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1.
Adv Exp Med Biol ; 1158: 247-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452144

RESUMO

The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular bioenergetics. This chapter will discuss the unique features of this circular genome including heteroplasmy, haplogroups, among others, along with the corresponding clinical relevance for each. The discussion also covers the nuclear-encoded mitochondrial genes (N > 1000) and the epistatic interactions between mtDNA and the nuclear genome. Examples of mitochondrial diseases related to specific mtDNA mutation sites of relevance for humans are provided. This chapter aims to provide an overview of mitochondrial genetics as an emerging hot topic for the future of medicine.


Assuntos
Metabolismo Energético , Mitocôndrias , DNA Mitocondrial/genética , Metabolismo Energético/genética , Epistasia Genética , Genes Mitocondriais/genética , Genoma/genética , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação
2.
Genome Biol ; 20(1): 137, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300006

RESUMO

Systems for CRISPR-based combinatorial perturbation of two or more genes are emerging as powerful tools for uncovering genetic interactions. However, systematic identification of these relationships is complicated by sample, reagent, and biological variability. We develop a variational Bayes approach (GEMINI) that jointly analyzes all samples and reagents to identify genetic interactions in pairwise knockout screens. The improved accuracy and scalability of GEMINI enables the systematic analysis of combinatorial CRISPR knockout screens, regardless of design and dimension. GEMINI is available as an open source R package on GitHub at https://github.com/sellerslab/gemini .


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas Genéticas , Software , Teorema de Bayes , Epistasia Genética
3.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Genética , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
4.
BMC Med Genet ; 20(1): 96, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151434

RESUMO

BACKGROUND: The highly conservative miR-15/107 family (also named as miR-15/107 gene group) including ten miRNA members is currently recognized strongly implicated in multiple human disorders. Some studies focus on the entire family rather than individual miRNA for a bigger picture, while there is also certain signature dysregulation for some of the individual miRNA implicated even in the same disorder. METHODS: Faced with the exponential growth of experimental evidence, our study tries to analyze their function and target interactions using various bioinformatics tools. RESULTS: Firstly, the evolutionary conservative "AGCAGC" sequence and possible clustered transcriptional pattern were described. Secondly, both the experimentally validated and bioinformatically predicted miRNA-target gene relationship of the entire family was analyzed to understand the mechanism of underlying collective effects for target regulation from the miR-15/107 family. Moreover, pathway analysis among miR-15/107 family was performed and displayed in detail, while its impact on cell proliferation is experimentally validated. Eventually, the dysregulation of miR-15/107 in diseases was discussed. CONCLUSIONS: In summary, our study proposes that the collective functions and implication of miR-15/107 family in various human diseases are achieved relying on the massive overlapping target genes. While the minor differences within target gene interaction among family members could also explain the signature behavior for some of the individual miRNA in aspects such as its disease-specific dysregulation and various participation in pathways.


Assuntos
Epistasia Genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Análise por Conglomerados , Biologia Computacional/métodos , Predisposição Genética para Doença/genética , Humanos , Família Multigênica , Transdução de Sinais/genética
5.
BMC Plant Biol ; 19(1): 171, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039735

RESUMO

BACKGROUND: Common bean is the most important staple grain legume for direct human consumption and nutrition. It complements major sources of carbohydrates, including cereals, root crop, or plantain, as a source of dietary proteins. It is also a significant source of vitamins and minerals like iron and zinc. To fully play its nutritional role, however, its robustness against stresses needs to be strengthened. Foremost among these is drought, which commonly affects its productivity and seed quality. Previous studies have shown that photosynthate remobilization and partitioning is one of the main mechanisms of drought tolerance and overall productivity in common bean. RESULTS: In this study, we sought to determine the inheritance of pod harvest index (PHI), a measure of the partitioning of pod biomass to seed biomass, relative to that of grain yield. We evaluated a recombinant inbred population of the cross of ICA Bunsi and SXB405, both from the Mesoamerican gene pool, to determine the effects of intermittent and terminal drought stresses on the genetic architecture of photosynthate allocation and remobilization in pods of common bean. The population was grown for two seasons, under well-watered conditions and terminal and intermittent drought stress in one year, and well-watered conditions and terminal drought stress in the second year. There was a significant effect of the water regime and year on all the traits, at both the phenotypic and QTL levels. We found nine QTLs for pod harvest index, including a major (17% of variation explained), stable QTL on linkage group Pv07. We also found eight QTLs for yield, three of which clustered with PHI QTLs, underscoring the importance of photosynthate remobilization in productivity. We also found evidence for substantial epistasis, explaining a considerable part of the variation for yield and PHI. CONCLUSION: Our results highlight the genetic relationship between PHI and yield and confirm the role of PHI in selection of both additive and epistatic effects controlling drought tolerance. These results are a key component to strengthen the robustness of common bean against drought stresses.


