Context-dependent selection sculpts mutational landscapes in the normal lung

Just as organismal evolution is driven by environmental changes, somatic evolution is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices, or by extrinsic exposures. We present deep mutational profiling using duplex sequencing of over 390 samples of non-malignant lung tissue from 202 subjects, showing how aging, smoking and different anti-cancer therapies are associated with selection for particular mutations in normal lung tissue. Mutations within known cancer driver genes exhibit selection in the normal tissue that differs from that for lung cancers, with a substantially expanded spectrum of sites under selection. Multiregional profiling of mutational landscapes reveals convergent evolution within each individual's lung. Understanding the forces controlling clonal selection as we age and due to lifetime exposures could be critical for controlling multiple diseases of old age.