The cycle of genome-directed medicine

Medical practice and research have entered the genome era. The evolution from medical genetics to genome medicine (or genomic medicine) has been gradual and reflects a continuum [1,2], but there has been a marked transition in the few years since the completion of the first human reference genome sequences [3,4]. From a predominant focus on single genes and disease-related mutations has emerged the technology to assay the genome in its entirety - with genotyping arrays or sequencing - and the first means to interpret findings in a comprehensive manner. The application of genomic medicine involves diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed by knowledge of the entire diploid genome and the molecules it encodes. The foundations of genetics as the study of heredity become illuminated when individual genes are seen in the context of the whole genome and environmental influences.Our growing understanding of the human genome and the processes it directs strengthens the foundation for this new paradigm in biomedicine. The term 'directs' quite explicitly describes the role of the genome with respect to phenotype, and the distinction from 'determines' is critical. Particularly in the transition to a genomic focus in medicine, we recognize factors that are individually more modest in their impact than those highly penetrant alleles amenable to earlier genetic analyses. Beyond the influence of the context of the full genome, there is interaction with epigenetic and non-genetic elements from the environment and experience.The cyclical nature of genome investigation is driven by a constant flow of knowledge between medical practice and research (both 'bench to bedside' and 'bedside to bench' [5]). A conceptual analogy can be made with another natural cycle: the water cycle (Figure 1). In such a model, genome investigation guides informed research questions, which yield solutions that feed back to indi