The major goals of this project are:

• to identify and functionally characterize regulatory sequences preferentially conserved in the primate lineage through the comparative analysis of large genomic intervals containing known “lipid” genes;
• to identify and functionally characterize primate specific transcription factor binding sites in both known and computationally predicted regulatory elements shared between primates and non-primate mammals; and
• to investigate the function of primate-specific regulatory sequences on their neighboring human genes in cell culture and in vivo studies and determine their contribution to primate-specific phenotypes.

The Role of Sequence Variation in the Human Genome
There is increasing evidence that variations in non-coding sequences that regulate gene expression play an important role in human disease. However, the identification of non-coding, regulatory polymorphisms contributing to disease is limited by our inability to identify which variants reside within gene regulatory sequences. Multiple recent studies indicate that highly conserved non-coding regions identified by comparative sequence analysis often possess gene regulatory activity. Thus, sequence conservation alone can prioritize noncoding sequences for gene regulatory function.

While it is reasonable to expect that variations in highly conserved non-coding regions are more likely to be deleterious, very little research has been directed to validate this hypothesis in clinical populations. Accordingly, Dr. Boffelli is investigating the utility of comparative genomics for the prioritization of functional non-coding sequence variations in several disease models.

To accomplish this, Dr. Boffelli is classifying non-coding sequence variations based on a range of comparative genomic criteria to estimate their likelihood of deleteriousness and test the validity of this classification in collaborative clinical studies. From this basis, web-based tools will be built to enable the widespread adoption of these strategies. Finally, Dr. Boffelli is using genetically modified mouse models to experimentally test the function of important sequence variants in the human genome.