Physiological genomics: from bench to bedside

This issue contains two papers based on a symposium entitled Physiological Genomics: from Bench to Bedside, which took place at the Experimental Biology meeting in Washington, DC, USA on 29th April 2007. The field of physiological genomics emerged from the need to link function to the thousands of mapped genes. In the past decade, several approaches have been developed to rapidly integrate complex physiological processes and interactions with the genome to aid in the understanding of complex diseases. Highthroughput phenotyping and genotyping, bioinformatics approaches and publicly available data are allowing scientists to begin to link gene function with integrative physiology. The ‘Physiological Genomics: from Bench to Bedside’ symposium was designed to present several integrative approaches available to translate gene function from the laboratory to the clinic. The two papers that follow provide examples of how information can be gained from cellular and molecular studies rapidly but must be expanded to enable understanding of the impact on health and disease in a living system. The first paper, by Dr G. L. Semenza, describes the role of the transcriptional regulator hypoxia inducible factor 1 (HIF-1) in angiogenesis, arteriogenesis and vasculogenesis by mediating adaptive responses to reduced partial pressure of O2 (Semenza, 2007). The majority of studies investigating the many roles of HIF-1 in both gain and loss of function have used cultured cells or animal models. However, several knockout mouse models (HIF-1α and HIF-1β) are lethal owing to lack of cardiac development or defects in cardiovascular development, which prevents further experiments to study normal development as well as the disease pathogenesis. In addition to the role in cardiovascular development and disease, variation in the HIF1A locus may be involved in the formation of collateral vessels downstream from the site of coronary artery stenosis. Although recent studies have used adenovirus and adeno-associated virus vectors to improve tissue perfusion in animal models, these studies need to be extended to animal models that mimic the complex diseases prior to additional preclinical or clinical testing. The second paper, by Dr N. H. Lee (Lee, 2007), presents a review on current gene expression profiling strategies that have been used to dissect genetic and environmental factors impacting multigenic common diseases. DNA microarray technology allows for highthroughput gene expression profiling, but can result in a very long list of significantly differentially expressed genes. This paper focuses on genetic and computational strategies to speed the identification of causative genes. By combining the microarray approach with consomic and congenic rat models, with linkage analysis on selectively bred strains or with genetic correlations of expression quantitative trait loci (eQTLs) and physiological QTLs (pQTLs), the list of candidate genes involved in a pathophysiological process can be narrowed. Through collaboration between two Programs for Genomic Applications, PhysGen PGA at the Medical College of Wisconsin and TREX PGA at the Institute for Genomic Research, both physiological and microarray data were collected for many consomic rat strains, in which an entire chromosome from a donor inbred strain is introgressed into the genomic background of a recipient inbred strain. Dr Lee’s paper outlines several ‘vignettes’ that demonstrate the power of the combined phenotyping and microarray results in identifying the role of genes under normal, control conditions as well as following environmental stressors in both male and female rats. The final two presentations in the symposium focused on available resources designed to enable and support researchers interested in expanding their research to translate genomic information to the entire organism. Dr K. Svenson, from the JAX Program for Genomic Applications, presented an overview of the on-going phenotypic characterization of many inbred mouse models and mutant mouse models (Svenson et al. 2007). Finally, Dr A. E. Kwitek, from the PhysGen Program for Genomic Applications, described how the PhysGen resources, data and tools can be used to translate genomic information to a living system and can ultimately be used in the clinical setting. The approach presented by Dr Kwitek begins by identifying common diseases in conserved regions, uses available gene and functional annotation, and finds a good animal model that mimics the disease. Ghrelin and the growth hormone secretagogue receptor (GHSR) have been implicated in human obesity and cardiovascular disease through human association studies. Using comparative genomic tools and the available PhysGen rat models, in vivo studies can be done to replicate the human studies and follow up with longitudinal studies to carefully investigate the role of ghrelin in cardiovascular and metabolic diseases. In conclusion, this symposium presents novel approaches to linking physiology to the genome by providing several unique strategies to identify genes involved in complex diseases and offering tools to validate the role of these genes. Together, these strategies provide tools and resources to complement hypothesis-driven research aimed at understanding the mechanisms involved in complex physiological and pathophysiological functions. This symposium was sponsored by the Physiological Genomics group of the American Physiological Society.