The long and the short of human non-crossover recombination

Dr C A May, Dr James Higgins

Applications accepted all year round
Self-Funded PhD Students Only

About the Project

Meiotic recombination plays a central role in generating DNA diversity, which in turn provides the capacity for a species to evolve. In humans, most attention has been paid to characterising meiotic crossover (CO) as this is essential for the correct segregation of homologous chromosomes and therefore avoidance of aneuploidy; it is also readily detectable. At Leicester we have pioneered the development of sperm DNA CO analysis to characterise recombination hotspots at the highest possible resolution and to establish that both cis- (local SNP variation) and trans-acting factors (PRDM9 zinc finger array type) can influence the distribution and frequency amongst different men [1,2]. We have also used similar sperm DNA approaches to provide real insight into human de novo non-crossover (NCO), that is short non-reciprocal meiotic recombination events occurring at the centre of crossover hotspots, typically only ~100 bp long [3,4]. Whilst highly informative, our approaches are not, however, readily scalable to the whole genome.

The beginning of this year, saw the publication of the first complete human recombination maps using whole genome sequencing of families from Iceland [5]. This genome-wide picture was able to reveal two interesting findings with respect to human NCO. Firstly, that unlike CO, there is no suppression of NCO close to the centromere and secondly that there are in fact two classes of NCO that differ with respect to their length, the more abundant short NCOs we were able to characterise, and the less common extended NCOs which are several kilobases in length.

In this project you will aim to examine NCOs that are not associated with CO, especially the new class of extended NCOs. You will leverage data from the Iceland study [5] to identify suitable regions of the genome and develop new sperm DNA assays capable of detecting these extended events. You will use our sperm DNA panel consisting of over 200 men of both North European and Sub-Saharan African descent that has been used to characterize over 30 different recombination hotspots dotted throughout our genome. You will adapt our existing approach to use long-range nanopore sequencing to characterise de novo events. You will then examine how local sequence variation and established PRDM9 genotype influence extended NCO and make direct comparisons with existing short NCO data from the same men. This sperm DNA approach will allow you to screen hundreds of thousands of potential offspring from individual men to quantify extended NCOs with great accuracy and investigate subtle but significant phenomena such as transmission distortion that leads to meiotic drive [6]. This approach will provide an unprecedented level of resolution and therefore insight that is impossible to achieve by family analysis alone.

Training opportunities:

Both the University of Leicester’s Doctoral College and College of Life Science offer a variety of training courses to support your development into an independent researcher and to supplement the in-house training for the wet lab techniques mentioned above. The Division of Genetics & Genome Biology has an active research seminar programme that will broaden your scientific perspective. You will also be encouraged to attend/present at relevant conference(s), e.g. annual British Meiosis Meeting, and publish your findings as appropriate.

Apply at:

https://le.ac.uk/study/research-degrees/research-subjects/genetics

PhD entry requirements:https://le.ac.uk/study/research-degrees/entry-reqs

Supervisor contact details:

Dr Celia May - cam5@le.ac.uk

Dr James Higgins - jh555@le.ac.uk