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1.
Am J Hum Genet ; 108(1): 49-67, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33326753

RESUMO

Although thousands of loci have been associated with human phenotypes, the role of gene-environment (GxE) interactions in determining individual risk of human diseases remains unclear. This is partly because of the severe erosion of statistical power resulting from the massive number of statistical tests required to detect such interactions. Here, we focus on improving the power of GxE tests by developing a statistical framework for assessing quantitative trait loci (QTLs) associated with the trait means and/or trait variances. When applying this framework to body mass index (BMI), we find that GxE discovery and replication rates are significantly higher when prioritizing genetic variants associated with the variance of the phenotype (vQTLs) compared to when assessing all genetic variants. Moreover, we find that vQTLs are enriched for associations with other non-BMI phenotypes having strong environmental influences, such as diabetes or ulcerative colitis. We show that GxE effects first identified in quantitative traits such as BMI can be used for GxE discovery in disease phenotypes such as diabetes. A clear conclusion is that strong GxE interactions mediate the genetic contribution to body weight and diabetes risk.


Assuntos
Variação Biológica da População/genética , Estudo de Associação Genômica Ampla/métodos , Interação Gene-Ambiente , Genótipo , Humanos , Fenótipo , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável
2.
PLoS One ; 15(10): e0239673, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33027289

RESUMO

This study used high throughput, image-based phenotyping (HTP) to distinguish growth patterns, detect facilitation and interpret variations to nutrient uptake in a model mixed-pasture system in response to factorial low and high nitrogen (N) and phosphorus (P) application. HTP has not previously been used to examine pasture species in mixture. We used red-green-blue (RGB) imaging to obtain smoothed projected shoot area (sPSA) to predict absolute growth (AG) up to 70 days after planting (sPSA, DAP 70), to identify variation in relative growth rates (RGR, DAP 35-70) and detect overyielding (an increase in yield in mixture compared with monoculture, indicating facilitation) in a grass-legume model pasture. Finally, using principal components analysis we interpreted between species changes to HTP-derived temporal growth dynamics and nutrient uptake in mixtures and monocultures. Overyielding was detected in all treatments and was driven by both grass and legume. Our data supported expectations of more rapid grass growth and augmented nutrient uptake in the presence of a legume. Legumes grew more slowly in mixture and where growth became more reliant on soil P. Relative growth rate in grass was strongly associated with shoot N concentration, whereas legume RGR was not strongly associated with shoot nutrients. High throughput, image-based phenotyping was a useful tool to quantify growth trait variation between contrasting species and to this end is highly useful in understanding nutrient-yield relationships in mixed pasture cultivations.


Assuntos
Fabaceae/crescimento & desenvolvimento , Nutrientes/metabolismo , Poaceae/crescimento & desenvolvimento , Agricultura/métodos , Variação Biológica da População/genética , Variação Biológica da População/fisiologia , Biomassa , Fabaceae/genética , Pradaria , Ensaios de Triagem em Larga Escala/métodos , Nitrogênio/metabolismo , Fósforo/metabolismo , Poaceae/genética , Solo
3.
PLoS One ; 15(9): e0238433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881964

RESUMO

Phenotypic switches are associated with alterations in the cell's gene expression profile and are vital to many aspects of biology. Previous studies have identified local motifs of the genetic regulatory network that could underlie such switches. Recent advancements allowed the study of networks at the global, many-gene, level; however, the relationship between the local and global scales in giving rise to phenotypic switches remains elusive. In this work, we studied the epithelial-mesenchymal transition (EMT) using a gene regulatory network model. This model supports two clusters of stable steady-states identified with the epithelial and mesenchymal phenotypes, and a range of intermediate less stable hybrid states, whose importance in cancer has been recently highlighted. Using an array of network perturbations and quantifying the resulting landscape, we investigated how features of the network at different levels give rise to these landscape properties. We found that local connectivity patterns affect the landscape in a mostly incremental manner; in particular, a specific previously identified double-negative feedback motif is not required when embedded in the full network, because the landscape is maintained at a global level. Nevertheless, despite the distributed nature of the switch, it is possible to find combinations of a few local changes that disrupt it. At the level of network architecture, we identified a crucial role for peripheral genes that act as incoming signals to the network in creating clusters of states. Such incoming signals are a signature of modularity and are expected to appear also in other biological networks. Hybrid states between epithelial and mesenchymal arise in the model due to barriers in the interaction between genes, causing hysteresis at all connections. Our results suggest emergent switches can neither be pinpointed to local motifs, nor do they arise as typical properties of random network ensembles. Rather, they arise through an interplay between the nature of local interactions, and the core-periphery structure induced by the modularity of the cell.


