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Studies of Genetic Copy Number Variations

Reveal New Biological Pathways
January 31, 2010

There are many different types of genetic variation. One of the newest to be appreciated are submicroscopic DNA deletions or duplications called copy number variants (CNV), and they have garnered much attention in the autism scientific community [see 2008 Recurrent Chromosome 16p11 Copy Number Variants in Autism]. In a companion paper1 to the GWAS study published in Nature in April 2009 [The First Successful Genome-Wide Association Studies for Autism], researchers took advantage of their expansive set of genetic data to conduct additional analyses that would explore CNVs in the autism genome. Along with revealing genes involved in biological pathways previously connected to ASD, their results also surprisingly implicated a new cellular pathway, known as the 'ubiquitin pathway,' in the pathology of autism.

Genes are the instructions that create proteins. Proteins are in turn the functional end of our biology. By studying autism genetics, researchers are not only uncovering factors that can be used to assess the risk of developing autism, they are simultaneously unlocking the mystery of what biological pathways underlie ASD. To date, the majority of autism-associated CNVs have been found to lie in genes whose proteins help neurons adhere to each other and establish proper connections. Results of this newest and largest CNV study continued to confirm this association, finding several CNV in neuronal adhesion and synapse-related genes. Some of these had previously been linked to ASD, such as neurexin 1 [see 2009 Genetic Findings Lead to New Mouse Model in Autism], while others were new, such as a gene called ASTN2. Overall, these genes are similar in function to those found through the GWAS studies.

The second major class of genes in which the investigators uncovered CNV is the ubiquitin pathway. The ubiquitin system is primarily involved with altering protein function and disposing of unused molecules within cells. At first glance, the report of CNVs associated with the ubiquitin pathway was somewhat surprising, even if one of the genes in the pathway, UBE3A, has previously been linked to ASD because of its involvement in Angelman Syndrome. However, the authors note that one of the major roles of the ubiquitin pathway is to regulate the turnover of synaptic components, especially those related to plasticity and learning, including the cell-adhesion molecules identified by both their GWAS and CNV analyses. Thus, the authors speculate that the two different types of gene networks their CNV analyses identified may actually be functionally related.

Taken together the genetic findings of 2009 are helping to refine our understanding of autism. For instance, the discovery of CNV in genes that govern the ubiquitin pathway represents a new finding in autism. However, the fact that this can be functionally related to other autism genetic discoveries, specifically through a role in synapse activity, suggests that many of these seemingly disparate and individually rare mutations are converging at the level of biology. Therefore, although identification of the various different types of genetic mutations may define different subclasses of autism, and thereby reveal individual opportunities for future therapeutic development, they also suggest the possibility of developing a more general approach to treatment by focusing on the common biological pathways.

1. Glessner et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009 May 28;459(7246):569-73. Epub 2009 Apr 28. [PubMed link:19404257]