C. elegans social behaviour as a functional approach to investigate the genetic determinants of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder which is clinically characterised by core behavioural deficits including disruption to social behaviour. ASD has a clear genetic underpinning and hundreds of genes, with varying penetrance, have been implicated in its aetiology. Here I use the model organism C. elegans as an experimental platform to investigate the effect of genetic mutation on social behaviour.
To do this I utilised a social paradigm in C. elegans that is based on observing a complex, sensory-integrative, food leaving behaviour. Adult worms increasingly leave an otherwise replete food source as the number of progeny populating the environment increases. This behaviour is mediated by a progeny-derived social cue and hence represent an inter-organismal social interaction. In this thesis I first designed a bioinformatic pipeline to filter high risk ASD-associated genes to select those that could be investigated using the progeny-induced food leaving assay. I identified several candidate human genes by defining C. elegans orthologues which when mutated result in selective deficits in social behaviour. This work highlights that genetic determinants within synaptic, cell signalling, epigenetic modification and phospholipid metabolism functional domains have a role in the co-ordination of C. elegans social behaviour. Using a null mutant, I show that C. elegans social behaviour is dependent on the nlg-1 gene. I refine this approach by generating a mutation in C. elegans which is synonymous to a highly penetrant ASD-associated variant identified in humans. In doing this I used and optimised a CRISPR/Cas9 technique to precisely edit C. elegans genes.
Overall, the combined use of social behaviour analysis and genetic intervention in C. elegans provides a useful model to investigate the genetic determinants of autism. ASD is a complex disorder in which disruption within the biological system can influence different levels of biological organisation. Therefore, this thesis provides an avenue for future research to probe the effect of genetic disruption at different levels of the biological system to further understand the emergence of disrupted social behaviour.

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Identifiers

ORCID for Linda Holden-Dye: orcid.org/0000-0002-9704-1217

ORCID for Vincent O'connor: orcid.org/0000-0003-3185-5709

ORCID for James Dillon: orcid.org/0000-0003-3244-7483

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