Assuntos
Variação Biológica da População/genética , Transição Epitelial-Mesenquimal/genética , Redes Reguladoras de Genes/genética , Retroalimentação Fisiológica/fisiologia , Humanos , Modelos Biológicos , Modelos Genéticos , Modelos Estatísticos , Fenótipo
4.
Eur. j. anat ; 24(5): 415-428, sept. 2020. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-195279

RESUMO

In order to explain the evolutionary process of ancient human populations that inhabited a specific geographical region from quantitative skull traits, it is advisable to know the evolutionary potential of metric characters. For this reason, the proportion of the maximum genetic variance or maximum heritability (h2m) of the variables studied was estimated. In addition, it was evaluated whether h2m changes between regions of the skull (face, base and vault) and the degree of association between the phenotypic variance and the maximum genetic variance. Twenty-one symmetrical variables on the left and right sides of the skull were measured in 245 skulls from five prehistoric samples from northwestern Argentina. The upper limit of heritability was estimated using the repeated measurement method. To test whether there are differences between the h2m of each group, the Kruskal-Wallis test was used. The maximum genetic values of each variable were obtained through a regression analysis (right measure on left measure). The relationship between phenotypic and maxi-mum genetic values was evaluated by correlation analysis. Significant bilateral difference is demon-strated in six of 21 characters. The average h2m is 0.77 and ranges between 0.58 and 0.93. The aver-age correlation between phenotypic values and maximum genotypic values was 0.8 (R2=0.65), suggesting that it is possible to make inferences of the genetic structure of the population from phenotypic information. The high proportion of maximum observed genetic variance indicates an important evolutionary potential of the craniofacial complex in ancient populations of northwestern Argentina


No disponible


Assuntos
Humanos , Masculino , Feminino , História Medieval , História do Século XV , Crânio/anatomia & histologia , Cefalometria , Variação Anatômica , Variação Genética , Fenótipo , Argentina , Antropologia/métodos , Variação Biológica da População/genética
5.
Arq. Ciênc. Vet. Zool. UNIPAR (Online) ; 23(1, cont.): e2311, 20200000. tab
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1129314

RESUMO

This study aimed at estimating genetic parameters for milk production and conformation characteristics in Girolando crossbred dairy cows reared in the High and Low Acre region using the restricted maximum likelihood methodology, under an animal model. We estimated the variance components and genetic parameters using the REML/BLUP procedure (Restricted Maximum Likelihood Methodology/Best Linear Unbiased Prediction). The estimated average for milk production for 305 days of lactation (P305) was of 1523.25 ± 481.11 kg, with a heritability of 0.38 for this characteristic. The conformation characteristics showed no significant correlation with milk production. The phenotypical correlations between the linear characteristics of type were, in general, positive and moderate. The P305 obtained in this study can be considered low and indicates that there is a possibility of increasing milk production through selection in herds along with the use of tested and proven bulls. The heritability estimate found (0.38) indicates that there is genetic variability for milk production, demonstrating that selection for this characteristic would result in genetic progress.(AU)


