Research Fellows Directory
Sir Alec Jeffreys FRS
University of Leicester
My research is aimed at understanding patterns of human DNA variation and how these are shaped by underlying processes of genome instability. This fundamental science underpins the analysis of variation in the human genome and the understanding of the origins of pathological DNA rearrangements. Our research addresses both of the fundamental processes that generate DNA diversity, namely mutation that creates genetic novelty, plus meiotic crossing over and other modes of recombination between paternal and maternal chromosomes that reshuffles patterns of DNA variation between generations.
A major focus continues to be the PRDM9 gene, shown by us and others to be the key regulator of human crossover, playing a major role in determining where crossovers are located in the human genome. Remarkably, different individuals can show completely different patterns of crossover depending on which PRDM9 variants they carry, demonstrating that the key process of meiotic crossing over is extraordinarily unstable and dynamic in human populations. We have shown that PRDM9 also affects aspects of genome instability, including two large-scale pathological DNA rearrangements as well as tandem repeat DNA instability. The key domain in PRDM9 that influences crossover and instability is itself encoded by tandem repeat DNA. We have therefore developed methods to detect new mutation events in the PRDM9 coding sequence itself to understand how this protein evolves. We find that recombination plays a major role in generating new PRDM9 variants that in turn specify new hotspots in the genome. Surprisingly, evidence to date suggests that this instability is not regulated by PRDM9 itself, pointing perhaps to the existence of another major regulator of recombination in humans. We are now integrating this information with population genetics to gain a full understanding of how hotspots rapidly appear and disappear in the human genome.