Using genomic similarities and differences to interpret mouse models of human development and cancer

Comparative genomic approaches have been used extensively to identify DNA sequences involved in the regulation of conserved human genes. These approaches are indeed powerful, permitting the ~5% of the genome that is comprised of critical functional elements to be distilled from the background of non-conserved DNA. Using genome alignment tools, promoters, enhancers and other types of regulatory sequences can be identified, providing ready access to DNA sequence elements that are difficult to identify by other means. Comparative genomic alignments can also reveal the presence of novel genes. However, while most studies focus on sequences that are similar between the human and the mouse, the differences between the two genomes are also revealing, exposing different mechanisms of gene regulation and function and even gene-content differences in humans and rodents. Both the similarities and differences in genomic structure are critical to the interpretation of rodent models for human disease. We are using comparative genomic approaches to define genes and regulatory elements associated with imprinting and developmental disorders in the mouse model system. I will discuss new data arising from the analysis of mouse mutant models expressing developmental disorders and susceptibility to cancer. In each case, comparative genomics approaches have been critical to identification of genes and regulatory elements that are central to development of disease-related symptoms in the animals. Differences in gene regulation and structure revealed by these studies will also aid in exptraloting results from these mouse models to similar diseases in human patients.