Lawson Heather A, Cheverud James M
The Department of Anatomy and Neurobiology, Washington University School of Medicine in St Louis, MO, USA.
Endocr Metab Immune Disord Drug Targets. 2010 Mar;10(1):25-40. doi: 10.2174/187153010790827948.
Animal models have enriched understanding of the physiological basis of metabolic disorders and advanced identification of genetic risk factors underlying the metabolic syndrome (MetS). Murine models are especially appropriate for this type of research, and are an excellent resource not only for identifying candidate genomic regions, but also for illuminating the possible molecular mechanisms or pathways affected in individual components of MetS. In this review, we briefly discuss findings from mouse models of metabolic disorders, particularly in light of issues raised by the recent flood of human genome-wide association studies (GWAS) results. We describe how mouse models are revealing that genotype interacts with environment in important ways, indicating that the underlying genetics of MetS is highly context dependant. Further we show that epistasis, imprinting and maternal effects each contribute to the genetic architecture underlying variation in metabolic traits, and mouse models provide an opportunity to dissect these aspects of the genetic architecture that are difficult if not impossible to ascertain in humans. Finally we discuss how knowledge gained from mouse models can be used in conjunction with comparative genomic methods and bioinformatic resources to inform human MetS research.
动物模型丰富了我们对代谢紊乱生理基础的理解,并推动了对代谢综合征(MetS)潜在遗传风险因素的识别。小鼠模型尤其适合此类研究,不仅是识别候选基因组区域的优秀资源,也是阐明MetS各个组成部分中可能受影响的分子机制或途径的良好工具。在这篇综述中,我们简要讨论代谢紊乱小鼠模型的研究结果,特别是鉴于近期大量人类全基因组关联研究(GWAS)结果所引发的问题。我们描述了小鼠模型如何揭示基因型与环境以重要方式相互作用,表明MetS的潜在遗传学高度依赖背景。此外,我们表明上位性、印记和母体效应均对代谢性状变异的遗传结构有贡献,并且小鼠模型为剖析遗传结构中这些在人类中难以(如果不是不可能)确定的方面提供了机会。最后,我们讨论如何将从小鼠模型中获得的知识与比较基因组方法和生物信息资源结合起来,为人类MetS研究提供信息。