Prioritising and validating causal variants underlying important cattle phenotypes at the University of Edinbrugh

Supervisors: James Prendergast, Simon Lillico and Tom Burdon

Closing Date:  5th January 2022

Many genomic loci linked to important disease, production and welfare phenotypes have been identified in cattle, but in almost all cases the precise genetic change underlying the phenotype is unknown. This is a major barrier to improving livestock through approaches such as genome editing, which rely on knowing what specific variants to edit. The aim of this project would be to use statistical and bioinformatics approaches to fine-map the variants and genes underlying thousands of cattle loci. The student will then validate via CRISPR-Cas9 editing the impacts of key variants in the lab. This project will consequently offer the student the rare opportunity to develop a combination of highly sought-after bioinformatics, statistics and genome editing skills.

Over 160,000 genomic loci in the cattle genome have been associated with traits ranging from milk fat yield to calving ease and response to tuberculosis infection. Due to the resolution of genetic association studies, in almost all cases the precise genetic change driving these differences in phenotypes between animals is unclear. However, previous work in humans has shown how it is possible to use bioinformatics and statistical approaches to prioritise underlying variants (for example see https://www.nature.com/articles/s41588-021-00945-5). Our labs are also generating unique cattle datasets on chromatin/epigenetic data and the location of regulatory variants using massively parallel reporter assays. The aim of this project will be to combine these statistical approaches and cattle datasets to fine-map variants across the loci linked to cattle traits. The student will then have the opportunity to validate examples in the lab via using CRISPR-cas9 approaches to introduce key changes into cells and test their impact on intermediate phenotypes such as gene expression. 

Mountjoy, E., Schmidt, E.M., Carmona, M. et al. An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00945-5

Broekema R. V., Bakker O. B. and Jonkers I. H. A practical view of fine-mapping and gene prioritization in the post-genome-wide association era. Open Biol. (2020). http://doi.org/10.1098/rsob.190221

Proudfoot, C., McFarlane, G., Whitelaw, B., Lillico, S. Livestock breeding for the 21st century: the promise of the editing revolution. Front. Agr. Sci. Eng., (2020). https://doi.org/10.15302/J-FASE-2019304

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