PhD project

Supervisor: Anjali Hinch

Overview

The chromosomes we inherit from our parents are not exact copies but mosaics of their chromosomes. These mosaics are created during the formation of eggs and sperm when cells cut chromosomes up and re-attach them, sometimes in new combinations (recombination). We have found that our cells make an unexpectedly large number of errors in this process leading to changes in DNA (mutations). Our DPhil project aims to answer fundamental questions on the nature of human de novo mutation and recombination, the mechanisms that generate them and their consequences on our health.

Our Research

We have discovered that a surprisingly large number of de novo mutations in humans stem from repair of DNA breaks induced by the meiotic recombination machinery. We inferred their underlying mechanisms and their impacts, which include a range of autosomal and X-linked disorders [Science, 2023].

We have done pioneering work on understanding how DNA changes take place in the germline. We showed that the landscape of recombination varies between individuals in different human populations, demonstrating the evolution of recombination in the human lineage [Hinch et al, Nature 2011]. PRDM9 is also the only known speciation gene in mammals, and our subsequent work characterised the molecular mechanisms underpinning its role in hybrid sterility [Davies et al, Nature 2016]. These discoveries opened up new research avenues, towards a mechanistic understanding of the underlying processes.

We developed a novel approach to DNA sequencing of single cells that allowed identification of key molecular factors that affect how DNA breaks are repaired in meiosis [Hinch et al, Science 2019]. Our specialised genome-wide experimental assays have since led to insights on the molecular drivers of DNA break repair in meiosis [Hinch et al, Mol Cell 2020].

Projects

We will aim to answer the following key questions:

• Do we vary in our propensity to acquire de novo mutations? If so, why?
• How do de novo mutations impact our health?
• What are the mechanisms underlying de novo mutations?

We take a data-driven approach to address these questions. Processes underlying de novo mutation and meiotic recombination are complex and dynamic, involving the interplay of numerous proteins. Our approach involves utilising large-scale genetic datasets such as the UK Biobank as well as performing a range of experimental assays including CRISPR-mediated genome-editing. We then use machine learning and other statistical techniques to characterise their interactions.

For further information and for the lab’s website see: https://germlinegenomics.web.ox.ac.uk/dphil-studentship

Keywords:

• Statistics, Bioinformatics, Biomedical Engineering, Biotechnology, Cell Biology / Development, Evolution, Genetics, Medical / Clinical Science, Molecular Biology, Obstetrics, Gynaecology & Reproduction

Publications:

• Hinch, R., Donnelly, P., Hinch, A.G. Meiotic DNA breaks drive multifaceted mutagenesis in the human gemline. Science (2023).
• Hinch, A.G., Becker, P. W., Li, T., Moralli, D., Zhang, G., et al. The configuration of RPA, RAD51 and DMC1 binding in meiosis reveals the nature of critical recombination intermediates. Molecular Cell.  (2020).
• Anjali G Hinch, Gang Zhang, Philipp W Becker, Daniela Moralli, Robert Hinch, et al. Factors influencing meiotic recombination revealed by whole-genome sequencing of single sperm. Science. Vol. 363, Issue 6433 (2019).
• Davies B, Hatton E, Altemose N, Hussin JG, Pratto F, Zhang G, Hinch AG, et al. Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice. Nature. 530, 171-176 (2016).
• Anjali G Hinch, Arti Tandon, Nick Patterson, Yunli Song, Nadin Rohland, et al. The landscape of recombination in African Americans. Nature. 2011; 476: 170-175.