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2.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207999

RESUMO

The family of retinoic acid receptors (RARs: RARα, -ß, and -γ) has remarkable pleiotropy characteristics, since the retinoic acid/RARs pathway is involved in numerous biological processes not only during embryonic development, but also in the postnatal phase and during adulthood. In this review, we trace the roles of RA/RARs signaling in the immune system (where this pathway has both an immunosuppressive role or is involved in the inflammatory response), in hematopoiesis (enhancing hematopoietic stem cell self-renewal, progenitor cells differentiation or maintaining the bone marrow microenvironment homeostasis), and in bone remodeling (where this pathway seems to have controversial effects on bone formation or osteoclast activation). Moreover, in this review is shown the involvement of RAR genes in multiple chromosomal rearrangements generating different fusion genes in hematological neoplasms, with a particular focus on acute promyelocytic leukemia and its variant subtypes. The effect of different RARs fusion proteins on leukemic transformation, on patients' outcome, and on therapy response is also discussed.


Assuntos
Rearranjo Gênico , Leucemia Promielocítica Aguda/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Tretinoína/metabolismo , Animais , Pleiotropia Genética , Humanos , Leucemia Promielocítica Aguda/genética , Receptores do Ácido Retinoico/genética
3.
BMC Plant Biol ; 19(1): 168, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035920

RESUMO

BACKGROUND: Identification of loci for grain yield (GY) and related traits, and dissection of the genetic architecture are important for yield improvement through marker-assisted selection (MAS). Two genome-wide association study (GWAS) methods were used on a diverse panel of 166 elite wheat varieties from the Yellow and Huai River Valleys Wheat Zone (YHRVWD) of China to detect stable loci and analyze relationships among GY and related traits. RESULTS: A total of 326,570 single nucleotide polymorphism (SNP) markers from the wheat 90 K and 660 K SNP arrays were chosen for GWAS of GY and related traits, generating a physical distance of 14,064.8 Mb. One hundred and twenty common loci were detected using SNP-GWAS and Haplotype-GWAS, among which two were potentially functional genes underpinning kernel weight and plant height (PH), eight were at similar locations to the quantitative trait loci (QTL) identified in recombinant inbred line (RIL) populations in a previous study, and 78 were potentially new. Twelve pleiotropic loci were detected on eight chromosomes; among these the interval 714.4-725.8 Mb on chromosome 3A was significantly associated with GY, kernel number per spike (KNS), kernel width (KW), spike dry weight (SDW), PH, uppermost internode length (UIL), and flag leaf length (FLL). GY shared five loci with thousand kernel weight (TKW) and PH, indicating significantly affected by two traits. Compared with the total number of loci for each trait in the diverse panel, the average number of alleles for increasing phenotypic values of GY, TKW, kernel length (KL), KW, and flag leaf width (FLW) were higher, whereas the numbers for PH, UIL and FLL were lower. There were significant additive effects for each trait when favorable alleles were combined. UIL and FLL can be directly used for selecting high-yielding varieties, whereas FLW can be used to select spike number per unit area (SN) and KNS. CONCLUSIONS: The loci and significant SNP markers identified in the present study can be used for pyramiding favorable alleles in developing high-yielding varieties. Our study proved that both GWAS methods and high-density genetic markers are reliable means of identifying loci for GY and related traits, and provided new insight to the genetic architecture of GY.


Assuntos
Genoma de Planta , Estudo de Associação Genômica Ampla , Triticum/genética , Alelos , China , Marcadores Genéticos , Pleiotropia Genética , Variação Genética , Haplótipos , Desequilíbrio de Ligação , Fenótipo , Desenvolvimento Vegetal/genética , Folhas de Planta , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Sementes/anatomia & histologia , Sementes/genética , Triticum/crescimento & desenvolvimento
4.
Genet Epidemiol ; 43(6): 609-616, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31045282

RESUMO

With the advent of very large scale genome-wide association studies (GWASs), the promise of Mendelian randomization (MR) has begun to be fulfilled. However, whilst GWASs have provided essential information on the single nucleotide polymorphisms (SNPs) associated with modifiable risk factors needed for MR, the availability of large numbers of SNP instruments raises issues of how best to use this information and how to deal with potential problems such as pleiotropy. Here we provide commentary on some of the recent advances in the MR analysis, including an overview of the different genetic architectures that are being uncovered for a variety of modifiable risk factors and how users ought to take that into consideration when designing MR studies.


