Stimulus Grant to Fund "Whole-Genome Sequencing" in Children with Autism
National Institute of Mental Health awards $4.5 million to apply next-generation technology to finding autism's causes
September 30, 2009
Boston, Mass. -- Children's Hospital Boston, with the Broad Institute and Harvard Medical School, has been awarded a Grand Opportunity grant from the National Institute of Mental Health as part of the federal stimulus package, to pursue "whole-genome" sequencing of patients with autism, using new technologies for rapid DNA sequencing to better understand autism's causes. The roughly $4.5 million grant, part of the federal stimulus package, officially starts September 30. All genetic sequence data will be made publicly available.
Autism frequently runs in families, and is the most highly genetic of neuropsychiatric disorders. About a dozen specific genes and mutations have been discovered, including several by researchers at Children's. Yet these genes still leave unexplained the vast majority of autism cases -- about 85 percent, says Christopher A. Walsh, MD, PhD, chief of Genetics at Children's Hospital Boston, who is leading the new initiative with co-investigators Michael Greenberg, PhD, head of Neurobiology at Harvard Medical School, and a team at the Broad Institute of MIT and Harvard, led by Stacey Gabriel, PhD, and David Altshuler, MD, PhD.
|A typical readout of data from "next generation" DNA sequencing, used by Walsh's lab in autism patients. The sequencer samples a patient's DNA in tens of millions short, overlapping bites--a few dozen letters of code--then strings these together to build the whole sequence.|
The project will first focus on 85 Middle Eastern patients, previously studied in Walsh's lab, whose parents share common ancestry and who have recessive forms of autism. These patients make good initial subjects for study because linkage analyses of their extended families have already narrowed the field of candidate mutations down to just 1 percent of their genome. Because autism is extremely variable genetically, rare large families with multiple affected individuals provide a good opportunity for mapping disease-causing genes, many of which also occur in autism patients generally.
As techniques are refined, Walsh and colleagues will begin to perform and interpret genetic sequence information from other groups of autism patients, including American families. "Within a year or two, we hope to develop technology and informatics techniques that should help to understand many kids with autism," Walsh says.
The team will begin by analyzing the "exome" - the 2 percent of the genome that directly codes for proteins. For patients whose genetic cause remains a mystery, a second phase of the study will sequence and analyze the entire genome's 3.2 billion base pairs (combinations of A, C, T and G) that make up our full complement of 20,000 to 25,000 genes. In this way, the researchers hope to discover noncoding portions of the genome -- sometimes called "junk" DNA -- that don't make proteins but may contain critical switches that control gene activity.
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. 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.
The Nancy Lurie Marks Foundation and the Simons Foundation provided the initial seed money for Walsh's team to research autism in the Middle Eastern families. Walsh is also supported by the Howard Hughes Medical Institute.
Children's Hospital Boston
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 12 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.