University of California, Davis

One of the greatest challenges facing biomedical research since the sequencing of the human genome has been to understand the role of genetic variation in human disease.  Many genetic variants have been associated with common diseases.  However, determining the functional consequences of these variants has been difficult.  Several variants are often inherited together in tightly linked blocks, making it difficult to determine the causative variant.  Additionally, people have millions of other genetic differences, making it difficult to correlate cellular phenotypes with a particular variant.  Different gene sets are expressed in different cells, but it is difficult to extract disease-relevant cells from large numbers of patients.  Here the PIs propose a new method for the functional analysis of genetic variation, using custom nucleases to genetically modify individual variants in induced pluripotent stem cells.  They will focus on variants at the 9p2l region of the genome that have been associated with coronary artery disease.  The methods developed should provide a new way to unlock the wealth of data from genome wide association studies, and to probe the genetic architecture of common diseases.