Assuntos
Secas , Phaseolus/genética , Fotossíntese , Biomassa , Epistasia Genética , Abastecimento de Alimentos , Pleiotropia Genética , Phaseolus/crescimento & desenvolvimento , Phaseolus/metabolismo , Fotossíntese/genética , Característica Quantitativa Herdável , Sementes/genética , Sementes/crescimento & desenvolvimento , Estresse Fisiológico
6.
BMC Plant Biol ; 19(1): 179, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053089

RESUMO

BACKGROUND: Fusarium head blight resistance genes, Fhb1 (for Type-II resistance), Fhb2 (Type-II), and Fhb5 (Type-I plus some Type-II), which originate from Sumai 3, are among the most important that confer resistance in hexaploid wheat. Near-isogenic lines (NILs), in the CDC Alsask (susceptible; n = 32) and CDC Go (moderately susceptible; n = 38) backgrounds, carrying these genes in all possible combinations were developed using flanking microsatellite markers and evaluated for their response to FHB and deoxynivalenol (DON) accumulation in eight environments. NILs were haplotyped with wheat 90 K iSelect assay to elucidate the genomic composition and confirm alleles' presence. Other than evaluating the effects of three major genes in common genetic background, the study elucidated the epistatic gene interactions as they influence FHB measurements; identified loci other than Fhb1, Fhb2, and Fhb5, in both recurrent and donor parents and examined annotated proteins in gene intervals. RESULTS: Genotyping using 81,857 single nucleotide polymorphism (SNP) markers revealed polymorphism on all chromosomes and that the NILs carried < 3% of alleles from the resistant donor. Significant improvement in field resistance (Type-I + Type-II) resulted only among the CDC Alsask NILs, not the CDC Go NILs. The phenotypic response of NILs carrying combinations of Sumai 3 derived genes suggested non-additive responses and Fhb5 was as good as Fhb1 in conferring field resistance in both populations. In addition to Fhb1, Fhb2, and Fhb5, four to five resistance improving alleles in both populations were identified and three of five in CDC Go were contributed by the susceptible parent. The introgressed chromosome regions carried genes encoding disease resistance proteins, protein kinases, nucleotide-binding and leucine rich repeats' domains. Complex epistatic gene-gene interactions among marker loci (including Fhb1, Fhb2, Fhb5) explained > 20% of the phenotypic variation in FHB measurements. CONCLUSIONS: Immediate Sumai 3 derivatives carry a number of resistance improving minor effect alleles, other than Fhb1, Fhb2, Fhb5. Results verified that marker-assisted selection is possible for the introgression of exotic FHB resistance genes, however, the genetic background of the recipient line and epistatic interactions can have a strong influence on expression and penetrance of any given gene.


Assuntos
Fusarium/fisiologia , Triticum/genética , Triticum/microbiologia , Alelos , Cromossomos de Plantas , Resistência à Doença/genética , Epistasia Genética , Genes de Plantas , Marcadores Genéticos , Genótipo , Padrões de Herança , Fenótipo , Mapeamento Físico do Cromossomo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia
7.
Nat Plants ; 5(5): 471-479, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31061537

