For a number of years, several laboratories and consortia have dedicated efforts to generating a significant amount of genomic regulatory information, in order to provide more meaningful interpretation of the non-coding portions of the human genome. The ENCODE Project methodically mapped regions of transcription, transcription factor association, chromatin structure and histone modification; resulting in the finding that ~80% of the genome potentially displayed functionality. This finding, however, continues to be debated; with many choosing to stick to previously estimated lower values of around 10%. While the actual functional proportion may lie somewhere in the middle of these estimates, what is known is that most human variation is found outside ~1.5% of the genome responsible for coding proteins. Thus, the remaining portion of functional DNA likely contains a considerable amount of genetic variation; which could contribute to phenotypic variation and susceptibility to disease. The focus of this study is the aforesaid non-coding “functional variation”. More specifically, we will examine variation within the portion of the genome responsible for the regulation of gene expression. Most regulation of gene expression occurs at the level of transcription initiation by regulatory elements and the transcription factors that interact with them.
The proposed study seeks to examine the patterns of variation within genomic and regulatory elements. These patterns may act as signposts to potential functionality, thus increasing confidence in annotation accuracy and providing additional targets in the search for functional variation.