Este estudo teve como objetivo estimar parâmetros genéticos para produção de leite e características de conformação em vacas leiteiras mestiças Girolando criadas na região do Alto e Baixo Acre, utilizando a metodologia da máxima verossimilhança restrita, sob modelo animal. As estimativas dos componentes de variância e dos parâmetros genéticos foram realizadas pelo procedimento REML/BLUP (Máxima verossimilhança restrita/Melhor predição linear não viesada). A média estimada para produção de leite aos 305 dias de lactação (P305) foi de 1.523,25 ± 481 kg e a herdabilidade para esta característica foi de 0,38. As características de conformação não apresentaram correlação significativa com a produção de leite. As correlações fenotípicas entre as características lineares de tipo foram em geral positivas e de magnitude moderada. A P305 obtida neste estudo pode ser considerada baixa e indica que existe a possibilidade de aumento da produção de leite através de seleção nos rebanhos, juntamente com a utilização de touros testados e provados. A estimativa de herdabilidade encontrada (0,38) indica que há variabilidade genética para produção de leite, demonstrando que a seleção para esta característica resultaria em progresso genético.(AU)


El objetivo del estudio fue estimar los parámetros genéticos para la producción de leche y las características de conformación en vacas lecheras cruzadas Girolando criadas en la región de Alto y Bajo Acre utilizando el método de máxima verosimilitud restringida, con un modelo animal. Estimamos los componentes de la varianza y los parámetros genéticos mediante el procedimiento REML / BLUP (metodología de máxima verosimilitud restringida / mejor predicción lineal insesgada). El promedio estimado para la producción de leche para los 305 días de lactancia (P305) fue de 1523.25 ± 481.11 kg, con una heredabilidad de 0.38 para esta característica. Las características de conformación no mostraron correlación significativa con la producción de leche. Las correlaciones fenotípicas entre las características lineales de tipo fueron, en general, positivas y moderadas. El P305 obtenido en este estudio puede considerarse bajo y muestra que existe la posibilidad de incrementar la producción de leche a través de la selección en rebaños, junto con el uso de toros probados y comprobados. La estimación de heredabilidad encontrada (0,38) indica que existe variabilidad genética para la producción de leche, lo que demuestra que la selección de esta característica daría lugar a un progreso genético.(AU)


Assuntos
Animais , Feminino , Bovinos , Lactação , Bovinos/genética , Parâmetros , Variação Biológica da População/genética , Leite
7.
PLoS One ; 15(2): e0221737, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017762

RESUMO

Bioethanol production from lignocellulosic biomass has received increasing attention over the past decade. Many attempts have been made to reduce the cost of bioethanol production by combining the separate steps of the process into a single-step process known as consolidated bioprocessing. This requires identification of organisms that can efficiently decompose lignocellulose to simple sugars and ferment the pentose and hexose sugars liberated to ethanol. There have been many attempts in engineering laboratory strains by adding new genes or modifying genes to expand the capacity of an industrial microorganism. There has been less attention in improving bioethanol-related processes utilizing natural variation existing in the natural ecotypes. In this study, we sought to identify genomic loci contributing to variation in saccharification of cellulose and fermentation of glucose in the fermenting cellulolytic fungus Neurospora crassa through quantitative trait loci (QTL) analysis. We identified one major QTL contributing to fermentation of glucose and multiple putative QTL's underlying saccharification. Understanding the natural variation of the major QTL gene would provide new insights in developing industrial microbes for bioethanol production.


Assuntos
Variação Biológica da População/genética , Etanol/metabolismo , Neurospora crassa/genética , Locos de Características Quantitativas , Fermentação , Microbiologia Industrial , Açúcares/metabolismo
8.
Int J Cancer ; 146(2): 363-372, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.


Assuntos
Neoplasias do Colo/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Adulto , Idoso , Variação Biológica da População/genética , Carcinogênese/genética , Estudos de Casos e Controles , Colo/patologia , Neoplasias do Colo/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/patologia , Reto/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Proteínas Supressoras de Tumor/genética , Adulto Jovem
9.
Pharmacol Res Perspect ; 7(6): e00538, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768259

