Mechanisms of proliferation-independent mutation

Introduction

DNA damage contributes to the ageing of tissues and causes mutations that drive cancer. However, the molecular mechanisms underlying many mutational processes are not understood, and neither is how much they contribute to disease. With a powerful new technology, I propose to close these major gaps for common "clock" mutations of unknown origin.

Background

The recent genome sequencing revolution has revealed unexpected diversity in mutational patterns. One pattern in particular is intriguing as it behaves as a molecular "clock": the number of mutations increases over time and correlates with age.

Although the textbook view of mutagenesis is that cell division is required to convert DNA damage into point mutations, surprisingly, non-dividing cells like neurons also accumulate "clock" mutations as a function of time. This indicates that "clock" mutations arise without genome replication.

Research Questions

Understanding how cells mutate independently of proliferation—and thus challenging the current paradigm of mutagenesis—is a fundamental question that has been hindered because assays to measure mutation require cell division.

Excitingly, I have overcome this major obstacle by establishing a powerful strategy to sensitively detect mutations in single cells, genome-wide. My group will combine this approach with targeted genetic manipulations in cells and mice to answer two central questions:

1. How do cells mutate independently of proliferation?
2. What drives these mutations in tissues?

Methodology

My novel insights into endogenous DNA damage from mouse genetics and genomics, combined with the innovative sequencing strategy that I have established, uniquely position me to answer these long-standing questions.

Impact

Together, the work proposed here will reveal the molecular mechanism(s) underlying the most common mutational process in humans: "clock" mutation. The methods, data, and insights from these groundbreaking studies will directly impact cancer research and uncover novel sources of DNA damage during aging.