Soon the genetic basis of most human Mendelian diseases will be solved. The next challenge will be to leverage this information to uncover basic mechanisms of disease and develop new therapies. To understand how this transformation is already beginning to unfold, we focus on the ciliopathies, a class of multi-organ diseases caused by disruption of the primary cilium. Through a convergence of data involving mutant gene discovery, proteomics and cell biology, over a dozen phenotypically distinguishable conditions are now united as ciliopathies. Sitting at the interface between simple and complex genetic conditions, these diseases provide clues to the future direction of human genetics.
Until a few years ago, identifying the genetic basis of an inherited human disease was an arduous undertaking, requiring potentially a decade or more of work in ascertainment of families for linkage analysis, followed by endless fine mapping of the locus, and finally sequencing of candidate genes one-by-one until that eureka moment when the likely causative gene was identified. The newly discovered disease gene was often entirely novel, without recognizable domains or a path to understand the disease mechanism. A mouse model was then generated, in which the disease gene was inactivated. In some cases, the mouse faithfully recapitulated the human phenotype, but more often showed no phenotype or phenotypes not clearly related to the human disease. Once established, the model was studied from multiple perspectives to understand the cell biological and biochemical basis of disease, culminating in attempts to test potential therapies. Although successful in a few instances such as losartan treatment for Marfan syndrome (Habashi et al., 2006), this path has not fulfilled the promises of genomic medicine.
This strategy has begun to change over the past ten years due to increased knowledge of human genetic diseases, annotation of the human genome, and an amazing suite of tools to explore disease mechanisms. It is not uncommon now to open up a journal to find that geneticists have solved the molecular basis of a dozen or more conditions. And since we now know a lot more about the function of genes, protein domains, and networks, frequently just the discovery of the molecular cause of a disease can often partially explain its mechanism. For instance, the discovery that the Rett syndrome gene encodes a methyl-CpG-binding protein (Amir et al., 1999) immediately set the stage for a host of important discoveries in epigenetics related to brain function. The types of mutations displayed by patients, known as allelic diversity (Fig. 1), can tell us something about the effect of these disease-causing variants on protein function. By identifying patients with different phenotypes due to specific types of mutations in the same gene (i.e. genocopies) we can understand human disease as a network of related signs and symptoms. For example, specific types of mutations in the gene encoding p53 predispose to very different types of cancers. By comparing the genes mutated in phenotypically related human diseases, we can learn about the disturbed protein networks that underlie them. Finally, by exploring gene-gene and gene-environment interactions, we can begin to characterize genetic and epigenetic modifiers of disease. Perhaps the best example is age-related macular degeneration, in which a substantial part of the risk of disease can be quantified based on gene-environment interactions (Chen et al., 2010).