RESUMO

Aldehyde Oxidase (hAOX1) is a cytosolic enzyme involved in the metabolism of drugs and xenobiotic compounds. The enzyme belongs to the xanthine oxidase (XO) family of Mo containing enzyme and is a homo-dimer of two 150 kDa monomers. Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) of hAOX1 have been reported as affecting the ability of the enzyme to metabolize different substrates. Some of these nsSNPs have been biochemically and structurally characterized but the lack of a systematic and comprehensive study regarding all described and validated nsSNPs is urgent, due to the increasing importance of the enzyme in drug development, personalized medicine and therapy, as well as in pharmacogenetic studies. The objective of the present work was to collect all described nsSNPs of hAOX1 and utilize a series of bioinformatics tools to predict their effect on protein structure stability with putative implications on phenotypic functional consequences. Of 526 nsSNPs reported in NCBI-dbSNP, 119 are identified as deleterious whereas 92 are identified as nondeleterious variants. The stability analysis was performed for 119 deleterious variants and the results suggest that 104 nsSNPs may be responsible for destabilizing the protein structure, whereas five variants may increase the protein stability. Four nsSNPs do not have any impact on protein structure (neutral nsSNPs) of hAOX1. The prediction results of the remaining six nsSNPs are nonconclusive. The in silico results were compared with available experimental data. This methodology can also be used to identify and prioritize the stabilizing and destabilizing variants in other enzymes involved in drug metabolism.


Assuntos
Aldeído Oxidase/genética , Variação Biológica da População/genética , Aldeído Oxidase/metabolismo , Biologia Computacional , Simulação por Computador , Desenvolvimento de Medicamentos , Polimorfismo de Nucleotídeo Único , Estabilidade Proteica
10.
World J Gastroenterol ; 25(38): 5850-5861, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636477

RESUMO

BACKGROUND: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? AIM: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. METHODS: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. RESULTS: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. CONCLUSION: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.


Assuntos
Doença de Crohn/tratamento farmacológico , Nucleotídeos de Guanina/sangue , Imunossupressores/efeitos adversos , Leucopenia/diagnóstico , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Tionucleotídeos/sangue , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Variação Biológica da População/genética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Valores de Referência , Estudos Retrospectivos , Adulto Jovem
12.
PLoS One ; 14(9): e0222646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527890

RESUMO

Genetic variation and population structure may reflect important information for invasion success of exotic plant species and thus help improve management of invasive plants. Spartina alterniflora is an invasive plant that is a major threat to the economy and environment of the coastal regions in China. We analyzed the genetic structure and diversity of six populations of S. alterniflora differing in invasion histories in Guangxi, China. A total of 176 individuals from the six populations produced 348 AFLP fragments. The average heterozygosity was significantly lower than in the native population. And genetic bottlenecks were also detected in most populations. Standardized FST statistics (Φpt = 0.015) and AMOVA results indicated weak genetic differentiation. Genetic admixture and obviously isolation by distance indicated populations in Guangxi come from a pre-admixed population by a single introduction. High phenotypic variations of S. alterniflora in Guangxi influenced by soil salinity and temperature might be an important reason for the successful invasion.


Assuntos
Variação Biológica da População/genética , Poaceae/genética , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados/métodos , China , Espécies Introduzidas , Fenótipo , Salinidade , Solo/química , Temperatura
13.
PLoS Genet ; 15(9): e1008395, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527910

RESUMO

Many microbes exhibit quorum sensing (QS) to cooperate, share and perform a social task in unison. Recent studies have shown the emergence of reversible phenotypic heterogeneity in the QS-responding pathogenic microbial population under laboratory conditions as a possible bet-hedging survival strategy. However, very little is known about the dynamics of QS-response and the nature of phenotypic heterogeneity in an actual host-pathogen interaction environment. Here, we investigated the dynamics of QS-response of a Gram-negative phytopathogen Xanthomonas pv. campestris (Xcc) inside its natural host cabbage, that communicate through a fatty acid signal molecule called DSF (diffusible signal factor) for coordination of several social traits including virulence functions. In this study, we engineered a novel DSF responsive whole-cell QS dual-bioreporter to measure the DSF mediated QS-response in Xcc at the single cell level inside its natural host plant in vivo. Employing the dual-bioreporter strain of Xcc, we show that QS non-responsive cells coexist with responsive cells in microcolonies at the early stage of the disease; whereas in the late stages, the QS-response is more homogeneous as the QS non-responders exhibit reduced fitness and are out competed by the wild-type. Furthermore, using the wild-type Xcc and its QS mutants in single and mixed infection studies, we show that QS mutants get benefit to some extend at the early stage of disease and contribute to localized colonization. However, the QS-responding cells contribute to spread along xylem vessel. These results contrast with the earlier studies describing that expected cross-induction and cooperative sharing at high cell density in vivo may lead to synchronize QS-response. Our findings suggest that the transition from heterogeneity to homogeneity in QS-response within a bacterial population contributes to its overall virulence efficiency to cause disease in the host plant under natural environment.


