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Scientists from King's College London have identified patterns of epigenetic changes involved in autism spectrum disorder (ASD) by studying genetically identical twins who differ in autism traits.
The researchers studied an epigenetic mechanism called DNA methylation. DNA methylation acts to block the genetic sequences that drive gene expression, silencing gene activity. They examined DNA methylation at over 27,000 sites across the genome using samples taken from 50 identical twin pairs (100 individuals) from the UK Medical Research Council (MRC) funded Twins Early Development Study (TEDS): 34 pairs who differed for ASD or autism related behaviour traits, 5 pairs where both twins have ASD, and 11 healthy twin pairs.
Dr Chloe Wong, first author of the study from King's College London's Institute of Psychiatry, says: "We've identified distinctive patterns of DNA methylation associated with both autism diagnosis and related behaviour traits, and increasing severity of symptoms. Our findings give us an insight into the biological mechanism mediating the interaction between gene and environment in autism spectrum disorder."
DNA methylation at some genetic sites was consistently altered for all individuals with ASD, and differences at other sites were specific to certain symptom groups. The number of DNA methylation sites across the genome was also linked to the severity of autism symptoms suggesting a quantitative relationship between the two. Additionally, some of the differences in DNA methylation markers were located in genetic regions that previous research has associated with early brain development and ASD.
Professor Jonathan Mill, lead author of the paper from King's College London's Institute of Psychiatry and the University of Exeter, says: "Research into the intersection between genetic and environmental influences is crucial because risky environmental conditions can sometimes be avoided or changed. Epigenetic changes are potentially reversible, so our next step is to embark on larger studies to see whether we can identify key epigenetic changes common to the majority of people with autism to help us develop possible therapeutic interventions."
Dr Alycia Halladay, Senior Director of Environmental and Clinical Sciences from Autism Speaks who funded the research, says: "This is the first large-scale study to take a whole genome approach to studying epigenetic influences in twins who are genetically identical but have different symptoms. These findings open the door to future discoveries in the role of epigenetics -- in addition to genetics -- in the development of autism symptoms."
New study of autism reveals a 'DNA tag' (methylation) amenable to treatment
Research in the FASEB Journal describes discrete epigenetic changes of DNA in a certain subgroup of twins and siblings with autism
A new discovery raises hope that autism may be more easily diagnosed and that its effects may be more reversible than previously thought. In a new study appearing online in The FASEB Journal (www.fasebj.org...), scientists have identified a way to detect the disorder using blood and have discovered that drugs which affect the methylation state ("DNA tagging") of genes could reverse autism's effects. This type of drug is already being used in some cancer treatments.
Dr. Akbarian has in mind a risk assessment of patients with brain and behavior disorders that might combine the insights of genetics and epigenetics. It will take some years before knowledge of the nervous system, and especially the brain and its complex neural networks, is extensive enough to support this approach. But his research and that of other neuroscience labs is beginning to paint a picture of what Dr. Akbarian calls ‘a risk constellation' that stitches together knowledge about places in the genome and epigenome where abnormalities correlate with pathology.
One very exciting, although still very new concept now being explored by Dr. Akbarian’s team is the use of various methods to target the enzymes that carry epigenetic marks to DNA (and the histones, which are proteins that are attached to it), and those which remove them. Epigenetic marks—chemical groups, such as CH3 (methyl groups)—are constantly being added and subtracted from the DNA letters that make up our genome.
Enzymes that add methyl groups to DNA are called methylases; enzymes that remove methyl groups from DNA are called demethylases. The object of a potential therapy might be to either add or subtract a methyl group at a particular position or positions in the genome, where research suggests doing one or the other would reverse an abnormality found to promote or be directly involved in disease pathology. This is not far-fetched by any means; a class of drugs called HDAC inhibitors have long been used as mood stabilizers in psychiatry. These drugs prevent an enzyme called deacetylase from removing epigenetic marks called acetyl groups.
Three of these regions show elevated methylation in autism brains relative to those from controls, the study found. These autism brains have less SHANK3 message than do either autism brains with typical methylation or control brains. They also have little to none of certain variants of the protein.
Treating cultured cells with a drug that blocks methylation lowers the levels of some of these SHANK3 variants and raises the levels of others, supporting the role of methylation in SHANK3 expression. The results suggest that SHANK3 may contribute to autism, even in individuals who have no mutations in the gene.