Summary: Researchers examined the sequences of more than 650 genes linked to autism and identified genomic features that set them apart from other brain-related genes.

Possible Genetic Basis for Autism Identified by Ben-Gurion University Researchers

Ben-Gurion University of the Negev (BGU) researchers have moved closer to clarifying the genetic underpinnings of autism spectrum disorder (ASD). Their findings, reported in the journal Behavior Genetics, reveal a distinctive evolutionary and genomic signature among genes associated with ASD that may help researchers find additional risk genes and improve earlier diagnosis.

The team analyzed the sequences of 651 genes previously associated with autism. By comparing these ASD-associated genes with other brain-expressed genes and genes linked to different diseases, the researchers identified several characteristics that appear unique to the autism gene set.

Key Findings

One of the most striking discoveries was that ASD-associated genes are, on average, considerably longer than other brain-specific genes and genes implicated in disorders such as Alzheimer’s disease and schizophrenia. In addition, these genes show reduced genetic variability relative to non-ASD genes. Specifically, the ASD gene set was found to be approximately 65% longer and about 20% less variable than comparable genes, with the reduction in variability especially pronounced for deleterious variants.

The observed shortage of damaging mutations in ASD genes is indicative of negative selection — an evolutionary force that removes harmful mutations from the population over generations. This pattern suggests that many variants that could disrupt these genes are purged by evolutionary processes, leaving a distinctive mutational profile in the surviving gene sequences.

Selection and Evolutionary Forces

In addition to signs of negative selection, the researchers looked for evidence of positive selection that would indicate autism-associated variants increased in frequency through adaptive advantage. They found no clear evidence that positive selection shaped these genes. This implies that the presence of autism susceptibility variants in the human genome is unlikely to be the result of recent adaptive benefit. Instead, autism is more likely to arise when these standing genetic variants interact with other genetic factors, non-genetic influences, or environmental triggers.

Overall, the genomic features identified — exceptional gene length combined with reduced variability for deleterious changes — create a unique evolutionary signature for ASD genes. According to the authors, this signature can serve as a tool to discover additional candidate genes involved in autism.

Implications for Diagnosis and Research

Autism spectrum disorder is a common neurodevelopmental condition characterized by difficulties in social interaction and communication. According to the U.S. Centers for Disease Control and Prevention (CDC), about one in 50 children in the United States is diagnosed with ASD. The prevalence of diagnosed ASD has increased dramatically since the 1980s, when estimates were roughly one in 5,000.

Researchers hope that identifying shared genomic features of ASD genes will support earlier, more accurate detection of genetic risk and guide future studies into the biological pathways that contribute to the disorder. The unique evolutionary signature may also improve the prioritization of candidate genes in whole-exome or whole-genome studies, focusing attention on genes that match the length and variability profile observed in this study.

When the researchers studied families with a child diagnosed with ASD, they observed a genomic signature shaped by negative selection, an evolutionary process that removes disruptive mutations over generations. Image used for illustration.

Study Details and Source

The study authors are Erez Tsur, Michael Friger, and Idan Menashe from the Ben-Gurion University of the Negev Department of Public Health and the Zlotowski Center for Neuroscience. The full research article, titled “The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder,” was published online in Behavior Genetics on August 11, 2016.

Abstract summary: The authors analyzed a whole-exome sequencing dataset of 651 ASD genes to search for evolutionary traces that explain how ASD persisted in the human population. They report that ASD genes are substantially longer and show less variability, especially for deleterious variants, compared to non-ASD genes. These genomic characteristics are distinct from other brain-specific genes and genes associated with other diseases, supporting the idea that ASD genes have evolved under complex evolutionary pressures. The authors suggest the identified signature can be used to find new candidate ASD genes.

Source: American Associates Ben-Gurion University. Original research: “The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder” by Erez Tsur, Michael Friger, and Idan Menashe, Behavior Genetics, published online August 11, 2016. DOI: 10.1007/s10519-016-9804-4.