Assuntos
Interações Hospedeiro-Patógeno/genética , Percepção de Quorum/genética , Xanthomonas/genética , Proteínas de Bactérias/genética , Variação Biológica da População/genética , Brassica/genética , Brassica/microbiologia , Doenças das Plantas/microbiologia , Transdução de Sinais , Virulência , Xanthomonas/metabolismo , Xanthomonas/patogenicidade
14.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544777

RESUMO

Rice blast is one of the most serious diseases in the world. The use of resistant cultivars is the most preferred means to control this disease. Resistance often breaks down due to emergence of new races; hence identification of novel resistance donors is indispensable. In this study, a panel of 80 released varieties from National Rice Research Institute, Cuttack was genotyped with 36 molecular markers that were linked to 36 different blast resistance genes, to investigate the varietal genetic diversity and molecular marker-trait association with blast resistance. The polymorphism information content of 36 loci varied from 0.11 to 0.37 with an average of 0.34. The cluster analysis and population structure categorized the 80 National Rice Research Institute released varieties (NRVs) into three major genetic groups. The principal co-ordinate analysis displays the distribution of resistant and moderately resistant NRVs into different groups. Analysis of molecular variance result demonstrated maximum (97%) diversity within populations and minimum (3%) diversity between populations. Among tested markers, two markers (RM7364 and pi21_79-3) corresponding to the blast resistance genes (Pi56(t) and pi21) were significantly associated and explained a phenotypic variance of 4.9 to 5.1% with the blast resistance. These associated genes could be introgressed through marker-assisted to develop durable blast resistant rice varieties. The selected resistant NRVs could be good donors for the blast resistance in rice crop improvement research.


Assuntos
Variação Biológica da População/genética , Resistência à Doença/genética , Oryza/genética , Análise por Conglomerados , Estudos de Associação Genética , Marcadores Genéticos , Magnaporthe/crescimento & desenvolvimento , Fenótipo , Melhoramento Vegetal , Polimorfismo Genético
15.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544799

RESUMO

Advanced marker technologies are widely used for evaluation of genetic diversity in cultivated crops, wild ancestors, landraces or any special plant genotypes. Developing agricultural cultivars requires the following steps: (i) determining desired characteristics to be improved, (ii) screening genetic resources to help find a superior cultivar, (iii) intercrossing selected individuals, (iv) generating genetically hybrid populations and screening them for agro-morphological or molecular traits, (v) evaluating the superior cultivar candidates, (vi) testing field performance at different locations, and (vii) certifying. In the cultivar development process valuable genes can be identified by creating special biparental or multiparental populations and analysing their association using suitable markers in given populations. These special populations and advanced marker technologies give us a deeper knowledge about the inherited agronomic characteristics. Unaffected by the changing environmental conditions, these provide a higher understanding of genome dynamics in plants. The last decade witnessed new applications for advanced molecular techniques in the area of breeding,with low costs per sample. These, especially, include next-generation sequencing technologies like reduced representation genome sequencing (genotyping by sequencing, restriction site-associated DNA). These enabled researchers to develop new markers, such as simple sequence repeat and single- nucleotide polymorphism, for expanding the qualitative and quantitative information onpopulation dynamics. Thus, the knowledge acquired from novel technologies is a valuable asset for the breeding process and to better understand the population dynamics, their properties, and analysis methods.


Assuntos
Produtos Agrícolas/genética , Melhoramento Vegetal/métodos , Variação Biológica da População/genética , Mapeamento Cromossômico/métodos , Produtos Agrícolas/história , Cruzamentos Genéticos , Genômica/métodos , Genótipo , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , História do Século XVIII , História Antiga , Repetições de Microssatélites/genética , Fenótipo , Melhoramento Vegetal/economia , Melhoramento Vegetal/história , Polimorfismo de Nucleotídeo Único
16.
PLoS Genet ; 15(8): e1008073, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31465442

RESUMO

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.


