DEVELOPING TARGETED SINGLE CELL SEQUENCING TO RAPIDLY CHARACTERISE THE T-CELL RECEPTOR REPERTOIRE ASSOCIATED WITH VIRUS RESPONSE IN DOMESTICATED PIGS

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

Sequencing technologies have enabled us to explore the variation within human and animal populations at unprecedented scale. However, while it is now possible to routinely sequence hundreds of mammalian genomes, a huge amount of genetic variation within mammalian populations remains unexplored by focusing only upon DNA that is encoded in the germline.
The T-cell is the Swiss army knife of the immune system; orchestrating immune responses to a variety of threats - from infections to cancer. Each T-cell expresses a receptor (TCR) that can see hundreds of targets, and mammals are each born with a fixed TCR repertoire that is quasi-randomly generated in utero. It is becoming increasingly obvious that understanding how the TCR repertoire - and the "extended genome" it represents - is formed and how it varies between individuals is critical for fully understanding human and animal health.
The TCR itself is encoded by a pair of loci formed by a rearrangement event that occurs during development. Both loci are located on separate chromosomes. As a result it is currently not possible to unambiguously pair these two chains, meaning it is currently impossible to accurately dissect the TCR repertoire at scale. This is a serious limitation as it means that we have little idea of how a TCR repertoire is structured in most mammals; limiting our ability to develop vaccines to key diseases that can have an enormous effect on the health, welfare and productivity of livestock.
This project will put you at the forefront of exploration to help us understand how the TCR repertoire is
constructed in pigs and how it can be utilised to enable protection against key pathogens. This project will combine cutting edge single cell sequencing and bioinformatics method development to dissect the TCR repertoire of pigs.
Working with world-class researchers at the Universities of Cardiff and Exeter, you will design microfluidic devices to capture individual cells prior to sequencing. You will then improve existing methodologies to extract nucleic acids, generate high throughput sequencing libraries, comparing these approaches using cutting-edge bioinformatics, developing a bioinformatics framework to characterise TCR repertoires. Using this framework, you will then characterise TCR repertoires from multiple pigs to examine how the repertoire differs between individuals that respond differently to viral disease, revolutionising our understanding of the immune system of this organism and demonstrating a ground-breaking new large mammalian model for the study of the immune system and human/animal disease.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M009122/1 01/10/2015 30/09/2023
1800166 Studentship BB/M009122/1 01/10/2016 01/04/2021 Joel Southgate
 
Description Current informatics approaches to influenza whole-genome sequencing datasets are often not sufficiently robust for routine public health applications. After identification of this issue, software has been developed to improve the pipelines used.
Exploitation Route The software developed can be used in epidemiological data processing pipelines.
Sectors Healthcare

 
Description Software and bioinformatics approaches for application to Influenza WGS data have been developed, and will be utilized by collaborators at Public Health Wales, providing impact for public health applications.
First Year Of Impact 2018
Sector Healthcare
Impact Types Policy & public services