RESUMEN
Metabolic syndrome is a cause of coronary artery disease and type 2 diabetes mellitus. Camk2n1 resides in genomic loci for blood pressure, left ventricle mass, and type 2 diabetes mellitus, and in the spontaneously hypertensive rat model of metabolic syndrome, Camk2n1 expression is cis-regulated in left ventricle and fat and positively correlates with adiposity. Therefore, we knocked out Camk2n1 in spontaneously hypertensive rat to investigate its role in metabolic syndrome. Compared with spontaneously hypertensive rat, Camk2n1-/- rats had reduced cardiorenal CaMKII (Ca2+/calmodulin-dependent kinase II) activity, lower blood pressure, enhanced nitric oxide bioavailability, and reduced left ventricle mass associated with altered hypertrophic networks. Camk2n1 deficiency reduced insulin resistance, visceral fat, and adipogenic capacity through the altered cell cycle and complement pathways, independent of CaMKII. In human visceral fat, CAMK2N1 expression correlated with adiposity and genomic variants that increase CAMK2N1 expression associated with increased risk of coronary artery disease and type 2 diabetes mellitus. Camk2n1 regulates multiple networks that control metabolic syndrome traits and merits further investigation as a therapeutic target in humans.
Asunto(s)
Proteínas Portadoras/genética , Hipertensión/genética , Hipertrofia Ventricular Izquierda/genética , Síndrome Metabólico/fisiopatología , Adiposidad/genética , Animales , Proteínas de Unión al Calcio , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Síndrome Metabólico/genética , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5' ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-δ-mediated displacement of Pol-α-synthesized DNA, resulting in incorporation of such Pol-α tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.
Asunto(s)
Replicación del ADN/genética , ADN/biosíntesis , ADN/genética , Genoma Humano/genética , Mutación/genética , Sitios de Unión , Cromatina/química , Cromatina/metabolismo , Secuencia Conservada/genética , ADN Polimerasa I/metabolismo , ADN Polimerasa III/metabolismo , Proteínas de Unión al ADN/metabolismo , Evolución Molecular , Humanos , Modelos Biológicos , Mutagénesis/genética , Unión Proteica , Saccharomyces cerevisiae/genética , Factores de Transcripción/metabolismoRESUMEN
We have used a polymorphism dataset on introns and coding sequences of X-linked loci in Drosophila americana to estimate the strength of selection on codon usage and/or biased gene conversion (BGC), taking into account a recent population expansion detected by a maximum-likelihood method. Drosophila americana was previously thought to have a stable demographic history, so that this evidence for a recent population expansion means that previous estimates of selection need revision. There was evidence for natural selection or BGC favouring GC over AT variants in introns, which is stronger for GC-rich than GC-poor introns. By comparing introns and coding sequences, we found evidence for selection on codon usage bias, which is much stronger than the forces acting on GC versus AT basepairs in introns.
