Public Release:  Mutation hotspots in autism genes

Cell Press

Genes implicated in autism and other human diseases are prone to frequent mutations, according to a study published by Cell Press on December 20th in the journal Cell. The study suggests that elevated mutation rates in certain parts of the genome contribute to disease risk in humans.

"Some disease-related genes are gluttons for punishment," says senior study author Jonathan Sebat of the University of California, San Diego. "Despite the fact that these genes are important for normal human development, they appear to be getting hammered with mutations."

Neurodevelopmental disorders such as autism have been associated with deletions and duplications of DNA in specific regions of the genome that tend to mutate at a high rate. But it was not known whether autism genes in particular undergo frequent mutations. In addition, it has not been clear whether autism can arise from hotspots of nucleotide substitutions, which account for most of the variation in the genome.

To answer these questions, Sebat and his team performed whole-genome sequencing on monozygotic (identical) twins with autism spectrum disorder and on their parents. They found that nucleotide substitutions clustered in certain parts of the genome. Mutation rates varied by as much as 100-fold across the genome, and this variation could be explained by intrinsic properties of genetic material, such as characteristics of the DNA sequence and how DNA is packed. Most strikingly, genes that have been linked to autism were more prone to mutation than the average gene, suggesting that some of the genetic culprits that contribute to autism are mutation "hotspots."

"This is truly the first chance anyone has had to explore the landscape of mutability in humans because an unbiased look at patterns of mutation in the genome was impossible before the development of high-throughput sequencing technologies," Sebat says.

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Michaelson et al.: "Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation."

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