RESUMO

Genome editing technologies are being widely adopted in plant breeding1. However, a looming challenge of engineering desirable genetic variation in diverse genotypes is poor predictability of phenotypic outcomes due to unforeseen interactions with pre-existing cryptic mutations2-4. In tomato, breeding with a classical MADS-box gene mutation that improves harvesting by eliminating fruit stem abscission frequently results in excessive inflorescence branching, flowering and reduced fertility due to interaction with a cryptic variant that causes partial mis-splicing in a homologous gene5-8. Here, we show that a recently evolved tandem duplication carrying the second-site variant achieves a threshold of functional transcripts to suppress branching, enabling breeders to neutralize negative epistasis on yield. By dissecting the dosage mechanisms by which this structural variant restored normal flowering and fertility, we devised strategies that use CRISPR-Cas9 genome editing to predictably improve harvesting. Our findings highlight the under-appreciated impact of epistasis in targeted trait breeding and underscore the need for a deeper characterization of cryptic variation to enable the full potential of genome editing in agriculture.


Assuntos
Domesticação , Epistasia Genética/genética , Duplicação Gênica/genética , Lycopersicon esculentum/genética , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Flores/crescimento & desenvolvimento , Duplicação Gênica/fisiologia , Edição de Genes/métodos , Variação Genética/genética , Variação Genética/fisiologia , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/fisiologia , Melhoramento Vegetal , Plantas Geneticamente Modificadas , Locos de Características Quantitativas/genética , Reprodução/genética , Reprodução/fisiologia
8.
BMC Bioinformatics ; 20(1): 268, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138121

RESUMO

BACKGROUND: Correcting a heterogeneous dataset that presents artefacts from several confounders is often an essential bioinformatics task. Attempting to remove these batch effects will result in some biologically meaningful signals being lost. Thus, a central challenge is assessing if the removal of unwanted technical variation harms the biological signal that is of interest to the researcher. RESULTS: We describe a novel framework, B-CeF, to evaluate the effectiveness of batch correction methods and their tendency toward over or under correction. The approach is based on comparing co-expression of adjusted gene-gene pairs to a-priori knowledge of highly confident gene-gene associations based on thousands of unrelated experiments derived from an external reference. Our framework includes three steps: (1) data adjustment with the desired methods (2) calculating gene-gene co-expression measurements for adjusted datasets (3) evaluating the performance of the co-expression measurements against a gold standard. Using the framework, we evaluated five batch correction methods applied to RNA-seq data of six representative tissue datasets derived from the GTEx project. CONCLUSIONS: Our framework enables the evaluation of batch correction methods to better preserve the original biological signal. We show that using a multiple linear regression model to correct for known confounders outperforms factor analysis-based methods that estimate hidden confounders. The code is publicly available as an R package.


Assuntos
Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas , Epistasia Genética , Genes , Área Sob a Curva , Regulação da Expressão Gênica , Humanos , Curva ROC , Gordura Subcutânea/metabolismo
9.
Microb Pathog ; 133: 103544, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121270

RESUMO

Interleukin-10 (IL-10) is an anti-inflammatory cytokine associated with the inhibition of HIV replication. IL-10 polymorphisms were found to be linked to drug-induced hepatotoxicity. Hence we examined the prevalence of IL-10 (-819C/T,-1082A/G) polymorphisms in a total of 165 HIV patients which included 34 patients with hepatotoxicity, 131 without hepatotoxicity and 155 healthy controls by the PCR-RFLP method. In HIV patients with hepatotoxicity, the IL-10-819TT genotype increased the risk of ARV associated hepatotoxicity severity (OR = 1.61, P = 0.35). IL-10-819TT genotype was overrepresented in patients with hepatotoxicity as compared to healthy controls (26.5% vs. 13.5%, OR = 1.61, P = 0.46). IL-10 -819CT genotype was associated with advance HIV disease stage (OR = 0.49, P = 0.045). In HIV patients without hepatotoxicity, the IL-10-819TT genotype was more prevalent in patients consuming tobacco as compared to non-users (OR = 1.60, P = 0.41). In HIV patients without hepatotoxicity using both alcohol + efavirenz along with IL-10 -819CT genotype resulted in increased risk for the acquisition of ARV associated hepatotoxicity (OR = 4.00, P = 0.36). In multivariate logistic regression, taking nevirapine was associated with the risk hepatotoxicity severity (OR = 0.23, P = 0.005). In conclusion, an insignificant association between IL-10 polymorphisms and susceptibility to ARV associated hepatotoxicity.


