Every time a child inherits DNA from their parents, two processes—mutation and recombination—scramble and alter the genetic code, and this project will watch those changes happen in real time inside individual sperm cells. We know a great deal about what human DNA looks like—its patterns and variations—but surprisingly little about the *how* and *why* of the underlying processes that create that variation. Mutation and recombination are the engines of all genetic diversity, yet their dynamics remain poorly understood. This research fills that gap by directly observing single DNA molecules as they undergo recombination, revealing where and why these events occur, what happens to the DNA during the process, and whether recombination itself triggers mutations. If successful, this work will clarify the fundamental origins of human genetic variation. That understanding could improve genetic counselling for inherited conditions, identify factors that predispose people to infertility or chromosome abnormalities, and produce new methods for detecting environmental influences on mutation rates. The project is primarily curiosity-driven fundamental science, but deeper knowledge of how DNA breaks and repairs itself has historically underpinned breakthroughs in cancer biology, reproductive medicine, and diagnostics for inherited anaemia.
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All normal and pathological variation in human DNA arises from two processes that operate when DNA is transmitted from parent to child. The first is mutation, causing changes in the sequence of DNA either at a single base or at the larger scale of deletion or insertion of pieces of DNA. The second is recombination between chromosomes, a process operating during egg and sperm production that reshuffles DNA diversity into the endless new combinations seen in human populations. Recombination can also cause mutation when chromosomes pair up incorrectly, leading to duplications and deletions which often have disease consequences. Thanks to genomics programmes, we know a lot about patterns of human DNA diversity. In contrast, we still understand little about the dynamics and processes of mutation and recombination, and how resulting genetic changes are moulded, by for example natural selection, into the patterns of diversity seen in human populations. We are addressing this problem by analysing single DNA molecules, particularly in sperm, to gain direct insights into the types and rates of change going on within our DNA. We will look at DNA as it goes through the recombination process to learn more about why recombination events occur where they do in human chromosomes, what happens to DNA during recombination, and whether there is a link between recombination and mutation. We will also look at how recombination can lead to changes in gene copy number in human DNA, with particular focus on very common types of mutation that result in inherited anaemia. We are also developing new methods for investigating how pieces of DNA can be spontaneously lost, how jumping ?parasitic? DNA moves around the human genome, and how fundamental changes to the DNA sequence itself can arise. This ambitious research will help to understand the basis of human genetic variation and how pathological changes arise in our DNA, with potential applied aspects ranging from assisting in genetic counselling, through identifying factors that predispose to infertility and chromosome abnormalities, to producing new methods for identifying environmental factors that might influence human mutation. This work will interface with other research on human DNA instability in the Leicester MRC Co-operative Group on Human Genetics, and will be presented to lay audiences through a programme of talks to the media, schools and the general public, where we use aspects of our work to inform on basic issues in human genetics.
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