Exploiting whole genome tagging of trypanosomes to identify new ciliopathy candidate genes in humans (360G-Wellcome-207282_Z_17_Z)

Ciliopathies are a range of human genetic diseases in which the normal functions of cilia/flagella are disrupted or prevented entirely. Ranging from mild to embryonically lethal, these diseases are often difficult to investigate as many do not appear to have clear links with particular genes or molecular mechanisms. This project aims to identify potential ciliopathy protein candidates and their corresponding human ciliary/flagellar genes by identifying previously unrecognised ciliary proteins conserved across eukaryotic life using the human parasite Trypanosoma brucei as a model organism. To start with, I plan to use TrypTag, a major new data resource, to identify which proteins localise to the flagellum and cilium. I shall then use bioinformatics tools and human genetic disease databases to identify which are conserved in humans not yet linked to a ciliopathy. Having excluded known ciliopathy-related proteins, I will then screen T. brucei deletion mutants for defects in flagellum growth, motility or flagellar beat. Those with defective phenotypes have the potential to be involved in human ciliopathies when mutated. The intended goal is to create a list of these novel candidate genes for involvement in human ciliopathies, with evidence for localisation and function in the flagellum/cilium of T. brucei.