Devastating diseases like cancer and autism can be caused by spontaneous changes to our DNA—mutations first appearing in the child, or in our tissues as we age. We are developing methods to discover these changes in individuals, tumors, and even single cells, to promote early detection and treatments
Michael Wigler’s work provides a new paradigm for understanding and exploring human disease. The Wigler lab studies human cancer and the contribution of new mutation to genetic disorders. The cancer effort (with James Hicks, Alex Krasnitz, and Lloyd Trotman) focuses on breast and prostate cancers. It involves collaborative clinical studies to discover mutational patterns predicting treatment response and outcome and the development of diagnostics to detect cancer cells in bodily fluids such as blood and urine. The major tools are single-cell DNA and RNA analysis. The single-cell methods, which are in development, are also being applied to problems in neurobiology (with Josh Huang and Pavel Osten) to characterize neuronal subtypes, somatic mutation, and monoallelic expression. The Wigler lab’s genetic efforts are a collaboration with Ivan Iossifov and Dan Levy, and this team focuses on determining the role of new mutations in pediatric disorders. In a large-scale population sequencing project with W. Richard McCombie and the Genome Sequencing Center at Washington University in St. Louis, and supported by the Simons Foundation, the team has proven the contribution of this mechanism to autism. The work further suggests a relationship between the mutational targets in autism and the process of neuroplasticity that lies at the heart of learning. Smaller-scale population studies of congenital heart disease and pediatric cancer (collaborations with scientists at Columbia University and Memorial Sloan- Kettering Cancer Center, respectively) also point to new mutation as a causal factor in these disorders.
Portrait of a Neuroscience Powerhouse
April 27, 2018
At noon every Tuesday from September through June, scenes from a revolution in neuroscience are playing out at Cold Spring Harbor Laboratory. Week after week, over 100 scientists cram themselves into a ground-floor meeting room in the Beckman Laboratory. It’s standing-room only as everyone in the Neuroscience Program settles in to hear details of the...
Autism genetics study calls attention to impaired motor skills, general cognitive impairment
February 7, 2018
Cold Spring Harbor, NY — A new study of the genetic factors involved in the causation of autism spectrum disorders (ASD) draws fresh attention to the impact these illnesses have on motor skills, and more broadly on cognitive function. “Diminished motor skills appear to be an almost universal property of children with autism,” says Professor...
New method to determine before surgery which prostate tumors pose a lethal threat
December 1, 2017
Prostate cancer is common and largely nonlethal. But for some 21,000 men—a small percentage of the total, but a nonetheless substantial number—the disease is fatal. For earlier and more accurate detection, the Krasnitz and Wigler labs have devised a new method to analyze tumor biopsies to identify the most lethal forms of prostate cancer.
Next-gen cancer test
November 24, 2017
Knowing that cancers become lethal when they spread, investigators at Cold Spring Harbor Laboratory (CSHL) seek a way of detecting tumors much earlier than now possible—when they’re more likely to be curable. Fleshing out an idea Professor Michael Wigler had years ago—before there was technology to act on it—research led by Associate Professor Alexander Krasnitz...
New statistical method finds shared ancestral gene variants involved in autism’s cause
June 21, 2017
Cold Spring Harbor, NY — The way you measure things has a lot to do with the value of the results you get. If you want to know how much a blueberry weighs, don’t use a bathroom scale; it isn’t sensitive enough to register a meaningful result. While much more is at stake, the same...
Where does autism come from when it doesn’t run in the family?
April 7, 2016
LabDish blog Autism genetics expert Ivan Iossifov breaks down recent research that sheds light on how unaffected parents can pass autism onto their child. Parents with no history of autism in their families have a child who is diagnosed with the disorder. It’s a common and upsetting story. A quick Google search for “autism causes” is...
Breaking down breast cancer at CSHL
October 30, 2015
LabDish blog Breast cancer awareness is important, but it’s action that saves lives. Whether developing more accurate and affordable tests for patients or mapping out the treacherous landscape of breast cancer genetics, researchers at CSHL certainly aren’t putting the fight on pause even as the pink ribbons dissipate. Explore how they’re attacking breast cancer from...
