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 .

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Mutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individual’s genome1,2. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with a hypermutated genome with between two and seven times more de novo single-nucleotide variants than expected. In most families (9 out of 12), the excess mutations came from the father. Two families had genetic drivers of germline hypermutation, with fathers carrying damaging genetic variation in DNA-repair genes. For five of the families, paternal exposure to chemotherapeutic agents before conception was probably a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease.

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 mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants 1 . While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known 2 . Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time. BackgroundThe most damaging genetic variants, gene deletions and protein-truncating variants (PTVs), are removed from the population by selection with strength that varies substantially from gene to gene 1,3 . The strength of selection against heterozygous PTVs has been estimated by the selection coefficient, s het , which exhibits a continuous spectrum across human genes 2,4 , although most attention has been focused on a subset of ~3,000 genes with the highest probability of Loss-of-function Intolerance (pLI) 1 .