol ; 2212: 93-103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733352

RESUMO

Transcriptome-wide association studies (TWASs) integrate expression quantitative trait loci (eQTLs) studies with genome-wide association studies (GWASs) to prioritize candidate target genes for complex traits. TWASs have become increasingly popular. They have been used to analyze many complex traits with expression profiles from different tissues, successfully enhancing the discovery of genetic risk loci for complex traits. Though conceptually straightforward, some steps are required to perform the TWAS properly. Here we provide a step-by-step guide to integrate eQTL data with both GWAS individual-level data and GWAS summary statistics from complex traits.


Assuntos
Epistasia Genética , Testes Genéticos/métodos , Modelos Genéticos , Herança Multifatorial , Software , Transcriptoma , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Incerteza
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