Assuntos
Antirretrovirais/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Predisposição Genética para Doença , Infecções por HIV/complicações , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas , Benzoxazinas/uso terapêutico , Estudos de Casos e Controles , Citocinas , Suscetibilidade a Doenças , Epistasia Genética , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Análise Multivariada , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Análise de Regressão , Fatores de Risco , Índice de Gravidade de Doença , Uso de Tabaco
10.
Mol Brain ; 12(1): 39, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036051

RESUMO

TMP21, a type I transmembrane protein of thep24 protein family, mediates protein trafficking and maturation. Dysregulation of TMP21 is implicated in the pathogenesis of Alzheimer's disease (AD). However, underlying mechanisms remain elusive. To reveal the function of TMP21 in the brain and the pathogenic role of TMP21 in the brain of AD, the global gene expression was profiled in the brain of TMP21 knockdown mice. We found that 8196 and 8195 genes are significantly altered in the hippocampus and cortex, respectively. The genes are involved in a number of brain function-related pathways, including glutamatergic synapse pathway, serotonergic synapse pathway, synaptic vesicle pathway, and long-term depression pathway. Moreover, the network analysis suggests that the TMP21 may contribute to the pathogenesis of AD by regulatingPI3K/Akt/GSK3ß signalling pathway. Our study provides an insight into the physiological function of TMP21 in the brain and pathological role of TMP21 in AD.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica , Proteínas de Membrana/metabolismo , Animais , Epistasia Genética , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transcrição Genética
11.
PLoS Genet ; 15(4): e1008079, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30969963

RESUMO

Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.


Assuntos
Evolução Molecular , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Aptidão Genética , Leveduras/genética , Leveduras/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Aminoácidos/genética , Aminoácidos/metabolismo , Epistasia Genética , Proteínas Fúngicas/química , Genes Fúngicos , Genótipo , Hidroliases/química , Hidroliases/genética , Hidroliases/metabolismo , Modelos Genéticos , Modelos Moleculares , Filogenia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
PLoS Genet ; 15(4): e1007954, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009456

RESUMO

One of the main outcomes of quantitative genetics approaches to natural variation is to reveal the genetic architecture underlying the phenotypic space. Complex genetic architectures are described as including numerous loci (or alleles) with small-effect and/or low-frequency in the populations, interactions with the genetic background, environment or age. Linkage or association mapping strategies will be more or less sensitive to this complexity, so that we still have an unclear picture of its extent. By combining high-throughput phenotyping under two environmental conditions with classical QTL mapping approaches in multiple Arabidopsis thaliana segregating populations as well as advanced near isogenic lines construction and survey, we have attempted to improve our understanding of quantitative phenotypic variation. Integrative traits such as those related to vegetative growth used in this work (highlighting either cumulative growth, growth rate or morphology) all showed complex and dynamic genetic architecture with respect to the segregating population and condition. The more resolutive our mapping approach, the more complexity we uncover, with several instances of QTLs visible in near isogenic lines but not detected with the initial QTL mapping, indicating that our phenotyping accuracy was less limiting than the mapping resolution with respect to the underlying genetic architecture. In an ultimate approach to resolve this complexity, we intensified our phenotyping effort to target specifically a 3Mb-region known to segregate for a major quantitative trait gene, using a series of selected lines recombined every 100kb. We discovered that at least 3 other independent QTLs had remained hidden in this region, some with trait- or condition-specific effects, or opposite allelic effects. If we were to extrapolate the figures obtained on this specific region in this particular cross to the genome- and species-scale, we would predict hundreds of causative loci of detectable phenotypic effect controlling these growth-related phenotypes.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Mapeamento Cromossômico , Cruzamentos Genéticos , Epistasia Genética , Variação Genética , Genoma de Planta , Endogamia , Herança Multifatorial , Fenótipo , Brotos de Planta/genética , Brotos de Planta/crescimento & desenvolvimento , Locos de Características Quantitativas , Recombinação Genética
13.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945677