Assuntos
Doença/genética , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla , Implementação de Plano de Saúde , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Padrões de Prática Médica/normas , Clínicos Gerais/normas , Humanos , Fatores de Risco
5.
BMC Genomics ; 20(1): 395, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113383

RESUMO

BACKGROUND: Many genome-wide association studies have detected genomic regions associated with traits, yet understanding the functional causes of association often remains elusive. Utilizing systems approaches and focusing on intermediate molecular phenotypes might facilitate biologic understanding. RESULTS: The availability of exome sequencing of two populations of African-Americans and European-Americans from the Atherosclerosis Risk in Communities study allowed us to investigate the effects of annotated loss-of-function (LoF) mutations on 122 serum metabolites. To assess the findings, we built metabolomic causal networks for each population separately and utilized structural equation modeling. We then validated our findings with a set of independent samples. By use of methods based on concepts of Mendelian randomization of genetic variants, we showed that some of the affected metabolites are risk predictors in the causal pathway of disease. For example, LoF mutations in the gene KIAA1755 were identified to elevate the levels of eicosapentaenoate (p-value = 5E-14), an essential fatty acid clinically identified to increase essential hypertension. We showed that this gene is in the pathway to triglycerides, where both triglycerides and essential hypertension are risk factors of metabolomic disorder and heart attack. We also identified that the gene CLDN17, harboring loss-of-function mutations, had pleiotropic actions on metabolites from amino acid and lipid pathways. CONCLUSION: Using systems biology approaches for the analysis of metabolomics and genetic data, we integrated several biological processes, which lead to findings that may functionally connect genetic variants with complex diseases.


Assuntos
Pleiotropia Genética , Genoma Humano , Metaboloma/genética , Metabolômica , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Afro-Americanos/genética , Algoritmos , Grupo com Ancestrais do Continente Europeu/genética , Humanos
6.
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
7.
Nat Hum Behav ; 3(5): 471-477, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31089300

RESUMO

Cigarette smoking is a risk factor for a wide range of human diseases1. To investigate the genetic components associated with smoking behaviours in the Japanese population, we conducted a genome-wide association study of four smoking-related traits using up to 165,436 individuals. In total, we identified seven new loci, including three loci associated with the number of cigarettes per day (EPHX2-CLU, RET and CUX2-ALDH2), three loci associated with smoking initiation (DLC1, CXCL12-TMEM72-AS1 and GALR1-SALL3) and LINC01793-MIR4432HG, associated with the age of smoking initiation. Of these, three loci (LINC01793-MIR4432HG, CXCL12-TMEM72-AS1 and GALR1-SALL3) were found by conducting an additional sex-stratified genome-wide association study. This additional analysis showed heterogeneity of effects between sexes. The cross-sex linkage disequilibrium score regression2,3 analysis also indicated that the genetic component of smoking initiation was significantly different between the sexes. Cross-trait linkage disequilibrium score regression analysis and trait-relevant tissue analysis showed that the number of cigarettes per day has a specific genetic background distinct from those of the other three smoking behaviours. We also report 11 diseases that share genetic basis with smoking behaviours. Although the current study should be carefully considered owing to the lack of replication samples, our findings characterized the genetic architecture of smoking behaviours. Further studies in East Asian populations are warranted to confirm our findings.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fumar Cigarros/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Pleiotropia Genética/genética , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Abandono do Hábito de Fumar , Adulto Jovem
8.
Lipids Health Dis ; 18(1): 111, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077211

RESUMO

BACKGROUND: Hepatic lipase (HL, encoded by LIPC) is a glycoprotein primarily synthesized and secreted by hepatocytes. Previous studies had demonstrated that HL is crucial for reverse cholesterol transport and affects the metabolism, composition, and level of several lipoproteins. In current study, we investigated the association of LIPC (Lipase C, Hepatic Type) variants with circulating and urinary biomarker levels by using subgroup and mediation analyses. METHODS: A total of 572 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs) by using TaqMan assay. Fasting levels of glucose, lipid profile, inflammation markers, urine creatinine and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The chi-square test, 2-sample t test and Analysis of variance (ANOVA) were used to examine differences among variables and genotype frequencies. RESULTS: SNPs rs2043085 and rs1532085 were significantly associated with urinary 8-OHdG levels, whereas all three SNPs were more significantly associated with Triglycerides (TG) or HDL-cholesterol (HDL-C) levels after additional adjustment for HDL-C or TG levels, respectively. Subgroup analyses revealed that the association of the LIPC SNPs with the levels of serum TG, HDL-C, and urinary 8-OHdG were predominantly observed in the men but not in the women. Differential associations of the LIPC SNPs with various lipid levels were observed in participants with different adiposity statuses. Mediation analyses indicated that TG levels acted as a suppressor masking the association of the LIPC genotypes with HDL-C levels, particularly in the men (Sobel test, all P < 0.01). CONCLUSION: Our data revealed that interaction and suppression effects mediated the pleiotropic association of the LIPC variants. The effects of the LIPC SNPs depended on sex, adiposity status, and TG levels. Thus, our findings can provide a method for identifying high-risk populations of cardiovascular diseases for clinical diagnosis.


