The similarities between the mouse and human genomes are striking: 2.5 Gb,cf. 2.9 Gb; around 30 000 protein-coding genes; about 80% of mouse genes have a single identifiable human orthologue, and fewer than 1% of mouse genes appear to be truly unique. Indeed, despite over 100 million years of evolutionary divergence, there remain huge regions of synteny (long stretches of homologous genes in a similar order) between various mouse and human chromosomes. Of 1022 human diseases that had been mapped to genes, 807 had clearly identifiable mouse homologues. Taken together, these facts hammer out the predictable assertion that the mouse is the obvious model organism for biomedical research. Obviously, this will also direct the focus of funding agencies worldwide increasingly toward mouse. At first sight, this may not seem like good news for `curiosity-directed' comparative physiology.
However, the following paper in Nature by the Mouse Genome Sequencing Consortium cruelly exposes the phenotype gap. The mouse transcriptome (all the mRNAs encoded by the genome) was mapped by a huge project, in which random cDNAs were sequenced at high volume, then clustered into groups corresponding to single genes. This is estimated to have `hit' at least 90% of mouse genes and, in so doing, identified 33 409 genes. However,while most of these can be assigned broad functions based on similarity to known protein classes (`G protein', `ABC transporter', etc.), relatively few of them have been named or investigated in any depth.
Functional genomics is defined as the elucidation of gene function in a genomic context or, in other words, finding out what all these genes do. In mouse, there is plenty of work to be done: only about a third of genes have been studied. But who is to work out the function of all the novel genes?Mouse has previously not been considered a major physiological model. This is the key: the mismatch between genetic and physiological understanding of an organism is called the `phenotype gap'. Put simply, the genome projects are crying out for physiologists who are both competent and interested in the genetic model organisms, like mouse, fly and worm. The `package' of experimental resources on offer is tempting: the availability of a sequenced genome, removing the need to hunt for new genes by homology; the free availability of cDNA clones corresponding to any of the genes described above,by post; the availability of comprehensive, ready-made microarrays covering the whole transcriptome; and the ability to address the simple physiologist's question `what does this gene do?' by creating a knockout and seeing what happens (`reverse genetics').
Does this genome-linked future mean the end for curiosity-led research? Not at all: there is no better time to pose the higher-level `integrative' biology questions about responses to environmental stress, homeostasis, circadian clocks or neural function.
Does the availability of the mouse genome compel scientists to work on mouse? Not at all – the very low number of mouse `unique' genes shows that, with human and mouse genomes available, it is possible to triangulate rather accurately on any gene in any closely related species (certainly among the mammals). It is thus possible to get appreciable leverage from a phylogenetically close genome project, without necessarily working in that organism.
