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(A*STAR) Understanding cilia as a complex system: insights from molecular co-evolution


Project Description

The cilium is a complex structure built from hundreds of proteins which must function as a single unit within the cell. A particular type of specialised motile cilia are present during development. In the mouse these cilia are found at a structure called the node, whilst in zebrafish they are found in the Kupffer’s vesicle. Additional organisms have variations on these cilia. In many organisms these motile cilia are required for the formation of the left-right axis, which directs the correct placement of internal organs during development. Because species differences exist in the composition of these specialised cilia, we can model how evolutionary changes have impacted the structure and function of node cilia. It is our hypothesis that co-evolution of interacting proteins has resulted in species-specific alterations in the motile cilia required during development to establish the left-right axis.

We will use a combination of computational and wet-lab approaches in this multi-disciplinary project. The student will create and run their own pipeline for analysing the evolution of cilia proteins. This will involve using standard bioinformatics tools as well as writing their own scripts. Typically, the student will download data from a variety of databases, and will model both the cilia proteome for each species and the evolution of the whole system. Species differences will be analysed to predict if they alter protein interactions or functions within the cilium, and the impact of these alterations will be evaluated in the context of experimental data on cilia motility from different species. The student will test predicted alterations in cilia function through wet-lab experiments using zebrafish and mouse models. Cell culture assays will examine if sequence alterations found in cilia components allow for preserved or disrupted interactions of molecules within the cilium.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Xu X, Eales J, Akbarov A, Guo H, Becker L, Talavera D, Ashraf F, Nawaz J, Pramanik S, Bowes J, Jiang X, Dormer J, Denniff M, Antczak A, Szulinska M, Wise I, Prestes P, Bogdanski P, Zukowska-Szczechowska E, Berzuini C, Woolf A, Samani NJ, Charchar F, Tomaszewski M. (2018) Molecular mechanisms underlying associations identified in genome-wide studies of chronic kidney disease and its defining traits. Nat Commun.9(1):4800.

Kabir M, Wenlock S, Doig AJ, Hentges KE. The Essentiality Status of Mouse Duplicate Gene Pairs Correlates with Developmental Co-Expression Patterns. Sci Rep. 2019 Mar 1;9(1):3224. doi: 10.1038/s41598-019-39894-9.

Arnaiz O, Cohen J, Tassin AM, Koll F. Remodeling Cildb, a popular database for cilia and links for ciliopathies.
Cilia. 2014 2014 Nov 17;3:9. doi:10.1186/2046-2530-3-9. eCollection 2014.

Choksi SP, Babu D, Lau D, Yu X, Roy S. Systematic discovery of novel ciliary genes through functional genomics in the zebrafish. Development. 2014 Sep;141(17):3410-9.

Vij S, Rink JC, Ho HK, Babu D, Eitel M, Narasimhan V, Tiku V, Westbrook J, Schierwater B, Roy S. Evolutionarily ancient association of the FoxJ1 transcription factor with the motile ciliogenic program. PLoS Genet. 2012;8(11):e1003019. doi: 10.1371/journal.pgen.1003019.

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