Towards an encyclopaedia of mammalian gene function: the International Mouse Phenotyping Consortium

摘要

Nearly 10 years after the completion of the human genome project, and the report of a complete sequence of the mouse genome, it is salutary to reflect that we remain remarkably ignorant of the function of most genes in the mammalian genome. This is clearly illustrated from the outputs of genome-wide association studies (GWAS), in which the detection of loci that are associated with genetic diseases is often still just a starting point for more detailed studies that investigate the function of genes in the vicinity of the identified locus. Most importantly, we are far from uncovering the multiple, pleiotropic functions of genes. Determining pleiotropy will be key to deciphering the genetic networks and systems that govern developmental and physiological mechanisms. The mouse has played an important role in deciphering gene function through the analysis of mutations generated by a variety of routes (Justice et al., 2011). The mouse toolkit is exceptionally rich and sophisticated, with the ability to engineer mutations into the genome, more or less at will. However, to date, we have only analysed knockout mutations for around 30% of mouse genes (Eppig et al., 2012). Moreover, the analysis of these mutations has inevitably focused on the phenotypic domains and systems that reflect the interests and expertise of the investigator and, as a consequence, key functions and pleiotropic effects certainly have been missed. We are also remarkably poor at predicting the functions of genes and their pleiotropic effects, so it is imperative to assess gene function without making any prior assumptions.