Abstract

Somatic mutations accumulate in health cells throughout life. They underpin the development of cancer and have been speculated to contribute to ageing. Directly studying these mutations in normal tissues has been challenging due to the difficulty of detecting mutations present in single cells or small clones in a tissue. Recent technical advances are beginning to enable the study of somatic mutation in normal tissues, revealing how our cells accumulate mutations at different rates and how clonal expansions of mutant cells can colonise tissues. Yet relatively little is known about how these processes operate in non-human species. We performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. This comparative analysis of somatic mutagenesis sheds light on the diversity of mutagenic processes across species, and on long-standing questions regarding the evolution of somatic mutation rates and their role in cancer and ageing. We are now developing duplex sequencing methods that will enable us to study somatic evolution across any cell type in any species across the tree of life (including plants). This will enable insights into the diversity of somatic mutational processes across species and their role in evolution, disease and ageing.

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