Our laboratory has three major areas of interest.

Human Genetics. We have been interested in cloning human disease genes, understanding how mutations in individual genes cause human disease and what approaches can be used to develop therapies for such diseases. One of the diseases that we have been interested is Noonan syndrome (NS). NS is an autosomal dominant disorder and mutations in several genes in the RAS-MAP Kinase pathway cause Noonan syndrome. Although many genes in this pathway are implicated in NS these genes together do not explain the molecular etiology of all Noonan patients. We are now using whole genome and exome sequencing technologies to identify additional genes, mutations in which lead to NS. We have also made mouse models for NS by introducing specific point mutations that cause NS into the mouse germline. We are using these mice to better under the molecular etiology of NS and to develop therapeutic strategies.

Mouse models for human cancer. We have a long-standing program to understand the role of genes involved in human colorectal cancer. Towards this goal, we used genetic engineering technologies to make mice with mutations in each of a large set of genes suspected to be involved in the initiation and progression of gastrointestinal cancer. These genes include, APC, MCC, N-RAS, SMAD2, SMAD4, MSH2, MSH3, MSH4, MSH5, MSH6, MLH1, FEN1 and ARVCF. Mice with mutations in Apc, Msh2, Msh6 and Mlh1 show a cancer predisposition phenotype. Mice with mutations in Smad4, Msh3, Fen1 and Arvcf do not develop tumors but mutations in these genes increase tumor susceptibility in Apc mutant mice. Several conditional knock out mice for some these genes are being used to better understand the processes involved in the initiation and progression of the cancer and in developing new therapeutic strategies.

Cancer Genome Atlas. We are part of a consortium to obtain very detailed genetic and genomic information of human tumors. This program is referred to as The Cancer Genome Atlas (TCGA). In this effort 500 tumors and their corresponding normal samples from each of 20 different tumor types are examined by modern technologies to decipher all of the genetic and genomic changes in each tumor type. We contribute to this effort by using high throughput genomic sequencing technologies to assess changes in copy numbers of whole chromosomes or segments of chromosomes and to detect chromosomal aberrations including translocations, deletions, duplications and inversions.