Causes and consequence of short tandem repeat instability

NIEDUSZYNSKI_E23DTP2

Expansions of short DNA repeats are responsible for almost 50 human diseases, including Huntington’s and Alzheimer’s and many important traits such as environmental adaptation in fish and Drosophila, gene expression variation in plants and animals, and antimicrobial drug resistance.

Repeat expansion is likely to be a consequence of impaired DNA replication, yet the underlying mechanism is poorly understood. We have recently developed a novel genomic technology that can detect impaired replication – this will allow us to discover pathways that the cell uses to protect the genome.

We offer a highly collaborative multi-disciplinary PhD between the Nieduszynski (DNA replication; technology development), Ding (nucleic acid structure) and Haerty (bioinformatics) groups. The main aim of the project is to determine whether short DNA repeats form stable secondary structures that impede replication fork progression and drive genome instability.

The student will work in a rapidly developing field and gain a unique expertise in nanopore single molecule sequencing, technology development and computational biology – skills that are in high demand for modern biological research in both academia and industry.

The project will be conducted at the Earlham Institute and John Innes Centre, BBSRC-supported, world-leading research centres in genomics and plant and microbial science. The student will have access to training and career development opportunities within the Institutes and on the Norwich Research Park as part of the Norwich Biosciences Doctoral Training Partnership.

References

Müller, C. A. et al. Capturing the dynamics of genome replication on individual ultra-long nanopore sequence reads. Nat Methods 16, 429–436 (2019).

Boemo, M. A. DNAscent v2: detecting replication forks in nanopore sequencing data with deep learning. BMC Genomics 22, 430 (2021).

Gymrek, M., et al., Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet, 2016. 48(1): p. 22-9.