RESUMEN
BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.
Asunto(s)
Neoplasias Óseas/veterinaria , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Enfermedades de los Perros/genética , Estudio de Asociación del Genoma Completo , Osteosarcoma/veterinaria , Animales , Neoplasias Óseas/genética , Variaciones en el Número de Copia de ADN , Perros , Evolución Molecular , Predisposición Genética a la Enfermedad , Variación Genética , Genoma , Humanos , MicroARNs/genética , Osteosarcoma/genéticaRESUMEN
The successfully functioning brain is a heavy user of metabolic energy. Alzheimer's disease, in which cognitive faculties decline, may be due, at least in part, to metabolic insufficiency. Using microarray analysis and quantitative RT-PCR, the expression of mRNA transcripts involved in glucose metabolism was investigated in Alzheimer's diseased post-mortem human hippocampal samples. Of the 51 members of the glycolytic, tricarboxylic acid cycle, oxidative phosphorylation, and associated pathways investigated by qPCR, 15 were confirmed to be statistically significantly (p<0.05) down-regulated in Alzheimer's disease. This finding suggests that reductions in the levels of transcripts encoded by genes that participate in energy metabolism may be involved in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Encéfalo/enzimología , Enzimas/genética , Regulación Enzimológica de la Expresión Génica/genética , Redes y Vías Metabólicas/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Ciclo del Ácido Cítrico/genética , Regulación hacia Abajo/genética , Metabolismo Energético/genética , Femenino , Perfilación de la Expresión Génica , Glucólisis/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación Oxidativa , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In 2003, the US National Human Genome Research Institute (NHGRI) agreed to fund a project to sequence the entire genome of a boxer dog named Tasha. Although the USA is a country of dog lovers, with approximately 38 million households owning one or more dogs, why did one of the National Institutes of Health countenance the use of 30 m dollars for such a purpose? The answer is that the NHGRI recognised the value of the dog as an unrivalled model for the study of human disease. In this paper, the reasons why the dog is such a good model are examined. Examples of where the study of disease in dogs is increasing the understanding of the genetic basis of human disease, of the development of improved diagnostic assays and of the evaluation of clinical therapies are provided.