The mechanism of recombination and its impacts on human mutation and disease

Meiotic recombination is essential for creation of haploid gametes. Errors in this process cause miscarriage, infertility, and developmental disorders.

Recombination proceeds via repair of programmed DNA breaks; however, the molecular mechanisms ensuring their repair are not well understood.

My work reveals that these breaks are a significant mutagenic force, leading to de novo mutations (DNMs) in 1 in 3 sperm and 1 in 13 eggs.

My proposed research will harness cutting-edge experiments in genetically-engineered mouse models to generate novel data and will further leverage existing population-scale human genetic and phenotypic data.

I will integrate these data through sophisticated statistical analyses to answer the following questions: - What are the properties, causes and impacts of recombination-associated mutations on human health? I will characterize these mutations comprehensively in humans and infer their molecular causes.

I will investigate their impact on common and rare diseases. - What is the mechanism of break repair in recombination?

I will build on my recent work and interrogate meiotic break repair through specialised experimental assays on key proteins in genetically-engineered mice. - What is the mechanism of mutagenesis?

I will characterize the impact of pathways that are identified above as causal by disrupting them in genetically-engineered mice.