The informatics part of the project, led by Timothy Yu, MD, PhD, in the Walsh Lab, will be the most important and challenging. With new machines, DNA sequencing has become relatively easy and cheap; what's hard is interpreting the flood of information. The researchers will compare sequence information from their autism patients with that from normal controls, using data from the international "1000 Genomes Project," allowing them to distinguish normal person-to-person genetic variations from variations that cause autism. "These new data should give us enormous power to interpret the findings in our autism patients, and figure out what's the signal and what's noise," Walsh says. "Three million letters in the DNA sequence may differ between you and me -- we need to figure out which changes are causing the disease."

A separate part of the project, led by Greenberg, will look at gene activity in human neurons, focusing on genes that lie in chunks of DNA that were previously found to be deleted in the Middle Eastern families with autism. In 2008, Greenberg and Walsh reported that some autism mutations may affect "promoter" or "enhancer" sequences, bits of DNA that act as "on/off" switches controlling gene activity. (See: childrenshospital/newsroom/Site1339/mainpageS1339P1sublevel445.html.) Now, Greenberg's lab will study living, active neurons to create a systematic map of these critical switches in the human genome, while the Children's hospital team searches for the relationship between these switches and autism.

Because Grand Opportunity funding requires that the grant money be spent within 18 months, the project will move rapidly. The project's ultimate goal is to relate different forms of clinical autism to variations in both DNA and gene activity, and to make this information available to all autism researchers.

Source: Children's Hospital Boston