By Julia Karow
This article, originally published Sept. 30, has been updated with additional information and with comments from a Broad Institute researcher.
The National Institute of Mental Health has made three Grand Opportunity stimulus awards for separate research projects into the genetics of autism that involve high-throughput sequencing.
Children's Hospital Boston, the Broad Institute, and Harvard Medical School will receive a $4.5 million grant to study human autism genetics and activity-dependent gene activation over 18 months.
Meanwhile, Cold Spring Harbor Laboratory has been awarded $1.4 million in fiscal year 2009 for a project that will sequence autism candidate genes in 2,000 families.
Yale University, for its project, will receive $1.2 million in fiscal year 2009 for genomic profiling and functional mutation analysis in autism spectrum disorders.
Total funding amounts for the CSHL and Yale projects were not immediately available from NIMH.
Children Hospital's 18-month project will focus on 85 Middle Eastern patients with a recessive form of autism whose parents share a common ancestry.
The patients have already been studied by Christopher Walsh, chief of genetics at Children's Hospital and the project's leader, who has conducted linkage studies of their extended families to identify regions in their genomes that are implicated in the disease.
The project also involves co-investigators Michael Greenberg, head of neurobiology at Harvard Medical School; as well as Stacey Gabriel, who will be in charge of sequencing for the project, and David Altshuler, both of the Broad Institute.
Gabriel told In Sequence last week that the researchers plan to sequence the exomes of the patients in the first year, using the hybrid selection method developed by the Broad Institute and Illumina sequencing. "That's our plan as of now," she said.
Later on during the project, when the cost of sequencing a sample drops so much that exome sequencing "is no longer a win," she said, the plan is to transition to whole-genome sequencing.
Whole-genome sequencing could involve some of the same 85 patients, or a different set of patients, according to Gabriel.
A separate part of the project, led by Greenberg, will study gene activity in human neurons, focusing on DNA regions found to be deleted in the families, according to a statement from Children's Hospital.
Later, the study will expand the genetic sequence analysis to other groups of autism patients. "Within a year or two, we hope to develop technology and informatics techniques that should help to understand many kids with autism," Walsh said in a statement.
Cold Spring Harbor's project, led by Michael Wigler, will focus on the Simons Simplex Collection, a high-quality set of samples from families with autism spectrum disorder, according to the grant abstract.
The aim is characterize the mutational spectrum of 100 known or predicted as well as novel ASD candidate genes in 2,000 families. The project complements an ongoing comparative genomic hybridization study that is designed to identify novel ASD candidate genes.
Yale's study, led by Matthew State, will analyze two proteins, contactin-associated protein 2 and piccolo, to clarify their roles in ASD, according to the grant abstract. In addition, the researchers plan to sequence genes in the contactin and contactin-associated pathways, as well as genes coding for proteins known to interact with piccolo, in a well-characterized and ethnically matched case-control sample using next-generation sequencing technologies.
The three projects are unrelated to another autism sequencing project, a collaboration between large-scale sequencing centers at the Broad Institute and at Baylor College of Medicine and autism research labs led by Mount Sinai School of Medicine, the University of Pennsylvania, and Vanderbilt University (see other story in this issue). That project, also funded by NIMH, received approximately $8 million in fiscal year 2009.