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[This corrects the article DOI: 10.1371/journal.pone.0002020.].
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PURPOSE: Increases in throughput and affordability of genotyping products have led to large sample sizes in genetic studies, increasing the likelihood that incidental genetic findings may occur. We set out to survey potential notifiable variants on arrays used in genome-wide association studies and in direct-to-consumer genetic services. METHODS: We used multiple bioinformatics strategies to identify, and map variants tested for genetic disorders in > or = 2 CLIA-approved laboratories (based on the GeneTests database). We subsequently surveyed 18 commercial single nucleotide polymorphism arrays and HapMap for these variants. RESULTS: Of 1,362 genes tested according to GeneTests, we identified 298 specific targeted mutations measured in more than or equal to two laboratories, encompassing 56 disorders. Only 88 of 298 mutations could be identified as known single nucleotide polymorphisms in genomic databases. We found 18 of 88 single nucleotide polymorphisms present in HapMap or on commercial single nucleotide polymorphism arrays. Homozygotes for rare alleles of some variants were identified in the Framingham Heart Study, an active genome-wide association studies cohort (n = 8,410). CONCLUSIONS: Variants in genes including APOE, F5, HFE, CYP21A2, MEFV, SPINK1, BTD, GALT, and G6PD were found on single nucleotide polymorphism arrays or in the HapMap. Some of these variants may warrant further review to determine their likelihood to trigger incidental findings in the course of genome-wide association studies or direct-to-consumer testing.
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Biomarcadores de Tumor/genética , Técnicas de Laboratorio Clínico/normas , Genoma Humano , Estudio de Asociación del Genoma Completo , Haplotipos/genética , Polimorfismo de Nucleótido Simple/genética , Biomarcadores de Tumor/metabolismo , Sistemas de Información en Laboratorio Clínico , Biología Computacional , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Sir2 regulates lifespan in model organisms, which has stimulated interest in understanding human Sir2 homolog functions. The human Sir2 gene family comprises seven members (SIRT1-SIRT7). SIRT1, the human ortholog of the yeast Sir2 by closest sequence similarity, is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase with enzymatic properties indistinguishable from the yeast enzyme. We studied the involvement of SIRT1 in normal human keratinocyte physiology by a transcriptional microarray analysis of primary keratinocytes either overexpressing or underexpressing SIRT1. Using a systems biology analytical approach, we predicted that SIRT1 induces keratinocyte differentiation through a pathway integral to or overlapping with that of calcium-induced differentiation. We experimentally assayed this prediction and found that the SIRT1 inhibitor nicotinamide inhibited expression of keratinocyte differentiation markers, whereas a SIRT1 activator, resveratrol, enhanced expression of keratinocyte differentiation markers. Similar results were obtained in keratinocytes manipulated to overexpress or underexpress SIRT1, and modulating SIRT1 significantly affected keratinocyte proliferation rates. We conclude that SIRT1 functions in normal human keratinocytes to inhibit proliferation and to promote differentiation.
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Queratinocitos/citología , Sirtuinas/genética , Calcio/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Queratinocitos/metabolismo , Modelos Biológicos , Modelos Genéticos , Niacinamida/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Plásmidos/metabolismo , Interferencia de ARN , Resveratrol , Sirtuina 1 , Estilbenos/farmacología , Transcripción GenéticaRESUMEN
Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.