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Approved Research

Characterising the causes and impacts of rare and structural variation on human traits

Principal Investigator: Dr Anjali Hinch
Approved Research ID: 100469
Approval date: March 30th 2023

Lay summary

The chromosomes we inherit from our parents are not exact copies but mosaics of their chromosomes. These mosaics are created during formation of eggs and sperm when cells cut chromosomes up and re-attach them, sometimes in new combinations, in a process known as recombination. In addition, we carry of the order of ~70 new DNA mutations - changes to our genetic code compared to the DNA inherited from our parents.  These mutations can be simple single-base-pair changes or large structural rearrangements of DNA. Together with recombination, mutations ultimately create the genetic diversity we observe in populations world-wide.


This genetic diversity is needed for populations to withstand pathogens and other diseases. However, mutations can themselves be causes of disease.  We plan to use the wealth of data generated by the UK Biobank to understand the processes of mutagenesis and their consequences for human phenotypes.  We are particularly interested in mutations that occur near DNA breaks, which are an essential part of the process of recombination but can also occur by accident leading to repair-related mutations. A major goal of our work is to understand the mechanisms that generate large structural changes in the genome, many of which are predicted to cause human disease through changes in or loss of gene function. We will link this genetic variation to phenotypes that show significant variation in human populations and to infection outcomes, and we will generate new analysis methods to support this.  Many of the biological processes that underpin mutagenesis in the germline also operate during normal cell division within the life of an individual, and so have implications for genetic diseases such as cancers. We will extend our findings to cancer-related phenotypes, such as type of cancer and age at diagnosis. Ultimately, we hope this work will generate new insight into the biological processes underpinning infection and DNA repair-related diseases, with the potential to improve interventions in future.