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Biological Ageing

Our interests in biological ageing are more recent and stem from our research programme on reproductive health. Ovaries undergo an accelerated rate of ageing compared to other organs, and our work has demonstrated that the ability of oocytes to maintain DNA integrity is what determines reproductive lifespan and fertility in women. This provides a model system to study biological ageing more generally, the hallmark of which is deterioration of DNA damage response (DDR) processes and the accumulation of mutations. Our interests in this area broadly covers clonal haematopoiesis, where we demonstrated that mosaic loss of the Y chromosome in leuckocytes is a unique biomarker of DDR, and the identification of germline cancer susceptibility loci

The papers highlighted below are selected from ~180 published research articles. I am starred first or last author on all papers unless otherwise stated, but all research was conducted in a multi-disciplinary, collaborative team environment across multiple institutions.

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Selected publications

1 / Stankovic et al, ‘Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring' Nature (In Press)

This was the first paper to demonstrate female mutation rate has a heritable genetic component, and that maternal genetic susceptibility to premature ovarian ageing increases de novo mutation rate in offspring. (link)

2 / Liu et al, ‘Genetic drivers and cellular selection of female mosaic X chromosome loss'
Nature (2024)

This was the first large-scale study to characterise the prevalence, genetic determinants and clinical consequences of mosaic X chromosome loss in women. (link)

3 / Brown et al, ‘Shared and distinct genetic etiologies for different types of clonal hematopoiesis
Nature Communications (2023)

This work demonstrates that different forms of clonal haematopoiesis all share a common genetic origin and biological basis. We use this shared biological basis to leverage identification of novel susceptibility genes for haematological cancer. (link)

4 / Zhao et al, ‘GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health' 
Nature Communications (2021)

Identifies GIGYF1 loss of function associated with a ~6 fold increased risk of both T2D and mosaic Y chromosome loss (the most common form of clonal haematopoiesis), connecting these two phenotypes to a shared biological mechanism of impaired IGF1 signalling. (link)

5 / Thompson et al, ‘Genetic predisposition to mosaic Y chromosome loss in blood’ ​Nature (2019)

Here we provide the first empirical evidence for the 'common soil' hypothesis linking clonal haematopoiesis to risk of non-haematological diseases. This work suggests that variation in DNA damage response mechanisms independently influences clonal haematopoiesis and diseases such as diabetes and cancer, rather than a direct effect of somatically acquired mutations in white blood cells on biological systems. (link)

6 / Wright et al, ‘Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility' ​Nature Genetics (2017)

This work was the first to suggest that mosaic Y chromosome loss (the most common form of clonal haematopoiesis) might serve as a unique biomarker of variation in DNA damage response (DDR) processes that can be measured at population scale. (link)

7 / Day et al, 'Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair’ ​Nature Genetics (2015)

This work, building on our previous observations, was the first to demonstrate that DDR is the major biological pathway governing variation in ovarian ageing. It also demonstrates that variation in ovarian ageing causally increases risk of hormone sensitive cancers. (link)

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