Assuntos
Desoxiguanosina/análogos & derivados , Estudos de Associação Genética , Pleiotropia Genética , Lipase/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/genética , Biomarcadores/sangue , HDL-Colesterol/sangue , Desoxiguanosina/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Obesidade/sangue , Obesidade/genética , Caracteres Sexuais , Triglicerídeos/sangue
9.
BMC Genomics ; 20(1): 327, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039790

RESUMO

BACKGROUND: Bacillus pumilus is a Gram-positive and endospore-forming bacterium broadly existing in a variety of environmental niches. Because it produces and secrets many industrially useful enzymes, a lot of studies have been done to understand the underlying mechanisms. Among them, scoC was originally identified as a pleiotropic transcription factor negatively regulating protease production and sporulation in B. subtilis. Nevertheless, its role in B. pumilus largely remains unknown. RESULTS: In this study we successfully disrupted scoC gene in B. pumilus BA06 and found increased total extracellular protease activity in scoC mutant strain. Surprisingly, we also found that scoC disruption reduced cell motility possibly by affecting flagella formation. To better understand the underlying mechanism, we performed transcriptome analysis with RNA sequencing. The result showed that more than one thousand genes were alternated at transcriptional level across multiple growth phases, and among them the largest number of differentially expressed genes (DEGs) were identified at the transition time point (12 h) between the exponential growth and the stationary growth phases. In accordance with the altered phenotype, many protease genes especially the aprE gene encoding alkaline protease were transcriptionally regulated. In contrast to the finding in B. subtilis, the aprN gene encoding neutral protease was transcriptionally downregulated in B. pumilus, implicating that scoC plays strain-specific roles. CONCLUSIONS: The pleiotropic transcription factor ScoC plays multiple roles in various cellular processes in B. pumilus, some of which were previously reported in B. subtilis. The supervising finding is the identification of ScoC as a positive regulator for flagella formation and bacterial motility. Our transcriptome data may provide hints to understand the underlying mechanism.


Assuntos
Bacillus pumilus/genética , Proteínas de Bactérias/antagonistas & inibidores , Regulação Bacteriana da Expressão Gênica , Pleiotropia Genética , Transcriptoma , Bacillus pumilus/citologia , Bacillus pumilus/crescimento & desenvolvimento , Bacillus pumilus/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Movimento Celular , Endopeptidases/metabolismo , Flagelos/fisiologia , Fenótipo
10.
Plant Genome ; 12(1)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30951092

RESUMO

Rice ( L.) end-use cooking quality is vital for producers and billions of consumers worldwide. Grain quality is a complex trait with interacting genetic and environmental factors. Deciphering the complex genetic architecture associated with grain quality provides essential information for improved breeding strategies to enhance desirable traits that are stable across variable climatic and environmental conditions. In this study, genome-wide association (GWA) analysis of three rice diversity panels, the USDA rice core subset (1364 accessions), the minicore (MC) (173 accessions after removing non-), and the high density rice array-MC (HDMC) (383 accessions), with simple sequence repeats, single nucleotide polymorphic markers, or both, revealed large- and small-effect loci associated with known genes and previously uncharacterized genomic regions. Clustering of the significant regions in the GWA results suggests that multiple grain quality traits are inherited together. The 11 novel candidate loci for grain quality traits and the seven candidates for grain chalk identified are involved in the starch biosynthesis pathway. This study highlights the intricate pleiotropic relationships that exist in complex genotype-phenotypic associations and gives a greater insight into effective breeding strategies for grain quality improvement.


