People are born with variable numbers of de novo germline mutations (DNMs), depending primarily on the ages of their parents. To explore additional causes, we developed an approach to call DNMs from nucleotide differences between siblings in genomic regions inherited identical by descent from both parents. Applying it to whole genome sequences from 28,985 sibling pairs of diverse genetic ancestries present in the UK Biobank and All of Us datasets, as well as 2,330 trios, we identified >800K autosomal DNMs and characterized mutation phenotypes in 27,645 sets of parents. We found subtle shifts in the mutation spectrum but no differences in total DNM rates among genetic ancestry groups, or between smokers and non-smokers. Testing for associations between parental mutation phenotypes and their burden of loss-of-function and deleterious missense variants in a set of 180 DNA repair and maintenance genes, we discovered that disruptions in REV1 and LIG1 increase germline mutation rates, and thus that rare mutator alleles segregate in population cohorts. ### Competing Interest Statement The authors have declared no competing interest. NIH, R35 GM083098

Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation rates at the end of l...

Mutations reflect the net effects of myriad types of damage, replication errors, and repair mechanisms, and thus are expected to differ across cell types with distinct exposures to mutagens, division ...

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A major focus of human genetics is to map severe disease mutations. Increasingly that goal is understood as requiring huge numbers of people to be sequenced from every broadly-defined genetic ancestry...

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