Somatic mutation rates scale with lifespan across mammals.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Influence of dust loading on the alpha-particle energy resolution of continuous air monitors for thin deposits of radioactive aerosols.

Alpha-particle continuous air monitors must sometimes be operated in dusty environments where significant dust loading of the filter can be anticipated. It is important to understand how this dust loading affects the response of the continuous air monitors. Not only must a filter be changed if there is a reduction in airflow, but a change may be necessary if the energy resolution deteriorates and the continuous air monitor loses sensitivity and specificity for the radioactive aerosols of interest. A series of experiments were conducted to investigate alpha-particle energy resolution of continuous air monitor filters, particularly under dust loading conditions. Aerosol particles of various sizes were tagged with radon decay products to serve as surrogates for radioactive aerosols of interest such as plutonium or uranium. While the size of radioactive aerosols, filter type, and dust type affected the energy resolution, the thickness of an underlying (nonradioactive) dust layer did not show significant effect for the materials studied and a loading range of 0.01-10 mg x cm(-2). Our results indicate that it is possible for continuous air monitors to detect the release of radioactive aerosols with little deterioration in energy resolution under conditions of significant dust loading provided that the deposited layer of radioactive aerosols remains thin (< or = 0.1 mg x cm(-2)).