From genotype to phenotype and back

Over the past 25 years, since the first reports of the stable and heritable alteration of the mouse genome (Gordon et al. 1980; Brinster et al. 1981; Costantini & Lacy, 1981; Wagner et al. 1981a,b), physiology has been increasingly influenced by genetic and genomic information that has emerged from forward genetic screens in lower organisms, designed genetic alterations in experimental animals, genome scale transcriptional profiling, and the progressive expansion of understanding of the structure and organization of genomes spanning the evolutionary landscape. At the same time, the progressive elucidation of mammalian gene function has required a continuing partnership between geneticists and physiologist in the design and interpretation of gene-based experiments, as the exploration of the subtleties and complexities of phenotype, the province of physiology, is essential for any but the most superficial understanding of genetic modifications. The progressive unravelling of the complex and multiplicative nature of genetic networks and the increasing sophistication of forward and reverse genetic biological approaches has only enhanced this vital partnership. In a collection of reviews in this issue of The Journal of Physiology, we have chosen several prominent examples of research at the intersection between genetics and physiology. Beginning with forward genetics, Roger Hardie describes a 15-years odyssey from the initial identification of transient receptor potential mutants in Drosophila melanogaster (Cosens & Manning, 1969), through the rigorous dissection of the electrophysiological basis of the defect, the molecular identity of the mutant channel and the discovery of the role of PIP2 in gating, and the plethora of physiological processes subserved by the seven distinct TRP subfamilies (Hardie, 2007). The widespread involvement of TRP channels in diverse sensory and motor processes, their deployment in a broad range of excitable and non-excitable tissues, and the complex and varied mechanisms underlying channel gating, assures that they will provide a rich terrain for physiological studies for many years to come. The review by Bjarte Furnes and John Schimenti describes an amibitious forward genetic screen in the mouse designed to uncover novel genes associated with infertility (Furnes & Schimenti, 2007), a process that has been particularly resistant to classical genetic approaches due to the loss of propagation of sterile mutants. Now 6 years on, this germline (N-ethyl-N-nitrosourea) and embryonic stem cell (ethylmethane sulphonate) mutagenesis screen has identified new genes involved in male and female reproductive failure. Screens of this kind often generate far more leads than can be dissected in depth and it is likely that the initially characterized and mapped mutations will provide a significant resource for in-depth analysis by reproductive physiologists. The third review in this series describes the enormous impact of spontaneous mutants at the dominant white spotting (W) mouse locus, on the understanding of gastrointestinal physiology. Numerous mutations were developed at this locus at the Jackson Laboratory, including ‘viable’ (WV) mutants described initially in the 1930s (Little & Cloudman, 1937), see (Geissler et al. 1981). The W locus was determined to be allelic with the protooncogene c-kit (Chabot et al. 1988; Geissler et al. 1988), but a major phenotype of W/WV mice was discovered only after careful physiological analysis revealed abnormal gastrointestinal motility (Maeda et al. 1992). Kenton Sanders and Sean Ward describe the subsequent physiological dissection of this phenotype, including the discovery of the role of Interstitial Cells of Cajal as pacemakers and the enormous impact that c-kit mutants have had on the understanding of rhythmogenesis (Sanders & Ward, 2007). The fourth review illustrates the mutual dependence of reverse genetics and physiology, as well as the difficulties likely to be encountered when reproducing human physiology in the mouse. Guy Salama and Barry London review efforts to produce mouse models of human long QT syndrome (Salama & London, 2007), which is caused by a variety of K+ channel pore forming and β subunit mutations (Keating & Sanguinetti, 2001; Marban, 2002). As the authors point out, the shorter action potentials and different K+ channels involved in repolarization in the mouse undermine efforts to reproduce human syndromes by mimicking mutations or polymorphisms in the channel homologues. However a thorough understanding of the role of specific channels in the mouse action potential leads to informative genetic alterations. The final review highlights an area of biology in which the confluence of genetics and molecular design are likely to substantially inform physiology (Kotlikoff, 2007). It summarizes the development of ‘sensor mice’ that are designed to improve the study of complex physiological processes by providing lineage defined, molecular scale information in vivo. Advances in the design of genetically encoded Ca2+ indicators (GECIs) are reviewed, with a specific focus on molecules that are likely to provide useful physiological information, and emerging genetic strategies to target them. While there is broad agreement that the next major task in biology is to assign function to the genes that have been decoded, the non-trivial determination of function requires an understanding of the full physiological consequences of genetic perturbations. This series of reviews provides a sampling of approaches that bridge the interface between genetics and physiology. We hope that the series provokes closer interactions between the ‘geno’ types and the ‘pheno’ types in the future.