A large genetic study has uncovered a single 'letter' change in DNA which is associated with autism. The multi-national collaborative team, who published their findings in Nature, also identified two further regions of the genome which could contain other rarer genetic changes that have an even greater influence on the condition. Coinciding with these discoveries and publishing their findings in the Proceedings of the National Academy of Sciences, a team led by Professor Thomas Sudhof of Stanford University has shed light on how a previously discovered genetic change may be resulting in the human disorder.
Autism is a complex brain disorder characterised by impaired social interaction and communication as well as restricted and repetitive behaviours. The prevalence of autism is currently one to two people per 1000 and is highly heritable - approximately 90 per cent of cases are thought to be at least partly influenced by genes. However, exactly which genes and how they bring about the disorder remain unknown.
In continued pursuit of autism's complex genetic architecture, a large multinational collaboration led by researchers at the Broad Institute of Harvard and MIT, Massachusetts General Hospital, Johns Hopkins University and elsewhere mounted a two-pronged, genome-scale approach.
The first component made use of a family-based method, called 'linkage'. Linkage studies compare the DNA from patients affected by a disorder with their family members in order to detect portions of the genome which could contain causal genetic variants. The results of the study identified regions of chromosome 6 and 20. Although further research is required to pinpoint the exact causal changes within these regions that contribute to autism, study author Mark Daly explains that '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'.
The second prong was a population-based method, referred to as an association study. This type of study examines DNA from unrelated individuals and uncovers genetic variants which are associated with a given disorder. With this method, the researchers found a single-letter change in the genetic code known as a SNP (pronounced 'snip') on chromosome 5 near a gene known as semaphorin 5A. This gene encodes a protein thought to help guide the growth of neurons.
'This study is key - it reinforces the notion that deficit in proper neuronal interaction is involved with autism neuropathology' said Dr Andy Shih, vice president of scientific affairs of Autism Speaks. 'If this finding holds and is further supported with additional research such as a functional study of the variant semaphorin 5A, this molecule could represent another biological target for pharmaceutical intervention in the future and possible treatment for some individuals with autism'.
Co-lead author Professor Lauren Weiss states, 'We can now begin to explore the pathways in which this novel gene acts, expanding our knowledge of autism's biology'.
A team led by Professor Thomas Sudhof did just this in response to the discovery that deletion of the gene neurexin-1alpha occurs in about 0.5 per cent of autism cases. 'Because of our longstanding interest in neurexin-1alpha, we already had mice that were bioengineered to be lacking in neurexin-1alpha,' Sudhof explains. 'So we decided to look closely at those mice to see whether this genetic deficiency led to any changes in communication between neurons and, if so, whether the disrupted or altered communication was correlated with any observable behavioural abnormalities reminiscent of those associated with human cognitive disorders such as autism or schizophrenia'.
The researchers noticed that the mutant mice had alterations in their 'synapses' - regions where nerve cells signalled to one another. Furthermore, the defect affected only excitatory synapses, as opposed to inhibitory. 'This selective change in the strength of one type of synapse, but not the other type, alters the balance between the two' said Sudhof.
The mutant mice displayed behavioural traits characteristic of those associated with autism, such as repetitive stereotypical behaviour. Similarly analogous to human patients, mice lacking the neurexin-1alpha gene were not compromised in day-to-day functions. Sudhof goes further to explain that 'they were actually better than the control mice at executing tasks requiring motor coordination, such as balancing atop a rotating rod without falling off'.Sudhof and his colleagues at the Stanford Institute for Neuro-Innovation and Translational Neurosciences now plan to investigate whether other autism-related genes affect the nervous system, including those identified in the above study published in Nature.