All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.

Senescence is a nearly universal feature of multicellular organisms, and understanding why it occurs is a long-standing problem in biology. The two leading theories posit that aging is due to (i) pleiotropic genes with beneficial early-life effects but deleterious late-life effects (''antagonistic pleiotropy'') or (ii) mutations with purely deleterious late-life effects (''mutation accumulation''). Previous attempts to distinguish these theories have been inconclusive because of a lack of unambiguous, contrasting predictions. We conducted experiments with Drosophila based on recent population-genetic models that yield contrasting predictions. Genetic variation and inbreeding effects increased dramatically with age, as predicted by the mutation theory. This increase occurs because genes with deleterious effects with a late age of onset are unopposed by natural selection. Our findings provide the strongest support yet for the mutation theory.S enescence is the decline in organismal fitness and performance with age, and it is a nearly universal feature of multicellular organisms (1-5). Two evolutionary models predict that senescence will evolve because, with few exceptions, the force of natural selection declines with adult age (6). Both theories require the existence of genes with age-specific effects, but the kind of age-specific gene action that is required differs (6). According to the antagonistic pleiotropy (AP) theory, pleiotropic alleles that increase survival or reproduction early in life but decrease survival or reproduction late in life can accumulate in populations, because the selective advantage of the early benefits outweighs the late-life disadvantage. Under the mutation accumulation (MA) theory, alleles with purely detrimental effects can also accumulate if those effects are confined to late life when selection against them is weak. Thus under both theories, populations harbor alleles that are deleterious in old but not in young individuals.Ramifications of the two theories are quite different. Under AP, senescence is due to a ''tradeoff'' between early-and late-life fitness, and any genetic or evolutionary change in senescence will be accompanied by changes in early-life fitness components. In contrast, the MA theory suggests that senescence is caused, at least in part, by alleles that are neutral early in life, and thus genetic or evolutionary changes in senescence need not be accompanied by any change in early-life fitness. In principle, senescence could be slowed or delayed by artificially selecting on late-life fitness or by genetic manipulation of late-acting deleterious alleles, and there would be no cost incurred at earlier ages.These two theories have been subjected to several experimental tests, but previous attempts to distinguish between them have been inconclusive because of a lack of clear and contrasting predictions (4, 7-9). Of the two, AP has received the strongest support, with studies consistently showing negative genetic correlations between early-and late-life fitness, which is...

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