Grant: CIHR Fellowship

Dramatic advances in whole genome sequencing (WGS) technology have now made it possible to analyze the entire genome of a large number of patients. This has incredible promise for improving our understanding of the genetic risk factors for a wide range of heritable disorders. In order to unlock this potential, however, we need to better understand the human genome. The genome consists of two portions: coding and non-coding. The coding portion contains the information required to make proteins,represents a small proportion of the genome, and is relatively well understood. In contrast, the non-coding portion regulates the activity of the coding portion, and despite the fact that it represents the majority of the genome, our knowledge of its composition and exact function is quite incomplete. In autism spectrum disorders (ASD), it has been reliably demonstrated that mutations in the coding region of the genome substantially increase risk for ASD. We have been able to associate these mutations because we understand the composition of the coding portion, and therefore, the effects of mutations in these regions. However, our lack of knowledge about non-coding regions has hindered investigation of the contribution of these regions to ASD risk. As a result, we are missing crucial information on the vast majority of the human genome. Therefore, this proposal will not only focus on identifying risk-carrying mutations, but also on interpretation of their effects. First, we will conduct WGS in families affected by ASD in order to identify coding and non-coding mutations. We will then develop novel methods, relying on newly collected data characterizing non-coding regions, to predict the effect of non-coding mutations. This approach has the potential to increase our understanding of the genetic architecture of ASD, and consequently, the biological underpinnings of this disorder. Both of these are necessary steps to move along the path towards developing therapeutics.