Balancing disease and productivity: Functional analysis of a Bardet Biedl Syndrome-associated mutation in livestock at the University of Edinburgh

Supervisors: Tom Burdon, Megan Davey and Denis Headon

Closing Date:  5th January 2022

Ciliopathies are human diseases caused by disruption of motile and non-motile primary cilia, and affect a range of organ systems leading to polycystic kidney disease, retinal degeneration, obesity, skeletal deformities and brain abnormalities 1. The BBSome is a multi-protein complex and essential centrosomal component regulating cilia function, which when dysregulated causes a number of related diseases (Bardet Biedl Syndromes) also characterised by obesity, blindness, polydactyly and kidney failure. Interestingly, as well as these human disorders, abnormal ciliogenesis has also been shown to underlie production traits in livestock. This project will investigate the function of the BBSome BBS9 protein and its contribution to a production trait associated with a naturally occurring genetic mutation in pigs.

The mutation, a 212kb deletion, truncates the pig BBS9 protein and interferes with expression of a neighbouring gene, BMPER 2.  Intriguingly, heterozygote pigs exhibit increased feed intake and growth, whilst the homozygote animals are not viable. These conflicting characteristics are typical of a “balancing allele” where positive traits linked to heterozygosity are selected in the population, but counterbalanced by losses due to lethality associated with homozygosity.

The aim of this project is to investigate BBS9 protein function, and how it affects cilia and signalling within the context of the balancing mutation. CRISPR/Cas9 editing of pig and human pluripotent stem cells (PSCs) 3 will be used to understand how BBS9 (and BMPER) mutations affect the BBSome, cilium structure, cell signalling, cell growth and developmental potential. This project provides an opportunity to unpick the good and bad characteristics of the balancing allele and is in line with the “One medicine” concept, potentially informing therapy for treating human disease and instruction of novel strategies to improve livestock productivity.

References

1. Reiter, J. F. & Leroux, M. R. Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18, 533–547 (2017). https://pubmed.ncbi.nlm.nih.gov/28698599/

1. Derks, M. F. L. et al. Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome. PLoS Genet. 14, e1007661 (2018). https://pubmed.ncbi.nlm.nih.gov/30231021/

1. Meek, S. et al. Stem cell-derived macrophages as a new platform for studying host-pathogen interactions in livestock. bioRxiv 2021.09.10.459580 (2021). doi:10.1101/2021.09.10.459580

We would encourage applicants to list up to three projects of interest (ranked 1st, 2nd and 3rd choice) from those listed with a closing date of 5th January 2022 at https://www.ed.ac.uk/roslin/work-study/opportunities/studentships

This opportunity is open to UK and international students and provides funding to cover stipend, tuition fees and consumable/travel costs.  Applications including a statement of interest and full CV with names and addresses (including email addresses) of two academic referees, should be emailed to [email protected].

When applying for the studentship please state clearly the project title/s and the supervisor/s in your covering letter.

A webinar will be held on Tuesday 14th December at 13.00hrs (UK time) to assist you in the application process and tell you a little more about studying for a PhD with us.  It will also give you an opportunity to ask any questions you may have.  If interested in joining us please send your name and email address to [email protected]by Friday 10th December and we will send you a link to the on line meeting

ALL APPLICATION PROCEDURES MUST BE COMPLETED BY THE CLOSING DATE 5th JANUARY 2022