Assuntos
Ácidos e Sais Biliares/metabolismo , Variação Biológica da População/genética , Microbioma Gastrointestinal/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Locos de Características Quantitativas/genética , Simportadores/genética , Animais , Ácidos e Sais Biliares/sangue , Camundongos de Cruzamento Colaborativo , Feminino , Firmicutes/crescimento & desenvolvimento , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Modelos Animais , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Verrucomicrobia/crescimento & desenvolvimento
17.
PLoS Genet ; 15(8): e1008340, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425500

RESUMO

Allele age has long been a focus of population genetic research, primarily because it can be an important clue to the fitness effects of an allele. By virtue of their effects on fitness, alleles under directional selection are expected to be younger than neutral alleles of the same frequency. We developed a new coalescent-based estimator of a close proxy for allele age, the time when a copy of an allele first shares common ancestry with other chromosomes in a sample not carrying that allele. The estimator performs well, including for the very rarest of alleles that occur just once in a sample, with a bias that is typically negative. The estimator is mostly insensitive to population demography and to factors that can arise in population genomic pipelines, including the statistical phasing of chromosomes. Applications to 1000 Genomes Data and UK10K genome data confirm predictions that singleton alleles that alter proteins are significantly younger than those that do not, with a greater difference in the larger UK10K dataset, as expected. The 1000 Genomes populations varied markedly in their distributions for singleton allele ages, suggesting that these distributions can be used to inform models of demographic history, including recent events that are only revealed by their impacts on the ages of very rare alleles.


Assuntos
Evolução Molecular , Genética Populacional/métodos , Genoma Humano , Modelos Genéticos , Seleção Genética , Alelos , Variação Biológica da População/genética , Conjuntos de Dados como Assunto , Feminino , Frequência do Gene , Heterogeneidade Genética , Humanos , Masculino , Fatores de Tempo
18.
World J Gastroenterol ; 25(21): 2539-2548, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210708

RESUMO

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Gastroenterologia/métodos , Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Medicina de Precisão/métodos , Variação Biológica da População/genética , Medula Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Gastroenterologia/normas , Testes Genéticos , Antígenos HLA/genética , Antígenos HLA/imunologia , Hematopoese/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Metiltransferases/genética , Metiltransferases/metabolismo , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Medicina de Precisão/normas , Prognóstico , Pirofosfatases/genética , Pirofosfatases/metabolismo , Medição de Risco/métodos , Resultado do Tratamento
19.
Am J Bot ; 106(5): 704-712, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31081927

RESUMO

PREMISE: Monardella villosa is an evolutionarily young species complex distributed across a large geographic range. Our goal was to determine whether the phenotypic difference between two subspecies of M. villosa was heritable and whether the alternative phenotypes were adaptive to their respective local habitats. METHODS: We collected seeds from 25 populations of M. villosa, 14 from subspecies franciscana, which grows closer to the coast, and 11 from subspecies villosa, which has a larger and more inland geographic distribution. We reciprocally transplanted the two subspecies into their respective habitats and compared plant germination, post-emergence survival, and growth. We used linear mixed models to quantify the effects of genotype and environment to determine whether subspecies were locally adapted and whether leaf traits that distinguish these subspecies were genetically based. RESULTS: Plants of both subspecies grown at the coastal site had significantly lower survival and biomass than the inland site. The subspecies were not locally adapted; however, the coastal subspecies franciscana did have a home site advantage. We also found that distinctive leaf morphological traits were genetically based, with high broad-sense heritability of traits. CONCLUSIONS: The two subspecies of Monardella villosa were not locally adapted to their respective habitat, but rather we found that selection for local genotypes may be stronger at the coastal site. Despite the lack of evidence for local adaptation in the strict sense, the subspecies had heritable variation in several leaf phenotypes, indicating that heterogeneous selection imposes an adaptive trade-off for leaf trichome production within this species.


Assuntos
Variação Biológica da População/genética , Hereditariedade , Lamiaceae/genética , Seleção Genética , California
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