During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The .

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.

Progression of chronic liver disease to hepatocellular carcinoma is caused by acquisition of somatic mutations affecting 20-30 cancer genes 1-8 . Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease 9-13 than normal liver [13][14][15][16] , enabling positive selection to shape the genomic landscape 9-13 . We analysed somatic mutations from 1590 genomes across 34 liver samples, including normal controls, alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD). Seven of the 29 patients with liver disease carried mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing insulin-mediated nuclear export of FOXO1. Strikingly, 6 of the 7 patients with FOXO1 S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to 9 distinct hepatocyte clones/patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes 17-19 , and GPAM, which produces storage triacylglycerol from free fatty acids 20,21 , also had significant excess of mutations. We again observed frequent convergent evolution: up to 14 independent clones/patient with CIDEB mutations and up to 7 clones/patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both ARLD and NAFLD, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and nonalcoholic fatty liver disease.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be 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 humans, although the relative contribution of each signature varied across species. Remarkably, 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 displaying a comparable association. Despite widely different life histories among the species surveyed, including ~30-fold variation in lifespan and ~40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of ~3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a determinant of lifespan.

Abstract. The EU FP7 Project MEGAPOLI: "Megacities: Emissions, urban, regional and Global Atmospheric POLlution and climate effects, and Integrated tools for assessment and mitigation" (http://megapoli. info) brings together leading European research groups, state-of-the-art scientific tools and key players from non-European countries to investigate the interactions among megacities, air quality and climate. MEGAPOLI bridges the spatial and temporal scales that connect local emissions, air quality and weather with global atmospheric chemistry and climate. The suggested concept of multi-scale integrated modelling of megacity impact on air quality and climate and vice versa is discussed in the paper. It requires considering different spatial and temporal dimensions: time scales from seconds and hours (to understand the interaction mechanisms) up to years and decades (to consider the climate effects); spatial resolutions: with model down-and up-scaling from street-to global-scale; and two-way interactions between meteorological and chemical processes.Published by Copernicus Publications.