Methylated CpG sites are saturated for T mutations in a sample of 390K human exomes, providing a test case for inferences about fitness effects in human genes, and insight into the interpretation of m...

Nature Reviews Genetics - In this Comment, the authors argue that understanding the genetic basis of adaptation requires considering the genetic architecture and ecological properties of traits...

Single-molecule DNA sequencing identifies recurrent somatic mutations in autoimmune B cells that may allow them to escape peripheral tolerance and cause autoimmune disease.

Milind et al. explore why loss-of-function variants and duplications tend to have average effects in the same direction on 94 complex traits. Using gene dosage response curves (GDRCs), they gather evi...

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

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...