Assuntos
Grão Comestível/genética , Oryza/genética , Qualidade dos Alimentos , Pleiotropia Genética , Variação Genética , Genoma de Planta , Estudo de Associação Genômica Ampla
11.
Nat Microbiol ; 4(7): 1221-1230, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936490

RESUMO

How does environmental complexity affect the evolution of single genes? Here, we measured the effects of a set of Bacillus subtilis glutamate dehydrogenase mutants across 19 different environments-from phenotypically homogeneous single-cell populations in liquid media to heterogeneous biofilms, plant roots and soil populations. The effects of individual gene mutations on organismal fitness were highly reproducible in liquid cultures. However, 84% of the tested alleles showed opposing fitness effects under different growth conditions (sign environmental pleiotropy). In colony biofilms and soil samples, different alleles dominated in parallel replica experiments. Accordingly, we found that in these heterogeneous cell populations the fate of mutations was dictated by a combination of selection and drift. The latter relates to programmed prophage excisions that occurred during biofilm development. Overall, for each condition, a wide range of glutamate dehydrogenase mutations persisted and sometimes fixated as a result of the combined action of selection, pleiotropy and chance. However, over longer periods and in multiple environments, nearly all of this diversity would be lost-across all the environments and conditions that we tested, the wild type was the fittest allele.


Assuntos
Meio Ambiente , Pleiotropia Genética , Variação Genética/genética , Bacillus subtilis/genética , Bacillus subtilis/crescimento & desenvolvimento , Biofilmes/crescimento & desenvolvimento , Evolução Molecular , Deriva Genética , Aptidão Genética , Glutamato Desidrogenase/genética , Mutação , Seleção Genética , Ativação Viral
12.
BMC Genomics ; 20(1): 309, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014246

RESUMO

BACKGROUND: Trait loss is a pervasive phenomenon in evolution, yet the underlying molecular causes have been identified in only a handful of cases. Most of these cases involve loss-of-function mutations in one or more trait-specific genes. However, in parasitoid insects the evolutionary loss of a metabolic trait is not associated with gene decay. Parasitoids have lost the ability to convert dietary sugars into fatty acids. Earlier research suggests that lack of lipogenesis in the parasitoid wasp Nasonia vitripennis is caused by changes in gene regulation. RESULTS: We compared transcriptomic responses to sugar-feeding in the non-lipogenic parasitoid species Nasonia vitripennis and the lipogenic Drosophila melanogaster. Both species adjusted their metabolism within 4 hours after sugar-feeding, but there were sharp differences between the expression profiles of the two species, especially in the carbohydrate and lipid metabolic pathways. Several genes coding for key enzymes in acetyl-CoA metabolism, such as malonyl-CoA decarboxylase (mcd) and HMG-CoA synthase (hmgs) differed in expression between the two species. Their combined action likely blocks lipogenesis in the parasitoid species. Network-based analysis showed connectivity of genes to be negatively correlated to the fold change of gene expression. Furthermore, genes involved in the fatty acid metabolic pathway were more connected than the set of genes of all metabolic pathways combined. CONCLUSION: High connectivity of lipogenesis genes is indicative of pleiotropic effects and could explain the absence of gene degradation. We conclude that modification of expression levels of only a few little-connected genes, such as mcd, is sufficient to enable complete loss of lipogenesis in N. vitripennis.


Assuntos
Evolução Molecular , Lipogênese/genética , Vespas/genética , Vespas/metabolismo , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Pleiotropia Genética , Transcrição Genética , Vespas/fisiologia
13.
Immunity ; 50(4): 812-831, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995501

RESUMO

Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy.


Assuntos
Citocinas/fisiologia , Pleiotropia Genética , Família Multigênica/fisiologia , Animais , Doenças Autoimunes/imunologia , Citocinas/genética , Regulação da Expressão Gênica , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-6/fisiologia , Camundongos , Subunidades Proteicas , Receptores de Citocinas/fisiologia , Receptores de Interleucina-6/fisiologia , Transdução de Sinais , Relação Estrutura-Atividade
14.
Genet Sel Evol ; 51(1): 9, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836944

