Grant: Operating Grant

Studies of human genetic variation have in the past largely focused on rare genetic variants which alter protein structure, also known as coding variants. Contemporary genetic studies have indicated that genetic susceptibility to common diseases (such as asthma, diabetes or cardiovascular disease) can be due to common genetic variants (present in over 5% of population) that do not alter protein structure and these non-coding variants, sometimes also called regulatory variants, are presumed to influence how human genes are regulated in cells and tissues. Non-coding DNA accounts for over 95% of human genome sequence. A challenge to understand the non-coding genetic variation is that as compared to coding variation we do not understand the genetic code underlying human gene regulation. We have developed new approaches to directly measure impact of non-coding genetic variation in panels of human cells derived from healthy donors. As opposed to previous studies we can separately assess the maternal and paternal influence on gene expression or regulatory protein - DNA interaction based, this allele specificity provides noise-free assessment of regulatory function. Using these sensitive and comprehensive assays in multiple cell type we are able to uncover 5-10x more genetic variation directly involved in regulation of human genes than realized to date. This functional map of inter-individual regulatory variation forms the basis of understanding how genetic susceptibility to common disease can be coded in our DNA and consequently we can show that genetic susceptibility to common diseases can be mediated by these DNA variants altering gene regulation.Our approach offers the promise for global understanding genetic variation in the "dark matter" of human genome in health and disease.