RESUMO

Understanding the genetic basis of biochemical traits of different cauliflower genotypes is essential for planning the effective breeding strategies in genetic improvement. To determine the mode of inheritance of dry matter content and biochemical traits, we made crosses using four genotypes of cauliflower, and obtained F1, F2, BC1 and BC2 populations. The six generations obtained were replicated thrice and evaluated in a randomized block design. The generation mean analysis of data showed the presence of duplicate epistasis in dry matter content which suggested the adoption of reciprocal recurrent selection and biparental mating for the improvement of the trait. However, in case of vitamin C, complementary type of epistasis was reported in three crosses, which indicated the exploitation of heterosis breeding of enhancing vitamin C. It can be concluded that the role of gene action was in general more complex for the traits studied. The nature and magnitude of gene effects varies character-wise as well as cross-wise. Hence, for the improvement of dry matter content and biochemical traits in a particular cross, a specific breeding strategy has to be implemented.


Assuntos
Ácido Ascórbico/análise , Brassica/genética , Brassica/metabolismo , Fenóis/análise , Locos de Características Quantitativas , Seleção Genética , Açúcares/análise , Altitude , Antioxidantes/análise , Brassica/crescimento & desenvolvimento , Mapeamento Cromossômico , Cromossomos de Plantas , Epistasia Genética , Índia , Melhoramento Vegetal
14.
Genetica ; 147(2): 197-203, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937602

RESUMO

Trifolium alexandrinum (Egyptian clover) is a widely cultivated winter annual fodder. Present work deals with inheritance of the seed coat colour in segregating progenies of the interspecific cross between T. alexandrinum and T. apertum. Although, both the parent species possessed yellow seed coat, the F1 seeds were black coloured in the reciprocal cross (T. apertum × T. alexandrinum). Seeds borne on individual F2 plants and the advancing generations segregated in yellow and black seed coat colour, which confirmed xenia effect. F2 seeds collected from individual F1 plants exhibited nine black and seven yellow segregation ratio. The segregation of the seed coat colour recorded from F3 to F5 generations revealed that yellow seed coat was true breeding (i.e. non-segregating) in this interspecific cross (including the reciprocal crosses). However, the black seeded progenies were either true breeding or segregated in nine black: seven yellow ratio or three black: one yellow ratio suggesting a complementary gene interaction or duplicate recessive epistasis. It indicated that the seed coat colour is controlled by complementary gene interaction along with xenia effect in interspecific crosses between T. alexandrinum and T. apertum. Occurrence of the complementary genes across the species could suggest T. apertum to be the progenitor of T. alexandrinum. Inheritance of seed coat colour in reference to its importance in Egyptian clover breeding is also discussed.


Assuntos
Epistasia Genética , Hibridização Genética , Sementes/genética , Trifolium/genética , Pigmentação , Polinização , Sementes/metabolismo , Trifolium/fisiologia
15.
PLoS Negl Trop Dis ; 13(4): e0007324, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30995222

RESUMO

Chagas Disease (CD) is an anthropozoonosis caused by Trypanosoma cruzi. With complex pathophysiology and variable clinical presentation, CD outcome can be influenced by parasite persistence and the host immune response. Complement activation is one of the primary defense mechanisms against pathogens, which can be initiated via pathogen recognition by pattern recognition molecules (PRMs). Collectin-11 is a multifunctional soluble PRM lectin, widely distributed throughout the body, with important participation in host defense, homeostasis, and embryogenesis. In complex with mannose-binding lectin-associated serine proteases (MASPs), collectin-11 may initiate the activation of complement, playing a role against pathogens, including T. cruzi. In this study, collectin-11 plasma levels and COLEC11 variants in exon 7 were assessed in a Brazilian cohort of 251 patients with chronic CD and 108 healthy controls. Gene-gene interactions between COLEC11 and MASP2 variants were analyzed. Collectin-11 levels were significantly decreased in CD patients compared to controls (p<0.0001). The allele rs7567833G, the genotypes rs7567833AG and rs7567833GG, and the COLEC11*GGC haplotype were related to T. cruzi infection and clinical progression towards symptomatic CD. COLEC11 and MASP2*CD risk genotypes were associated with cardiomyopathy (p = 0.014; OR 9.3, 95% CI 1.2-74) and with the cardiodigestive form of CD (p = 0.005; OR 15.2, 95% CI 1.7-137), suggesting that both loci act synergistically in immune modulation of the disease. The decreased levels of collectin-11 in CD patients may be associated with the disease process. The COLEC11 variant rs7567833G and also the COLEC11 and MASP2*CD risk genotype interaction were associated with the pathophysiology of CD.


