View Program - 63rd Annual Drosophila Research Conference

Glycosylation is one of the most common post-translational modifications. Defects in glycan biogenesis pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to rare, multi-systemic disorders classified as Congenital Disorders of Glycosylation (CDG). CDGs typically present with seizures, hypotonia, and developmental delay, but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes affect the phenotypes. I am employing evolutionary approaches to identify modifier genes of CDGs.
Evolutionary Rate Covariation (ERC) relies on the premise that proteins that interact physically or genetically or are functionally related coevolve at similar rates. ERC values are calculated using the correlation coefficient of evolutionary rates of gene pairs in a species tree. I used ERC values to look genome wide for coevolution with CDG genes, specifically genes involved in GPI anchor synthesis.
There was enriched coevolution among GPI anchor synthesis proteins. Unexpectedly, there was also enriched coevolution between GPI anchor synthesis proteins and proteins in other glycosylation pathways, suggesting more overlap between the different pathways than appreciated. Gene Ontology analysis of top genes that coevolve with GPI anchor synthesis proteins showed enrichment in genes involved in RNA modification and mitochondrial gene expression, suggesting interactions between these processes and GPI anchor synthesis. Gene pairs with the highest coevolutionary scores included both HTT and PIGG and ATG7 and PIGG. HTT and ATG7 are associated with neurodegenerative disorders possible indicating overlap in pathophysiology between the disorders.
To functionally validate these exciting signals, I screened for genetic interactions using the Drosophila eye. Many GPI anchor synthesis genes are necessary for Drosophila eye development and knockdown of these genes leads to rough and disorganized eyes. By creating double knockdowns of GPI anchor synthesis genes and coevolving genes in the Drosophila eye, I identified genetic interactions between genes previously thought to be unrelated. Many of the strongest evolutionary signals validate as interactors in this in vivo analysis. Coevolution is an underutilized tool for identifying interactions between unrelated proteins. These connections could lead to better understanding of glycosylation pathways and potential treatments for CDGs.

Coevolution is pervasive between unrelated glycosylation pathways and points to potential disease modifiers