Kennedy Trust Prize Studentships
Understand the genetics of inflammatory bowel disease using single-cell data
In recent years, genome-wide association studies (GWAS) have uncovered many hundreds of genetic variants that increase or decrease the risk of developing inflammatory diseases, such as inflammatory bowel disease (IBD). However, we know very little about the genes that these variants act on, and the elements of the immune system where these genes of active.
Linking risk variants to immune function is complicated by the sprawling nature of the immune system, which has a large (and unknown) number of cell types spread across every tissue in the body. However, new single-cell sequencing technologies allow us to take a snap-shot of the gene expression in all cells in tissue, which can allow us to generate detailed maps of the immune system in that tissue.
During this project, you will develop new computational tools to analyse both single-cell data and GWAS, in order to discover which cell types and immune functions IBD risk variants are impacting. Both single-cell and GWAS data are rich, complex and messy, and you will need to learn and develop new computational and statistical techniques for handling the uncertainty, confounding and size of these datasets.
As the project evolves, and you learn more about both genetics and single-cell sequencing, you will be able to decide the direction you wish to take your PhD in. You may wish to develop methods for analyzing single-cell epigenetic data, in order to tie genetic risk variants to specific epigenetic marks in specific cell types. You may instead wish to develop new techniques for understanding the variation in single-cell maps from person to person, and defining new IBD-related global phenotypes of the cellular immune map. Or you may wish to collaborate more closely with experimental scientists at the Kennedy Institute or the WIMM to generate new data, and dig deeper into the immune pathways that are active in the cell types you have discovered. Students applying for this project should be confident in their ability to drive their own research and decide on the biological questions they wish to answer.
This project will be based at Dr Jostins’ Statistical Genetics group at the Kennedy Institute, and will be co-supervised by Prof Simmons at the WIMM. During this project, you will collaborate with computational and statistical biologists at the Kennedy Institute, WIMM and Big Data Institute to develop new computational tools, and share them with the community. You will analyse both public data from large international consortia (like the Human Cell Atlas), as well as collaborating with other Simmons group members to analyse single-cell datasets specifically generated to study the biology of IBD.
Figure: An example of a single-cell immune map from peripheral blood, with IBD-GWAS-associated cells highlighted in red. Data processed in collaboration with Dr Steve Sansom’s group at the Kennedy.
- Jostins, Ripke, et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 491(7422):119–124.
- Muraro and Simmons (2016) An integrative analysis of gene expression and molecular interaction data to identify dys-regulated sub-networks in inflammatory bowel disease. BMC Bioinformatics. 17:42.
- Huang, Fang, Jostins, et al (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 547(7662):173-178.