Assuntos
Doença de Chagas/genética , Doença de Chagas/fisiopatologia , Colectinas/genética , Epistasia Genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Casos e Controles , Colectinas/sangue , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
J Appl Genet ; 60(2): 127-135, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877656

RESUMO

The objective of this study was to assess genotype by environment interaction for 1000-kernel weight in spring barley lines grown in South Poland by the additive main effects and multiplicative interaction model. The study comprised of 32 spring barley (Hordeum vulgare L.) genotypes (two parental genotypes-breeding line 1 N86 and doubled haploid (DH) line RK63/1, and 30 DH lines derived from F1 hybrids), evaluated at six locations in a randomized complete block design, with three replicates. 1000-kernel weight ranged from 24.35 g (for R63N/42 in 2011) to 61.46 g (for R63N/18 in 2008), with an average of 44.80 g. AMMI analyses revealed significant genotype and environmental effects as well as GE interaction with respect to 1000-kernel weight. In the analysis of variance, 16.86% of the total 1000-kernel weight variation was explained by environment, 32.18% by differences between genotypes, and 24.50% by GE interaction. The lines R63N/61, R63N/22, and R63N/1 are recommended for further inclusion in the breeding program because their stability and the highest averages of 1000-kernel weight. The total additive effect of all genes controlling the trait and the total epistasis effect of 1000-kernel weight were estimated. Additive gene action effects based on DH lines were always larger that this parameter estimated on the basis of parental lines. Estimates of additive gene action effects based on the all DH lines were significantly larger than zero in each year of study. Epistasis effects based on all DH lines were statistically significant in 2011 and 2013.


Assuntos
Ammi/genética , Epistasia Genética , Hordeum/genética , Locos de Características Quantitativas/genética , Ammi/crescimento & desenvolvimento , Interação Gene-Ambiente , Genótipo , Haploidia , Hordeum/crescimento & desenvolvimento
17.
Cell Prolif ; 52(3): e12593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30847993

RESUMO

OBJECTIVES: The evolutionary conserved JNK pathway plays crucial role in cell death, yet factors that modulate this signalling have not been fully disclosed. In this study, we aim to identify additional factors that regulate JNK signalling in cell death, and characterize the underlying mechanisms. MATERIALS AND METHODS: Drosophila were raised on standard media, and cross was carried out at 25°C. The Gal4/UAS system was used to express proteins or RNAi in a specific temporal and spatial pattern. Gene expression was revealed by GFP fluorescence, X-gal staining or immunostaining of 3rd instar larval eye and wing discs. Cell death was visualized by acridine orange (AO) staining. Images of fly eyes and wings were taken by OLYMPUS microscopes. RESULTS: We found that licorne (lic) encoding the Drosophila MKK3 is an essential regulator of JNK-mediated cell death. Firstly, loss of lic suppressed ectopic Egr-triggered JNK activation and cell death in eye and wing development. Secondary, lic is necessary for loss-of-cell polarity-induced, physiological JNK-dependent cell death in wing development. Thirdly, Lic overexpression is sufficient to initiate JNK-mediated cell death in developing eyes and wings. Furthermore, ectopic Lic activates JNK signalling by promoting JNK phosphorylation. Finally, genetic epistatic analysis confirmed that Lic acts in parallel with Hep in the Egr-JNK pathway. CONCLUSIONS: This study not only identified Lic as a novel component of the JNK signalling, but also disclosed the crucial roles and mechanism of Lic in cell death.