Genetic analysis supports prediction that spontaneous rare mutations cause half of autism
September 22, 2015
Quantitative study identifies 239 genes whose “vulnerability” to devastating de novo mutation makes them priority research targets Cold Spring Harbor, NY — A team led by researchers at Cold Spring Harbor Laboratory (CSHL) this week publishes in PNAS a new analysis of data on the genetics of autism spectrum disorder (ASD). One commonly held theory...
Mathematical ‘Gingko trees’ reveal mutations in single cells that characterize diseases
September 4, 2015
The Schatz lab, in collaboration with the Wigler and Atwal labs, has developed a new interactive, open-source analysis program called Gingko that can be used to reduce the uncertainty of single-cell analysis and visualize patterns in copy number mutations across populations of cells.
A shift in the code: New method reveals hidden genetic landscape
August 18, 2014
Scientists develop algorithm to uncover genomic insertions and deletions involved in autism, OCD Cold Spring Harbor, NY — With three billion letters in the human genome, it seems hard to believe that adding a DNA base here or removing a DNA base there could have much of an effect on our health. In fact, such...
Iossifov, I. and O'Roak, B. J. and Sanders, S. J. and Ronemus, M. and Krumm, N. and Levy, D. and Stessman, H. A. and Witherspoon, K. T. and Vives, L. and Patterson, K. E. and Smith, J. D. and Paeper, B. and Nickerson, D. A. and Dea, J. and Dong, S. and Gonzalez, L. E. and Mandell, J. D. and Mane, S. M. and Murtha, M. T. and Sullivan, C. A. and Walker, M. F. and Waqar, Z. and Wei, L. and Willsey, A. J. and Yamrom, B. and Lee, Y. H. and Grabowska, E. and Dalkic, E. and Wang, Z. and Marks, S. and Andrews, P. and Leotta, A. and Kendall, J. and Hakker, I. and Rosenbaum, J. and Ma, B. and Rodgers, L. and Troge, J. and Narzisi, G. and Yoon, S. and Schatz, M. C. and Ye, K. and McCombie, W. R. and Shendure, J. and Eichler, E. E. and State, M. W. and Wigler, M. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515(7526) pp. 216-221.
Levy, D. and Wigler, M. (2014) Facilitated sequence counting and assembly by template mutagenesis. Proceedings of the National Academy of Sciences of the United States of America, 111(43) pp. E4632-E4637.
Narzisi, G. and O'Rawe, Jason and Iossifov, I. and Fang, Han and Lee, Y. H. and Wang, Zihua and Wu, Yiyang and Lyon, Gholson J. and Wigler, M. H. and Schatz, M. C. (2014) Accurate de novo and transmitted indel detection in exome-capture data using microassembly. Nature Methods, 11(10) pp. 1033-1036.
Sebat, J. and Lakshmi, B. and Malhotra, D. and Troge, J. E. and Lese-Martin, C. and Walsh, T. and Yamrom, B. and Yoon, S. and Krasnitz, A. and Kendall, J. T. and Leotta, A. and Pai, D. and Zhang, R. and Lee, Y. H. and Hicks, J. B. and Spence, S. J. and Lee, A. T. and Puura, K. and Lehtimaki, T. and Ledbetter, D. and Gregersen, P. K. and Bregman, J. and Sutcliffe, J. S. and Jobanputra, V. and Chung, W. and Warburton, D. and King, M. C. and Skuse, D. and Geschwind, D. H. and Gilliam, T. C. and Ye, K. and Wigler, M. H. (2007) Strong Association of De Novo Copy Number Mutations with Autism. Science, 316(5823) pp. 445-449.
Wigler, M. H. and Weinstein, I. B. (1975) Preparative Method for Obtaining Enucleated Mammalian-Cells. Biochemical and Biophysical Research Communications, 63(3) pp. 669-674.Additional materials of the author at
CSHL Institutional Repository