RESUMO

BACKGROUND: In livestock, deleterious recessive alleles can result in reduced economic performance of homozygous individuals in multiple ways, e.g. early embryonic death, death soon after birth, or semi-lethality with incomplete penetrance causing reduced viability. While death is an easy phenotype to score, reduced viability is not as easy to identify. However, it can sometimes be observed as reduced conception rates, longer calving intervals, or lower survival for live born animals. METHODS: In this paper, we searched for haplotypes that carry putatively recessive lethal or semi-lethal alleles in 132,725 genotyped Irish beef cattle from five breeds: Aberdeen Angus, Charolais, Hereford, Limousin, and Simmental. We phased the genotypes in sliding windows along the genome and used five tests to identify haplotypes with absence of or reduced homozygosity. Then, we associated the identified haplotypes with 44,351 insemination records that indicated early embryonic death, and postnatal survival records. Finally, we assessed haplotype pleiotropy by estimating substitution effects on estimates of breeding value for 15 economically important traits in beef production. RESULTS: We found support for one haplotype that carries a putatively recessive lethal (chromosome 16 in Simmental) and two haplotypes that carry semi-lethal alleles (chromosome 14 in Aberdeen Angus and chromosome 19 in Charolais), with population frequencies of 8.8, 15.2, and 14.4%, respectively. These three haplotypes showed pleiotropic effects on economically important traits for beef production. Their allele substitution effects are €2.30, €3.42, and €1.47 for the terminal index and €1.03, - €3.11, and - €0.88 for the replacement index, where the standard deviations for the terminal index are €22.52, €18.65, and €22.70 and for the replacement index they are €31.35, €29.82, and €35.79. We identified ZFAT as the candidate gene for semi-lethality in Aberdeen Angus, several candidate genes for the lethal Simmental haplotype, and no candidate genes for the semi-lethal Charolais haplotype. CONCLUSIONS: We analysed genotype, reproduction, survival, and production data to detect haplotypes that carry putatively recessive lethal or semi-lethal alleles in Irish beef cattle and identified one lethal and two semi-lethal haplotypes, which have pleiotropic effects on economically important traits in beef production.


Assuntos
Bovinos/genética , Frequência do Gene , Genes Recessivos , Pleiotropia Genética , Haplótipos , Carne Vermelha/normas , Animais , Estudo de Associação Genômica Ampla/veterinária , Genótipo , Característica Quantitativa Herdável
15.
BMJ ; 364: l476, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842065

RESUMO

OBJECTIVE: To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction. DESIGN: Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence. SETTING: Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study. PARTICIPANTS: 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation. MAIN OUTCOME MEASURES: Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death. RESULTS: Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes. CONCLUSIONS: Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.


Assuntos
Insuficiência Cardíaca/genética , Infarto do Miocárdio/genética , Testosterona/genética , Tromboembolia/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Pleiotropia Genética/fisiologia , Variação Genética/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Reino Unido
16.
Dis Model Mech ; 12(3)2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30833296

RESUMO

Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction in mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. The zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In this study, we characterized the mitochondrial phenotype of mpv17-/- larvae and found early and severe ultrastructural alterations in liver mitochondria, as well as significant impairment of the respiratory chain, leading to activation of the mitochondrial quality control. Our results provide evidence for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality, while its effects on mtDNA copy number seem to be subordinate. Considering that a role in nucleotide availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17-/- knockouts (KOs) and that mpv17-/- KOs have impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). Treatment with OA, an easily available food supplement, significantly increased both iridophore number and mtDNA content in mpv17 -/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.


Assuntos
Pleiotropia Genética , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Homologia de Sequência de Aminoácidos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Vias Biossintéticas , DNA Mitocondrial/genética , Transporte de Elétrons , Dosagem de Genes , Humanos , Larva/genética , Larva/metabolismo , Fígado/metabolismo , Proteínas de Membrana/genética , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , Mutação/genética , Nucleotídeos/metabolismo , Fenótipo , Pirimidinas/biossíntese , Estresse Fisiológico , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
17.
Nat Rev Endocrinol ; 15(6): 356-365, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30899100

RESUMO

The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.


Assuntos
Pleiotropia Genética/fisiologia , Nível de Saúde , Hiperprolactinemia/metabolismo , Osteoporose/metabolismo , Prolactina/metabolismo , Animais , Feminino , Homeostase/fisiologia , Humanos , Hiperprolactinemia/genética , Osteoporose/genética , Prolactina/deficiência , Prolactina/genética , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
18.
Gene ; 694: 111-120, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30738968

RESUMO

Codon usage bias (CUB) is a universal feature of genomes, and in most species CUB of protein coding genes is positively correlated with expression level and degree of evolutionary conservation. There is mounting experimental evidence that CUB is due in part to selection for translational efficiency and/or accuracy, i.e., translational selection. However, there is a paucity of experimental data on whether and how CUB acts in trans - does the usage of preferred codons in a highly expressed gene affect the translation of other genes by freeing up more ribosomes, thereby increasing their availability to translate all mRNA transcripts in the cell? We investigated this question by creating two extreme versions of the highly expressed Escherichia coli ß-lactamase (bla) gene, one comprised almost entirely of unpreferred codons, and a second comprised almost entirely of preferred codons. We monitored the fitness effects of these synonymous mutations over hundreds of generations in two selective environments that allowed us to disentangle translational effects acting in cis from those acting in trans. In a selective environment for maximizing translational efficiency in trans of a gene (tetA) encoding a tetracycline resistance protein, unpreferred synonymous mutations had a negative impact on long-term fitness, whereas preferred mutations had a positive impact on long-term fitness, providing strong experimental evidence for a pleiotropic effect of translational selection.