Assuntos
Morte Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases/metabolismo , Animais , Animais Geneticamente Modificados , Morte Celular/genética , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epistasia Genética , Olho/crescimento & desenvolvimento , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes de Insetos , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Quinases/genética , Interferência de RNA , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
18.
Nat Commun ; 10(1): 1002, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824696

RESUMO

Gene essentiality is a variable phenotypic trait, but to what extent and how essential genes can become dispensable for viability remain unclear. Here, we investigate 'bypass of essentiality (BOE)' - an underexplored type of digenic genetic interaction that renders essential genes dispensable. Through analyzing essential genes on one of the six chromosome arms of the fission yeast Schizosaccharomyces pombe, we find that, remarkably, as many as 27% of them can be converted to non-essential genes by BOE interactions. Using this dataset we identify three principles of essentiality bypass: bypassable essential genes tend to have lower importance, tend to exhibit differential essentiality between species, and tend to act with other bypassable genes. In addition, we delineate mechanisms underlying bypassable essentiality, including the previously unappreciated mechanism of dormant redundancy between paralogs. The new insights gained on bypassable essentiality deepen our understanding of genotype-phenotype relationships and will facilitate drug development related to essential genes.


Assuntos
Epistasia Genética , Genes Essenciais , Genes Fúngicos/genética , Schizosaccharomyces/genética , Mapeamento Cromossômico , Cromossomos , Bases de Dados Genéticas , Evolução Molecular , Redes Reguladoras de Genes , Genótipo , Modelos Genéticos , Fenótipo , Plasmídeos/genética , Especificidade da Espécie
19.
Genet Test Mol Biomarkers ; 23(3): 180-187, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30875252

RESUMO

PURPOSE: The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes that encode forkhead box p3 (Foxp3) (rs3761549 C>T, rs2280883T>C, rs2232365 A>G and rs3761548 C>A) and transforming growth factor (TGF)-ß1 (rs11466359 C>T, rs11466345 A>G and rs1800469 T>C) are associated with pre-eclampsia (PE) risk in Chinese women. MATERIALS AND METHODS: SNPs were identified by polymerase chain reaction and ligase detection reaction. Allelic variant and genotype frequencies for Foxp3 and TGF-ß1 were compared between PE women (n = 203) and healthy pregnant (HP) controls (n = 243). RESULTS: The TGF-ß1 rs1800469 TT genotype was found more frequently in PE patients than in HP controls [CC vs. CT+TT: odds ratio (OR) = 1.71; 95% confidence interval (CI): 1.04-2.81; p = 0.033], indicating that the T allele of rs1800469 confers a risk for PE [OR = 1.46; 95% CI: 1.12-1.92; p = 0.006]. The Foxp3 rs2232365 A allele was associated with severe PE specifically [OR = 1.70; 95% CI: 1.12-2.58; p = 0.01], compared with mild PE. There were no haplotype associations with PE. CONCLUSIONS: These findings indicate that allelic variants of TGF-ß1 rs1800469 T influence PE risk in Chinese women. Pregnant Han Chinese women carrying the rs1800469 TT genotype were at increased risk of PE.


Assuntos
Fatores de Transcrição Forkhead/genética , Pré-Eclâmpsia/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Epistasia Genética , Feminino , Fatores de Transcrição Forkhead/fisiologia , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Fatores de Risco , Fator de Crescimento Transformador beta1/fisiologia
20.
Hum Genet ; 138(4): 293-305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30840129

RESUMO

The understanding that differences in biological epistasis may impact disease risk, diagnosis, or disease management stands in wide contrast to the unavailability of widely accepted large-scale epistasis analysis protocols. Several choices in the analysis workflow will impact false-positive and false-negative rates. One of these choices relates to the exploitation of particular modelling or testing strategies. The strengths and limitations of these need to be well understood, as well as the contexts in which these hold. This will contribute to determining the potentially complementary value of epistasis detection workflows and is expected to increase replication success with biological relevance. In this contribution, we take a recently introduced regression-based epistasis detection tool as a leading example to review the key elements that need to be considered to fully appreciate the value of analytical epistasis detection performance assessments. We point out unresolved hurdles and give our perspectives towards overcoming these.


Assuntos
Interpretação Estatística de Dados , Epistasia Genética/fisiologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Cultura , Reações Falso-Positivas , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único
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