Jonathan Sebat, Ph.D., Cold Spring Harbor Laboratory

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Map of copy number polymorphisms (CNPs) detected by Bgl II ROMA: CNPs identified in multiple individuals are shown in yellow. CNPs identified in one individual are shown in red. Additional CNPs identified by Hind III ROMA are shown in blue.

Jonathan Sebat
Assistant Professor
Ph.D. University of Idaho, 2002
Copy number variation; segmental duplication; genetics; neurogenetics; ROMA; microarray

email sebat@cshl.edu, phone (516) 422-4196

Large-scale differences in gene copy number, known as copy number polymorphisms (CNPs), are a significant source of human genetic variation. In contrast to DNA sequence variants such as SNPs and microsatellite repeats, CNPs have not been well characterized. Much remains to be learned about the genomic locations, frequency, and stability of these structural variants and their importance in human genetic disease.

Our laboratory is interested in the role of gene copy number variation in neurological disease. Almost invariably, visible alterations of the genome result in cognitive defects. In addition, some neurological disorders are the result of heritable chromosomal variants invisible at the cytogenetic level. We hypothesize that submicroscopic alterations in gene dosage are underlying causes of diseases such as autism, schizophrenia, and Parkinson’s disease. We are currently investigating chromosomal variation in disease using a method for high-resolution analysis of DNA copy number called Representational Oligonucleotide Microarray Analysis (ROMA).

We have previously applied ROMA to the analysis of cytogenetic aberrations. This analysis has served to validate the method and to illustrate the resolution with which we can define chromosomal imbalances. In addition, through our studies of “normal” genetic variation, we have shown that CNPs are abundant and widely distributed in the human genome. We have now adapted ROMA for use in population studies of genomic variation. Our flagship project is an exploration of copy number variation in familial and sporadic autism.

Selected Publications

Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K., and Wigler, M. 2007. Strong association of de novo copy number mutations with autism. Science 316: 445–449.

Jobanputra,V., Sebat, J., Chung, W., Anyane-Yeboa, K., Wigler, M., and Warburton, D. 2005. Application of ROMA (representational oligonucleotide microarray analysis) to patients with cytogenetic rearrangements. Genet. Med. 7: 111–118.

Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T.C., Trask, B., Patterson, N., Zetterberg, A., and Wigler, M. 2004. Large-scale copy number polymorphism in the human genome. Science 305: 525–528.

Lucito, R., Healy, J., Alexander, J., Reiner, A., Esposito, D., Chi, M., Rodgers, L., Brady, A., Sebat, J., Troge, J., West, J.A., Rostan, S., Nguyen, K.C., Powers, S., Ye, K.Q., Olshen, A., Venkatraman, E., Norton, L., and Wigler, M. 2003. Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res. 13: 2291–2305.