Our group arose out of the Human Genome Project with an interest in understanding DNA function within our genome and how it goes awry in human disease. One focus has been on noncoding DNA, which represents 98% of the human genome and the identification of previously elusive distant-acting transcriptional “enhancers”. This was initially accomplished through our use of comparative genomics across vertebrates, building on the observations that the most highly conserved noncoding regions of our genome are highly enriched for enhancers and could be validated through in vivo experimentation. One particular class of such sequences are ultraconserved enhancers and we have spent almost 20 years exploring their functional properties and the evolutionary drivers of their extreme conservation. We also demonstrated the power of using epigenomics data (ChIP-, ATAC-, DNaseI-Seq) to build genome-wide maps of tissue-specific enhancers. Importantly, all of these foundational efforts have provided a human genome annotation of gene regulatory elements to complement our strong knowledge of the location of the 20,000 protein-encoding genes in our genome.
Our current interest is in functionally assessing human variation to determine its impact on human biology and disease. The sequencing of a human genome now costs less than $1000 and massive resequencing projects are generating hundreds of thousands and soon millions of human whole genomes annually. With millions upon millions of DNA sequence variants in the human population, a grand challenge in genetics is determining which ones are important biologically and/or contribute to human disease? Our current efforts focus on developing and applying scalable and sophisticated in vivo genome engineering methods to functionally assess such relationships.