Профиль

and adding her co-author @linpoyraz.bsky.social who I discovered is on Bluesky

Thanks to many people, and congratulations in advance to Vanesa Getseva, who defends her PhD in a couple of hours... 13/13

We find evidence that disruptions in at least two genes, REV1 and LIG1, influence germline mutation rates; both are strong candidates for the specific traits with which they are associated. Thus, rare mutator alleles are segregating in human population cohorts. 12/n

Next, we impute parental genotypes from siblings and test for associations between parental mutation phenotypes and disrupting variants in a set of 180 DNA repair and maintenance genes. 11/n

When we cluster samples by their genetic similarity, there is no difference in the DNM rate across groups; controlling for parental age, present-day germline mutation rates are similar across recent ancestry groups. However, we detect subtle differences in mutation types (notably at C>T). 10/n

We then used these mutation phenotypes to investigate causes of variation in germline mutation rates. 9/n

By this approach, we could identify >800K autosomal DNMs, distributed across the genome, and characterize mutation phenotypes in ~28K sets of parents. 8/n

We applied the approach to WGS data from ~29K sibling pairs of diverse genetic ancestries present in the UK Biobank and All of Us databases, as well as 2.3K trios. To weed out errors and gene conversion events, we tuned our filters on duplicates and tested them on quads. 7/n

Two siblings provide two estimates for a 1/4 of the genome on average, so about half the information in a trio, but without the need for parental data. 6/n

As a first step, we developed an approach to call de novo mutations (DNMs) from differences between siblings in genomic regions inherited identical by descent from both parents (i.e., that are IBD2). 5/n

In humans, the heritability of mutation rates seems to lay among rare variants (Kaplanis et al. 2022; Garcia Salinas et al. 2025). So we set out to conduct a burden test for mutation phenotypes. 4/n

But male mutation rates, at least, are heritable and in a couple of cases, children with high nbs of mutations turn out to have fathers who have lost a repair gene (Kaplanis et al. 2022). In species, such modifiers of germline mutation rates have been mapped (e.g, in mice; Sasani et al. 2022). 3/n

Our starting point was the observation that people differ substantially in the number of de novo germline mutations that they carry. Beyond chance fluctuations, those differences are mainly due to the ages of their mother and father at conception. 2/n

Thanks to many people & reviewers for helpful discussions and/or comments.

Thanks to many people and to reviewers for helpful discussions & comments.