De novo mutations and human disease: the role of sex, age and selfishness

Because mutations are at the origin of all genetic variations, understanding the factors that influence the rate at which they occur in our genome is crucial to the study of evolution and disease. Over the last decade, thanks to the systematic implementation of Next-Generation Sequencing, it has become apparent that de novo mutations (DNMs) are an important contributor to human disease, causing developmental disorders in >1:300 births. While it is widely thought that DNMs occur randomly as DNA copy-errors during spermatogenesis, we have challenged this assumption by showing that so-called ‘selfish’ mutations are able to hijack spermatogonial stem cell homeostasis, leading to their preferential transmission to the next-generation – where they cause severe disorders associated with strong paternal age effects.

In this presentation I will summarise our current understanding of DNMs in humans, the impact of advanced paternal age and their importance for human disease. I will then describe the findings that have led to the discovery of the ‘selfish selection’ process in human testes and propose that this mechanism contributes to genome heterogeneity and to the mutational burden associated with complex disorders.

After an undergraduate degree in Engineering (Agronomy) at the Université Libre de Bruxelles (Belgium), Anne Goriely obtained a PhD studying the development of the nervous system of the Drosophila embryo. She spent 4 years in New York at Cornell Medical School and Rockefeller University, before moving to the UK to work on the nervous system development of the chick embryo. In 2000 she joined the MRC Weatherall Institute of Molecular Medicine (University of Oxford) to study the origin of rare human developmental disorders associated with paternal age effects.

She is currently Professor of Human Genetics based at the MRC Weatherall Institute of Molecular Medicine in Oxford. Using a human genetics approach, her group’s main interests lie in elucidating the mechanisms by which we acquire new germline mutations and the implications of such processes in health and disease.