Professor
Ph.D., Columbia University, 1978

Human genetic disorders; population genetics; cancer genomics

email wigler@cshl.edu phone (516) 367-8377, fax (516) 367-8381

Our laboratory has for many years studied the molecular basis of cancer, in particular the genetic mutations that drive the evolution of the cancer cell. In recent years this has been extended to the study of the genetic mutations that underlie devastating genetic diseases such as congenital heart disease and autism. Common to both areas are a set of genome technologies for measuring copy number variation between cells. With this technique, the entire genome of the cell can be scanned at very high resolution (Lucito et al., 2003), and changes in gene copy numbers resulting from deletions and amplifications can be readily detected. We are applying these methods to a large set of clinically annotated breast and ovarian cancers, making correlations with clinical outcome, and discovering new disease causing genes. The same technique has application in the analysis of spontaneous mutations in the germ-line. Hence, we are applying the methodology to finding the lesions causing sporadic genetic disease. The laboratory has a particularly intense need for bioinformatics and algorithmic interpretation from genome-wide experimental data.

Representational Oligonucleotide Microarray Analysis (ROMA) is a technique that was developed by Michael Wigler and Rob Lucito at the Cold Spring Harbor Laboratory in 2003. Michael Wigler and Rob Lucito currently run laboratories at CSHL using ROMA to explore genomic copy number variation in cancer and other genetic diseases.

In this technique two genomes are compared for their differences in copy number on a microarray. The ROMA technology emerged from a previous method called Representational Difference Analysis (RDA). ROMA, in comparison to other comparative genomic hybridization (CGH) techniques, has the advantage of reducing the complexity of a genome with a restriction enzyme which highly increases the efficiency of genomic fragment hybridization to a microarray. In ROMA, a genome is digested with a restriction enzyme, ligated with adapters specific to the restriction fragment sticky ends and amplified by PCR. After the PCR step, representations of the entire genome (restriction fragments) are amplified to pronounce relative increases, decreases or preserve equal copy number in the two genomes. The representations of the two different genomes are labeled with different fluorophores and co-hybridized to a microarray with probes specific to locations across the entire human genome. After analysis of the ROMA microarray image is completed, a copy number profile of the entire human genome is generated. This allows researchers to detect with high accuracy amplifications (amplicons) and deletions that occur across the entire genome.

In cancer the genome becomes very unstable, resulting in specific regions that may be deleted (if they contain a tumor supressor) or amplified (if they contain an oncogene). Amplifications and deletions have also been observed in the normal human population and are refered to as Copy Number Polymorphisms (CNPs). Jonathan Sebat was one of the first researchers to report in the journal 'Science' in 2003 that these CNPs give rise to human genomic variation and may contribute to our phenotypic differences. Tremendous research efforts are being conducted now to understand the role of CNPs in normal human variation and neurological diseases such as autism. By understanding which regions of the genome have undergone copy number polymorphisms in disease, scientists can ultimately identify genes that are overexpressed or deleted and design drugs to compensate for these genes to cure genetic diseases.