Our laboratory has three major areas of interest.

Mammalian Genomics

Our laboratory has been involved in the mapping and sequencing of the human/ and mouse genomes using yeast artificial chromosomes and later, bacterial artificial chromosomes. We made a detailed physical map of human chromosome 12. In collaboration with the Genome Center at Baylor College of Medicine, we are now engaged in finishing the sequence of this chromosome. We were involved in mapping and cloning several human disease genes on this chromosome. They include, Noonan syndrome, Darier disease, Cornea plana and Holt-Oram syndrome. We are part of an international consortium to sequence the mouse genome. We use the mapping and sequencing expertise to clone new human disease genes.

Molecular etiology of velo-cardio-facial/ DiGeorge syndrome (VCFS/DGS)

VCFS/DGS is a relatively common human syndrome. Children with VCFS/DGS present with a spectrum of phenotypes including cardio-vascular defects, immunological abnormalities, muscle weakness, hypernasal speech and learning disabilities. As they grow older, a large portion of them also develop psychiatric illness. The disorder results from haploinsufficiency of a 3 Mb region on human chromosome 22q11. We constructed detailed maps of this region and identified genes encoded by the DNA in 22q11. Using genetic engineering technologies, we made mice that carry a deletion in a region of the genome that corresponds to human 22q11. These mice exhibit some of phenotypes observed in VCFS/DGS patients. Using BAC complementation, we narrowed the critical region and identified a candidate gene, Tbx1. When Tbx1 is mutated, the mice develop vascular defects similar to those seen in human VCFS/DGS patients. We are now interested in understanding how haploinsufficiency of Tbx1 causes the major phenotypes of VCFS/DGS.

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. Mice with mutations in MlH1, Msh4 and Msh5 are sterile. The sterility is caused by meiotic arrest. We are interested in examining the roles of these and other genes in cancer initiation and progression.

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