Identification and functional analysis of long noncoding RNAs involved in cognitive function

This project will combine human genetic data with rodent models to investigate the molecular basis of cognitive abilities. Genome-wide association studies (GWAS) have identified many human genomic regions (called haplotype blocks) that are linked to cognitive traits such as memory, attention, intelligence, problem-solving and reasoning. These regions generally lack sequences that code for proteins, but most express long noncoding RNAs (lncRNAs). These lncRNA molecules are emerging as master organisers of the epigenetic regulation of gene expression in cell and developmental biology and therefore are prime candidates for the mechanistic basis of learning, memory and cognition. Studying the link between lncRNAs and cognitive traits is challenging in humans due to ethical and technical limitations; however, our preliminary analyses indicate that many of these lncRNA have orthologs (equivalents) in rodents, offering an exciting new avenue to studying the causal link between molecular factors and cognitive processes.

This project will identify and characterise the rat orthologs of human cognition-associated lncRNAs by synteny mapping (equivalent positions in genomes), targeted RNA sequencing, and spatial transcriptomics. We will then investigate their role in cognitive functions by combining knockdown of brain lncRNAs with comprehensive cognitive behavioural phenotyping paired with real-time read out of neuronal activity.

The supervisory team combines the world-leading knowledge of lncRNA biology pioneered by John Mattick with the extensive expertise of Kelly Clemens in behavioural neuroscience. The project will link human genetic data for the first time to molecular pathways involved in cognition, identify lncRNAs involved, and ultimately inform our understanding of the genetic basis of cognition.

This project will create new knowledge in four ways. It will: (i) provide an extensive open-access library of lncRNA homologs between human and rodents, a significant advance permitting wider functional analysis of the role lncRNAs play in the brain that is not possible through analysis of post-mortem human tissue; (ii) create the first publicly available spatial mapping of lncRNAs and their co-localisation across the rat brain; (iii) offer the first comprehensive analysis and demonstration of the association between lncRNAs and cognitive processes, providing a causal link through knockdown studies; and (iv) establish a link between lncRNAs and neuronal activity in vivo, permitting mechanistic connection between lncRNAs and cognitive functions. The impacts of the project extend well beyond these immediate objectives, as it provides an exemplar and a template for investigating the roles of lncRNAs in the wide range of complex traits that have been mapped by genome-wide association studies. It will provide a window to new discoveries not only in neuroscience, but also the molecular aetiology of quantitative traits in mammals more broadly.

Scholarship