I am interested in understanding the role of DNA sequence variation in human disease. My laboratory approaches this problem with a variety of experimental strategies that include mapping and sequencing the human genome, using this information to identify human DNA variation, using genomic and genetic information to isolate human disease genes, and analyzing the functions of genes that have been shown to be involved in inherited diseases that affect the nervous system. In our genome research, we are generating high-resolution maps of the human genome and participating in world-wide efforts to determine large amounts of human DNA sequence. These sequencing efforts are devoted to establishing the infrastructure and technology to allow the efficient and cost-effective sequencing of tens of megabases of the human genome per year. We are using the mapping and sequencing information to identify DNA sequence differences between individuals for analyzing genetic variation in populations.
We are using the genomic maps, sequences and variant DNA segments to identify genes that play a role in particular diseases in humans. In one study, we are using sib-pair analysis and linkage disequilibrium methods to search for genes involved in autism. We used similar approaches to identify the gene responsible for Progressive Myoclonus Epilepsy (EPM1), the weaver gene, which plays a role in cerebellar development in the mouse, and, with Dr. Matthew Scott and colleagues, a gene involved in the most common form of skin cancer. Finally, my laboratory studies the functions of the genes responsible for Huntington disease and EPM1. We are using biochemical and cell biological methods to study the proteins encoded by these genes, and mouse genetic approaches to generate models for both diseases. We recently found that mice expressing mutant versions of the Huntington disease protein develop aberrant movements and behaviors suggestive of the symptoms in humans.