The message in the noise: characterisation and quantification of noise in alternative splicing in the brain.

Nearly all human genes undergo alternative splicing (AS) - the process by which different transcripts are generated from a single gene. 

AS can generate transcripts with strikingly different functions, either due to truncation of the protein coding sequence or alteration of functional domains. AS is highly regulated during development and across tissues, its disruption being a hallmark of cancer.

We use long-read sequencing to study AS across scales - from single cells to tissues - identifying thousands of novel transcripts. In most cases, only one or two dominant transcripts represent the bulk of the expression arising from a gene, with the remaining transcripts lowly expressed and considered to be ‘noise’.

The characterisation of AS diversity across cells in steady state and during differentiation can provide novel insights into the regulation of this fundamental process. Specifically, we aim to answer whether individual cells exhibit the same distribution of transcript expression as seen in bulk and how often functional switching - from dominant to noisy transcript - occurs in cell differentiation.

We offer a highly collaborative PhD project between the Haerty (bioinformatics) and Macaulay (molecular biology, technology development) groups.

The student will work in a rapidly developing field and gain unique expertise in experimental (cell culture, single cell biology) and computational (bioinformatics, transcriptomics, proteomic) biology. 

This project strongly aligns with our BBSRC-funded Institute Strategic Programme, Cellular Genomics, providing access to resources, mentorship, and expertise.
The project will be conducted at the Earlham Institute, a UKRI-BBSRC research centre of excellence for bioinformatics and sequencing technology development, in close collaboration with scientists at the University of Oxford and Wellcome Sanger Institute. 

The student will benefit from access to training and career development opportunities at the Institute and from our partners on the Norwich Research Park.
 

Further Reading:

• Clark, M.B., Wrzesinski, T., Garcia, A.B. et al. Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain. Molecular Psychiatry. http://dx.doi.org/10.1038/s41380-019-0583-
• Wright, D.J., Hall, N.A.L., Irish, N. et al. Correction to: Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes. BMC Genomics 23: 79
• Mincarelli, L., Uzun, V., Wright, D. et al. Single-cell gene and isoform expression analysis reveals signatures of ageing in haematopoietic stem and progenitor cells. Communications Biology 6: 558
• Gupta, I., Collier, P., Haase, B. et al. Single-cell isoform RNA sequencing characterizes isoforms in thousands of cerebellar cells. Nature Biotechnology. http://dx.doi.org/10.1038/nbt.4259

Further Information:

Application deadline: Monday 20 November 2023 (23:59 i.e.,midnight).

Shortlisted applicants will be interviewed on 23, 24 or 25 January 2024.

Visit the NRPDTP website for further information on eligibility and how to apply.

Our partners value diverse and inclusive work environments that are positive and supportive. Students are selected for admission without regard to gender, marital or civil partnership status, disability, race, nationality, ethnic origin, religion or belief, sexual orientation, age or social background.

This project is awarded with a 4-year Norwich Research Park Biosciences Doctoral Training Partnership (NRPDTP) PhD studentship.

The studentship includes payment of tuition fees (directly to the University), a stipend to cover living expenses (2023/4 stipend rate: £18,622), and a Research Training Support Grant of £5,000pa for each year of the studentship.

Entry requirements:
At least UK equivalence Bachelors (Honours) 2:1 or UK equivalence Master's degree. English Language requirement (Faculty of Science equivalent: IELTS 6.5 overall, 6 in each category).