Assuntos
Escherichia coli/genética , Mutação Silenciosa/fisiologia , beta-Lactamases/genética , Códon , Proteínas de Escherichia coli/genética , Evolução Molecular , Pleiotropia Genética/genética , Modelos Genéticos , Mutação/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Seleção Genética/genética , Mutação Silenciosa/genética , beta-Lactamases/metabolismo
19.
Genetics ; 212(1): 267-276, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30808620

RESUMO

A long-standing prediction in evolutionary biology is that organisms experience a so-called "cost of complexity" manifested as a decreasing rate of adaptation in populations as organisms or selective environments become increasingly complex. This theory assumes the ubiquity of antagonistic pleiotropy, or trade-offs in fitness, for mutations affecting multiple traits or phenotypes. A particular manifestation of antagonism thought to be at play in adaptive dynamics involves the relationship between viral growth rate and capsid stability, an interaction that may impede the adaptation of viral pathogens to novel hosts and environments. Here, we present a comparison of the genetics of adaptation for populations of bacteriophages undergoing complete adaptive walks under both simple and complex selective conditions, with complexity being determined by the number of traits under directional selection. We found no evidence for a long-term cost of complexity in viruses experiencing complex selection, with on average at least as great a rate of adaptation under more complex conditions, and rampant evidence for synergistic, rather than antagonistic, pleiotropy. The lack of evident trade-offs between multiple phenotypes implies that emerging pathogens may be able to improve their growth in many different hosts or environments simultaneously, and to do so at a faster rate than previously anticipated.


Assuntos
Bacteriófagos/genética , Evolução Molecular , Pleiotropia Genética , Mutação , Evolução Biológica , Escherichia coli/virologia , Aptidão Genética , Seleção Genética , Sequenciamento Completo do Genoma
20.
BMC Evol Biol ; 19(1): 53, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744572

RESUMO

BACKGROUND: Germ lines are the cell lineages that give rise to the sperm and eggs in animals. The germ lines first arise from primordial germ cells (PGCs) during embryogenesis: these form from either a presumed derived mode of preformed germ plasm (inheritance) or from an ancestral mechanism of inductive cell-cell signalling (induction). Numerous genes involved in germ line specification and development have been identified and functionally studied. However, little is known about the molecular evolutionary dynamics of germ line genes in metazoan model systems. RESULTS: Here, we studied the molecular evolution of germ line genes within three metazoan model systems. These include the genus Drosophila (N=34 genes, inheritance), the fellow insect Apis (N=30, induction), and their more distant relative Caenorhabditis (N=23, inheritance). Using multiple species and established phylogenies in each genus, we report that germ line genes exhibited marked variation in the constraint on protein sequence divergence (dN/dS) and codon usage bias (CUB) within each genus. Importantly, we found that de novo lineage-specific inheritance (LSI) genes in Drosophila (osk, pgc) and in Caenorhabditis (pie-1, pgl-1), which are essential to germ plasm functions under the derived inheritance mode, displayed rapid protein sequence divergence relative to the other germ line genes within each respective genus. We show this may reflect the evolution of specialized germ plasm functions and/or low pleiotropy of LSI genes, features not shared with other germ line genes. In addition, we observed that the relative ranking of dN/dS and of CUB between genera were each more strongly correlated between Drosophila and Caenorhabditis, from different phyla, than between Drosophila and its insect relative Apis, suggesting taxonomic differences in how germ line genes have evolved. CONCLUSIONS: Taken together, the present results advance our understanding of the evolution of animal germ line genes within three well-known metazoan models. Further, the findings provide insights to the molecular evolution of germ line genes with respect to LSI status, pleiotropy, adaptive evolution as well as PGC-specification mode.


Assuntos
Evolução Molecular , Células Germinativas/metabolismo , Animais , Abelhas/genética , Caenorhabditis/genética , Linhagem da Célula , Regulação da Expressão Gênica no Desenvolvimento , Genes de Insetos , Pleiotropia Genética , Células Germinativas/citologia , Padrões de Herança/genética , Filogenia , Análise de Sequência de Proteína , Especificidade da Espécie
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