Bioinformatics Group, MRC Mammalian Genetics Unit, Harwell, Oxfordshire, United Kingdom.
PLoS One. 2011;6(5):e19693. doi: 10.1371/journal.pone.0019693. Epub 2011 May 19.
The laboratory mouse is the pre-eminent model organism for the dissection of human disease pathways. With the advent of a comprehensive panel of gene knockouts, projects to characterise the phenotypes of all knockout lines are being initiated. The range of genotype-phenotype associations can be represented using the Mammalian Phenotype ontology. Using publicly available data annotated with this ontology we have constructed gene and phenotype networks representing these associations. These networks show a scale-free, hierarchical and modular character and community structure. They also exhibit enrichment for gene coexpression, protein-protein interactions and Gene Ontology annotation similarity. Close association between gene communities and some high-level ontology terms suggests that systematic phenotyping can provide a direct insight into underlying pathways. However some phenotypes are distributed more diffusely across gene networks, likely reflecting the pleiotropic roles of many genes. Phenotype communities show a many-to-many relationship to human disease communities, but stronger overlap at more granular levels of description. This may suggest that systematic phenotyping projects should aim for high granularity annotations to maximise their relevance to human disease.
实验小鼠是解析人类疾病途径的首要模式生物。随着全面的基因敲除面板的出现，对所有敲除系表型特征进行描述的项目正在启动。基因型-表型关联的范围可以使用哺乳动物表型本体来表示。我们使用带有此本体注释的公开可用数据构建了表示这些关联的基因和表型网络。这些网络显示出无标度、层次和模块化的特征以及社区结构。它们还表现出基因共表达、蛋白质-蛋白质相互作用和基因本体论注释相似性的富集。基因社区与一些高级本体论术语之间的密切关联表明，系统表型分析可以提供对潜在途径的直接洞察。然而，一些表型在基因网络中分布更为广泛，这可能反映了许多基因的多效性作用。表型社区与人类疾病社区之间存在多对多的关系，但在更细粒度的描述层次上具有更强的重叠。这可能表明，系统表型分析项目应该以高粒度注释为目标，以最大限度地提高其与人类疾病的相关性。
