Med school research, a 2010 breakthrough

Researchers at the School of Medicine are breaking old boundaries.

His research lauded as one of the “Breakthroughs of the Year” by Science Magazine in 2010, neurosurgery professor Murat Gunel and colleagues have discovered that mutations in a particular gene, WDR62, can hinder brain development and result in disorders such as mental retardation. Highlighted for both its contribution to the field and technological innovation, the study used a new method of DNA sequencing, called “exome sequencing,” that targets specifically the 1 percent of the human genome responsible for protein production. Researchers involved in the study said exome sequencing could be the first step to uncovering individualized disease treatments.

Gunel said the discovery, one of the first to involve exome sequencing, holds promise to improve the diagnosis and treatment of brain disorders like autism.

“Discovery of these genes mutated in cortical abnormalities allow us to learn how the human brain develops,” Gunel said.

Gunel and his team of researchers, including Sterling Professor of Genetics Richard Lifton and associate psychiatry and genetics professor Matthew State, began the DNA sequencing that led to the discovery of the gene’s link to brain malformations during the summer of 2009.

The researchers knew that the traditional methods of DNA mapping were not likely to lead them to identify the genetic culprit due to the high cost and ineffiency of whole-genome sequencing, Gunel and neurosurgery researcher Kaya Bilguvar said.

So they applied the new tactic of exome sequencing, a technological innovation used in the laboratory with which they sifted through 30 million — rather than 3 billion — protein-coding DNA base pairs and reduced their costs “10-fold,” Gunel said. The researchers also saved time, taking only three months to sequence the DNA selection and identify the mutated gene as the cause of the disorder.

But the research might not have happened without the financial support of the medical school.

Under the direction of Dean Robert Alpern and Deputy Dean Carolyn Slayman, the medical school has invested both in the creation of the neurogenetics program as well as in building the sequencing technology Gunel used in his research, Gunel said. The funds provided to the neurogenetics program allowed Gunel’s team to gather enough samples to apply for funding from the National Institute of Neurological Disorders and Stroke, he said.

Exome sequencing has the potential to have a “huge role” in the future by allowing doctors to better understand the cause of diseases and develop more individualized treatments, Gunel said.Already he, Lifton and State are applying the technology to research that aims to better understand the genetic basis of disorders ranging from cancer to hypertension to autism.

Bilguvar said the use of exome sequencing will ultimately allow researchers to identify new genes for new disorders and for diseases that have stumped doctors for years.

Meanwhile, the Yale research team has moved on to the next step of their attempt to understand the cause of cortex malformations, Bilguvar said.

“We now need to do the functional biological studies to understand how mutations in this gene leads to the malformation,” Bilguvar said.

Exome sequencing was one of five breakthroughs highlighted in the Dec. 17 issue of Science Magazine, including advances in human spaceflight and the use of biochemistry in cancer research.

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