Systematic Phenomics Analysis of Autism-Associated Genes Reveals Parallel Networks Underlying Reversible Impairments in Habituation
This week we profile a recent publication in PNAS from Troy McDiarmid (pictured, back row right) in the laboratory of
Dr. Catharine Rankin (front row, second from right) at the Djavad Mowafaghian Centre for Brain Health.
Can you provide a brief overview of your lab’s current research focus?
My lab is a behavioral neurogenetics lab, meaning we investigate the cellular and molecular mechanisms underlying behavior. In particular, I am interested in the mechanisms of habituation, a simple form of non-associative learning observed as a behavioral response decrement to repeated stimulation. Studies in my lab were the first to demonstrate that the genetic model organism Caenorhabditis elegans could learn, and since then we have characterized the neural circuit controlling habituation, and identified several genes that play critical roles in this form of learning. Recently, we have been using our skills in genetic engineering and high-throughput behavioral analysis to gain insight into the function of genes associated with various neurodevelopmental and neurodegenerative disease, including Alzheimer disease and Autism Spectrum Disorder (ASD), that latter of which is the focus of the present publication.
What is the significance of the findings in this publication?
Recently, researchers have had a lot of success identifying genes that increase risk for ASD. There are now >100 genes associated with ASD, many of which are already being used to aid diagnosis. However, we still don’t know what roles many of these genes play in the nervous system. Our recent paper is based on the concept that a powerful way to discover the function of a gene is to inactivate it in a model organism and observe the effects on the model’s development and behavior. In order to do this for a large number of genes quickly we used Caenorhaditis elegans, a microscopic worm with a three-day lifespan that is easy to genetically engineer.
In this paper, we used our automated tracking system to quantify 26 measures spanning morphology, locomotion, tactile sensitivity and habituation learning in 135 strains of C. elegans, each carrying a mutation in a gene associated with ASD. We found that loss of function mutations in many of these genes delayed development, and also that many of the genes impaired the animal’s ability to habituate. The result was that many of the strains kept responding to sensory stimuli when they should have learned to stop. We then clustered strains based on similarities in how they affected each of the 26 measures, and used this information to identify new interactions between ASD-associated genes that were previously unknown. We then used a genome editing technique to restore normal function of gene in adulthood and found that it was able to reverse some of the learning disruptions caused by the gene being absent during development.
We’ve made all of the data for the 135 strains freely available to facilitate future experiments by the community.
This work was a large collaborative project including work from the Pavlidis, Haas, Mizumoto, and Rand labs that represents the benefits of teamwork between bench scientists and bioinformaticians.
What are the next steps for this research?
We are very interested in investigating what other ASD-associated genes produce reversible alterations in behavior. This type of work is critical for determining when a treatment tailored to a particular gene would be effective, and we can get answers for many ASD-associated genes quickly with C. elegans. These findings can then be used to prioritize and guide more time-consuming and costly experiments in rodents, and eventually humans.
This work was funded by:
This work was supported by the Canadian Institutes of Health Research (CIHR), the Simons Foundation Autism Research Initiative, and Autism Speaks. This work also wouldn’t have been possible without the C. elegans knockout consortium, the National Bioresource Project of Japan, and the C. elegans Genetics Center, who are large consortia who create, maintain and distribute C. elegans strains.