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While scientists have long known autism is highly hereditary, their challenge has been identifying the genetic factors associated with it. In a recent study, researchers took an important step toward developing a better understanding of this complex neurodevelopmental disorder.
The study uncovered a simple change in the genetic code that is associated with autism, implicating a neuronal gene that has not previously been tied to the disorder. The genetic code is a long chain of four letters (A, C, G and T) in varying sequences that specify genetic information, and researchers found that a particular single-letter change, or mutation, in this code could play an important role in autism. The research highlighted two other regions of the genome which are likely to contain rare genetic differences that may also influence autism risk.
The study was a large multinational collaboration led by researchers at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts, founded in 2003 to use new genome-based knowledge in medical research. Other participants included Massachusetts General Hospital and Johns Hopkins University.
"These genetic findings give us important new leads to understand what's different in the developing autistic brain compared with typical neurodevelopment," said Lauren Weiss, the co-lead author of the study's results, which were published in the October 8 issue of the journal Nature. Weiss, a former postdoctoral fellow at MGH and the Broad Institute, is currently an assistant professor of psychiatry and human genetics at University of California, San Francisco. "We can now begin to explore the pathways in which this novel gene acts, expanding our knowledge of autism's biology."
Support for the study was provided by the Autism Consortium, the Nancy Lurie Marks Family Foundation, NARSAD, the National Center for Research Resources, the National Institute of Mental Health, the Simons Foundation, and others.
Using a Two-Pronged Approach
In order to better understand the complex genetics behind autism, the researchers devised a two-pronged approach that looked at the entire genome, which is all of an organism's hereditary information. The first prong analyzed DNA from autism patients and their family members. The goal of this family-based method was detecting portions of the genome that harbor rare but large-effect DNA variants.
The second prong, a population-based method known as "association," examined DNA from unrelated individuals. This step is useful for exposing common genetic variants that are associated with autism and tend to exert more modest effects.
"The biggest challenge to finding the genes that contribute to autism is having a large and well studied group of patients and their family members, both for primary discovery of genes and to test and verify the discovery candidates," said Aravinda Chakravarti, professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, and one of the study's senior authors. He also notes the study would not have been possible without genomic scanning technologies.
Identifying the Relevant Genomic Regions
The researchers' results highlight three regions of the human genome. These include parts of chromosomes 6 and 20, the top-scoring regions to emerge from the family-based linkage studies. Although further research is needed to localize the exact causal changes and genes within these regions that contribute to autism, these findings can help guide future work.
"The genomic regions we've identified help shed additional light on the biology of autism and point to areas that should be prioritized for further study," said Mark Daly, one of the study's senior authors, a senior associate member at the Broad Institute and an associate professor at the Center for Human Genetic Research at MGH. "Given the genetic complexity of autism, it's unlikely that a single method or type of genomic variation is going to provide us with a complete picture. Our approach of combining multiple complementary methods aims to meet this critical challenge."
Although the Nature paper identifies a handful of new genomic regions, the researchers emphasize that the findings are just one piece of a very large - and mostly unfinished - puzzle. Future studies involving larger patient cohorts and higher resolution genomic technologies, such as next-generation DNA sequencing, promise to yield a deeper understanding of autism and its complex genetic roots.
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