Raju Kucherlapati

Department of Genetics
Harvard-Partners Center for Genetics and Genomics
77 Avenue Louis Pasteur, Suite 250
Boston, MA 02115
Tel: (617) 525-4445
Fax: (617) 525-4440
Email: rkucherlapati@partners.org
Web Page: The Kucherlapati Lab Page

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 have finished 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 were a 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. We have identified that haploinsufficiency of TBX1, located in this region causes many of the VCFS/DGS phenotypes. 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.

References:

• Wang Y, Putnam CD, Kane MF, Zhang W, Edelmann L, Russell R, Carrion DV, Chin L, Kucherlapati R, Kolodner RD, Edelmann W. (2005) Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. Nat Genet. 37:750-7555.
• Lin Q, Clark AB, McCulloch SD, Yuan T, Bronson RT, Kunkel TA, Kucherlapati R. Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. (2006) Cancer Res. 66:87-94.
• Scherer SE, Muzny DM, Others, Nelson D, Kucherlapati R, Weinstock G, Gibbs RA; Baylor College of Medicine Human Genome Sequencing Center Sequence Production Team. (2006) The finished DNA sequence of human chromosome 12. Nature. 440:346-351.
• Kucherlapati MH, Nguyen AA, Bronson RT, Kucherlapati RS. (2006) Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract. Cancer Res. 66:3576-3583.