Autism spectrum disorder (ASD) refers to related neurodevelopmental disorders characterized by deficits in reciprocal communication and social interactions, coupled with restricted and repetitive patterns of behavior, interests and activities. Because ASD tends to run in families, much effort has been spent on genetic analyses to identify genetic variations that either cause or elevate risk for ASD.
Over the years, such studies have implicated an increasing number of candidate genes (now in the hundreds), but with relatively poor reproducibility among different study groups, most likely due to the clinical heterogeneity within the autistic population.
Recent studies demonstrating differential expression of hundreds to thousands of genes in peripheral cells and brain tissues of individuals with ASD indicate the need to look beyond genetics to uncover additional factors that contribute to ASD.
Indeed, the observed large-scale dysregulation of gene expression suggests the involvement of “master switches” that can turn on or off batteries of genes that are involved in critical pathways that have been shown to be disrupted in ASD.
Epigenetic mechanisms which can alter gene expression and phenotype without inducing changes in DNA sequence are precisely poised to serve as these master switches.
Epigenetic Mechanisms in Autism
What are epigenetic mechanisms? Epigenetic mechanisms include a variety of processes that act upon DNA and result in altered gene expression. These include:
- DNA methylation, in which a methyl (chemical) group is reversibly attached to the cytosine base in DNA,
- Histone modifications, in which proteins (histones) that help to organize DNA are reversibly modified by the attachment of methyl or acetyl groups, and
- Noncoding RNA, both small and large, which also help to orchestrate the repertoire of expressed genes in any given cell or tissue.
Notably, recent studies have reported the involvement of all of these epigenetic mechanisms in ASD. Moreover, many environmental agents (pollutants?) that cause disease or developmental aberrations act through epigenetic mechanisms, thus highlighting the need to also study epigenetics of gene-environment interactions that increase risk for ASD. The significance of epigenetic changes with respect to ASD is that they are potentially reversible (as has been shown for some that cause cancer), and may be passed through generations if they occur in germline (i.e., sperm and egg) cells, as has been demonstrated in animal models.
Contributed by Valerie W. Hu, Ph.D.; Professor of Biochemistry and Molecular Medicine;
The George Washington University School of Medicine and Health Sciences
Washington, DC 20037
For more on this topic, please see the review article by Dr. Hu, entitled: The expanding genomic landscape of autism: discovering the ‘forest’ beyond the ‘trees’; Future Neurology 8(1):29-42 (2013).