Our Research

Recombination and Mutation

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 discovered that our cells make an unexpectedly large number of errors in this process leading to changes in DNA (mutations).

We are interested in the mechanisms underlying recombination and mutagenesis. They are complex and dynamic, involving the interplay of numerous proteins. We perform a range of experimental assays, including CRISPR-Cas9 mediated genome-editing, to learn how these proteins interact with the genome. We then use machine learning and other statistical techniques to unravel their elegant choreography. 

We also work to understand the consequences of germline mutations on our health using statistical analyses of human genetic and disease datasets.

See our publications here. 

 Mechanisms underlying meiotic recombination 

For chromosomes to exchange DNA and reassemble correctly, they must find each other and pair up. This is more difficult than it sounds as our genomes are large and the chromosomes in each pair have genetic differences from each other.

It is achieved through dozens of sites on each chromosome working both individually and collaboratively to find their counterparts, a bit like a flotilla of ships searching for a way home after being blown off-course and separated by a storm. We have shown that essentially all of these sites are determined by the gene PRDM9, one of the fastest evolving genes in the genome. It turns out that it has a double role: in addition to initiating the search, it helps locate the destination, like a flag on an island fortress signalling to ships that they are approaching friendly shores. This role makes it the only known speciation gene in mammals.

We research the mechanisms underlying the search for the 'homologous chromosome' and the repair of DNA required for successful pairing and meiosis. For further details, please see Hinch et al Nature 2011, Davies et al Nature 2016, Hinch et al Science 2019, and Hinch et al Molecular Cell 2020. 

The nature, mechanisms and impacts of germline mutations

Creation of eggs and sperm requires successful pairing of chromosomes (see above). This is achieved through repair of hundreds of DNA breaks, which are programmed (i.e., these DNA breaks are induced deliberately unlike many kinds of DNA damage that are due to environmental factors).

We investigate how often cells make mistakes while repairing these breaks leading to mutations. We research the nature and types of these mutations and the underlying biochemical processes that give rise to them.

We also investigate the impacts of de novo mutations on human health. For further details, see Hinch et al Science 2023.