New methods of genome analysis and the application of these methods to the study of the human and other genomes are the main focuses of our research, much of which is carried out at the University of Washington Genome Center. A major scientific focus of the Center's research program involves the study of natural variation in DNA sequences. In human DNA, most of the variation involves simple base-pair substitution polymorphisms: typical humans are heterozygous at approximately one base pair in a thousand throughout most of the genome. However, there are some regions in which sequence variation is as high as several percent of the nucleotides. We are developing new methods to detect these "variation hot spots" and to analyze the evolutionary forces that gave rise to them.

In parallel with the human studies, we are analyzing genetic variation in the opportunistic human pathogen Pseudomonas aeruginosa. The Genome Center recently determined the sequence of the 6.3-Mbp genome of this bacterium and is now analyzing variation in the genome across different clinical isolates of P. aeruginosa and across time during chronic infections of individual patients. In this research, our principal focus is on pulmonary infections of cystic fibrosis patients. The airways of most CF patients become infected with P. aeruginosa, and these infections now account for most of the morbidity and mortality in CF.