Ciliopathies and oligogenic phenomena

Published on January 19, 2015   55 min

Other Talks in the Series: Molecular Genetics of Human Disease

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Hello, everybody. My name is Nicholas Katsanis. I am the director for the Center for Human Disease Modeling at Duke University and I am a professor in the Department of Cell Biology and Pediatrics. My interests focus on how does the genotype match the phenotype in humans and how can you use a mixture of technologies, such as sequencing and implementation of model organisms, to understand causality in human genetic disease and complex genetic interactions? Today, I will be giving a lecture that is focused on ciliopathies and the lessons that we've learned in oligogenic phenomena during our journey.
Before I begin, I really thought I should highlight some questions that have really persisted during the last hundred years, truly since the discovery of Mendel's laws. If we think fundamentally about the types of questions that we're all trying to investigate, while in the old days, we used to use things like karyotyping, in the modern days, we try to address these problems with next generation sequencing and tools of that sort. Nonetheless, the questions have remained fundamentally the same. The first question is what variants cause disease? And of course, we're dealing with humans, but the question naturally applies to all model organisms as well. It is fair to say that we have made significant, rather impressive progress in that regard. We have identified thousands of alleles in thousands of genes that are associated causally with both common and rare genetic disorders. However, there's a second question here, and this question is, what variants might be associated with disease modulation? That question is both harder and has proven to be more difficult to track experimentally for a number of reasons, some of which I will highlight later in my talk. And of course, the subtext of all this is, is there a difference between alleles that appear to be genetically sufficient to cause a disease and alleles that appear to confer susceptibility, or interaction, or epistasis, or some of these perhaps used to be exotic phenomena in human genetics? So the fundamental question underneath all of this is, we have always tried to understand the effect of a single allele on a single gene in a vacuum. However, it is important that we remember that the presence of rare alleles highly directly resembles, and the context, of course, is going to be important, but everything occurs in the context and in the backdrop of the entire genome, the epigenome, and of course the environment. Indeed, one of the greatest difficulties that we have at the moment is we cannot really discern context-dependent effect of alleles on the phenotype.