Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune syst...

Exogenous and endogenous mutagens generate a wide variety of DNA lesions, including bulky adducts, chemical modifications, and single- or double-stranded breaks. A phenomenon called “lesion segregation,” in which lesions evade repair and persist for multiple cell divisions, has recently been documented in tumors and healthy somatic tissues from mice and humans, respectively. Persistent lesions can generate multi-allelic variants (MAVs) by serving as templates for multiple rounds of error-prone replication. By reanalyzing data from a large C. elegans mutagenesis experiment, we observed robust evidence for MAVs at a small fraction (∼0.2%) of mutated sites in the offspring of strains treated with alkylating agents. Because these sequencing data were derived from the progeny of a single F1 animal — itself the offspring of a mutagenized P0 — all mutations should be biallelic. The presence of multi-allelic variation implies that some DNA lesions are transmitted to the F1 zygote, evade repair, and are repeatedly bypassed by error-prone polymerases during embryogenesis. We suspect that many more lesions are inherited than is suggested by MAV prevalence, and that a large fraction of biallelic mutations are also caused by inherited lesions. Our results demonstrate that DNA lesions serve as durable, transgenerational templates for mutagenesis in C. elegans . We speculate that lesion segregation in the early embryo may be a source of mosaicism and genetic diversity in humans, as well. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, https://ror.org/01cwqze88, R01HG012252

Spermatogonial stem cells (SSCs) maintain male fertility, but how their clonal dynamics change with age remains poorly understood. Here, we use in vivo CRISPR barcoding in zebrafish to label SSCs and ...

Sweeping proposed rule, now open for comments, would also restrict foreign collaborations and remove federal funding for open-access fees

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

Analysis of data from pre-implantation genetic testing sheds light on the genetic basis of meiotic-origin aneuploidy, the leading cause of human pregnancy loss, identifying common genetic variants ass...

Founded in 1850, The University of Utah is the flagship institution of higher learning in Utah, and offers over 100 undergraduate and more than 90 graduate degree programs to over 30,000 students. Uni...

Postzygotic mutations (PZMs) arising post-fertilisation, prior to primordial germ cell specification, may be subsequently inherited by both somatic and germ cells, causing somatic mosaicism in the par...

Mutational signatures contain valuable information about the mutational processes shaping cancer genomes. However, despite dozens of tools to identify signatures in cancer samples, there is not an est...

Germline mutation rates in mice are shaped by two mutator alleles that interact epistatically, showing that DNA repair defects that map to different loci can have snowballing effects.