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1.
Obesity (Silver Spring) ; 27(3): 479-488, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30741480

RESUMEN

OBJECTIVE: Whereas the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are nonexistent. This study assessed genetic contributions to spontaneous adiposity in this species. METHODS: Phenotypic variation by age class and sex for BMI, waist to height ratio, waist to thigh ratio, and waist circumference was assessed in 583 macaques. Total and sex-specific heritability for all traits was estimated, including waist to thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. In addition, functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 was assessed in four animals with extreme spontaneous adiposity. RESULTS: Trait heritability in the combined sample was low to moderate (0.14-0.32), whereas sex-specific heritability was more substantial (0.20-0.67). Heritability was greater in females for all traits except BMI. All traits were robustly correlated, with genetic correlations of 0.63 to 0.93 indicating substantial pleiotropy. Likely functional variants were discovered in the four macaques at all eight human obesity genes, including six missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1 and, notably, one nonsense mutation in LEPR. CONCLUSIONS: A moderate polygenic contribution to adiposity in rhesus macaques was found, as well as mutations with potentially larger effects in multiple genes that influence obesity in humans.


Asunto(s)
Obesidad/genética , Adolescente , Adulto , Anciano , Animales , Niño , Preescolar , Humanos , Macaca mulatta , Persona de Mediana Edad , Adulto Joven
2.
DNA Repair (Amst) ; 72: 1-9, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30389308

RESUMEN

Formaldehyde is a ubiquitous DNA damaging agent, with human exposures occurring from both exogenous and endogenous sources. Formaldehyde exposure can result in multiple types of DNA damage, including DNA-protein crosslinks and thus, is representative of other exposures that induce DNA-protein crosslinks such as cigarette smoke, automobile exhaust, wood smoke, metals, ionizing radiation, and certain chemotherapeutics. Our objective in this study was to identify the genes necessary to mitigate formaldehyde toxicity following chronic exposure in human cells. We used siRNAs that targeted 320 genes representing all major human DNA repair and damage response pathways, in order to assess cell proliferation following siRNA depletion and subsequent formaldehyde treatment. Three unrelated human cell lines frequently used in genotoxicity studies (SW480, U-2 OS and GM00639) were used to identify common pathways involved in mitigating formaldehyde sensitivity. Although there were gene-specific differences among the cell lines, four inter-related cellular pathways were determined to mitigate formaldehyde toxicity: homologous recombination, DNA double-strand break repair, ionizing radiation response and DNA replication. Additional insight into cell line-specific response patterns was obtained by using a combination of exome sequencing and Cancer Cell Line Encyclopedia genomic data. The results of this DNA damage repair pathway-focused siRNA screen for formaldehyde toxicity in human cells provide a foundation for detailed mechanistic analyses of pathway-specific involvement in the response to environmentally-induced DNA-protein crosslinks and, more broadly, genotoxicity studies using human and other mammalian cell lines.


Asunto(s)
Daño del ADN , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Formaldehído/toxicidad , Interferencia de ARN , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Genómica , Humanos
3.
Nat Commun ; 7: 11588, 2016 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-27174753

RESUMEN

Cancer development is presumed to be an evolutionary process that is influenced by genetic background and environment. In laboratory animals, genetics and environment are variables that can largely be held constant. In humans, it is possible to compare independent tumours that have developed in the same patient, effectively constraining genetic and environmental variation and leaving only stochastic processes. Patients affected with von Hippel-Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. Here we perform whole-genome sequencing on 40 tumours from six von Hippel-Lindau patients. We confirm that the tumours are clonally independent, having distinct somatic single-nucleotide variants. Although tumours from the same patient show many differences, within-patient patterns are discernible. Single-nucleotide substitution type rates are significantly different between patients and show biases in trinucleotide mutation context. We also observe biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.


Asunto(s)
Carcinoma de Células Renales/genética , Exposición a Riesgos Ambientales/efectos adversos , Neoplasias Renales/genética , Polimorfismo de Nucleótido Simple/genética , Enfermedad de von Hippel-Lindau/genética , Adulto , Carcinógenos Ambientales , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Cromosomas Humanos/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Femenino , Genoma Humano/genética , Humanos , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven , Enfermedad de von Hippel-Lindau/patología , Enfermedad de von Hippel-Lindau/cirugía
4.
PLoS One ; 8(8): e72241, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23951301

RESUMEN

The rhesus macaque is an important model for human atherosclerosis but genetic determinants of relevant phenotypes have not yet been investigated in this species. Because lipid levels are well-established and heritable risk factors for human atherosclerosis, our goal was to assess the heritability of lipoprotein cholesterol and triglyceride levels in a single, extended pedigree of 1,289 Indian-origin rhesus macaques. Additionally, because increasing evidence supports sex differences in the genetic architecture of lipid levels and lipid metabolism in humans and macaques, we also explored sex-specific heritability for all lipid measures investigated in this study. Using standard methods, we measured lipoprotein cholesterol and triglyceride levels from fasted plasma in a sample of 193 pedigreed rhesus macaques selected for membership in large, paternal half-sib cohorts, and maintained on a low-fat, low cholesterol chow diet. Employing a variance components approach, we found moderate heritability for total cholesterol (h²=0.257, P=0.032), LDL cholesterol (h²=0.252, P=0.030), and triglyceride levels (h²=0.197, P=0.034) in the full sample. However, stratification by sex (N=68 males, N=125 females) revealed substantial sex-specific heritability for total cholesterol (0.644, P=0.004, females only), HDL cholesterol (0.843, P=0.0008, females only), VLDL cholesterol (0.482, P=0.018, males only), and triglyceride levels (0.705, P=0.001, males only) that was obscured or absent when sexes were combined in the full sample. We conclude that genes contribute to spontaneous variation in circulating lipid levels in the Indian-origin rhesus macaque in a sex-specific manner, and that the rhesus macaque is likely to be a valuable model for sex-specific genetic effects on lipid risk factors for human atherosclerosis. These findings are a first-ever report of heritability for cholesterol levels in this species, and support the need for expanded analysis of these traits in this population.


Asunto(s)
Colesterol/sangre , Lipoproteínas/sangre , Macaca mulatta/sangre , Triglicéridos/sangre , Factores de Edad , Animales , Aterosclerosis/sangre , Aterosclerosis/genética , Colesterol/genética , Femenino , Variación Genética , Humanos , Lipoproteínas/genética , Macaca mulatta/genética , Masculino , Linaje , Fenotipo , Factores Sexuales , Triglicéridos/genética
5.
J Bioinform Comput Biol ; 10(6): 1250016, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22817111

RESUMEN

Genome sequences contain a number of patterns that have biomedical significance. Repetitive sequences of various kinds are a primary component of most of the genomic sequence patterns. We extended the suffix-array based Biological Language Modeling Toolkit to compute n-gram frequencies as well as n-gram language-model based perplexity in windows over the whole genome sequence to find biologically relevant patterns. We present the suite of tools and their application for analysis on whole human genome sequence.


Asunto(s)
Genoma , Genómica/métodos , Modelos Estadísticos , Algoritmos , Interpretación Estadística de Datos , Humanos , Alineación de Secuencia/métodos , Análisis de Secuencia de ADN/métodos
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