In just a few years, our understanding of mutations in human cells has exploded. Huge studies have mapped their characteristics and genomic locations, adding up to a “landscape” of mutation. This work, especially in cancer, has generated catalogues of mutational “signatures” that represent patterns of mutation and can yield clues to mutations underlying disease. One of these signatures, with the license plate-sounding name SBS5, is a standout for at least three reasons: 1) it is very common, in cancers and in normal cells; 2) its presence increases with age; and 3) no one knows what causes it.
A new preprint suggests an answer to that mystery: this signature is created by two mutational mechanisms (translesion synthesis during replication and repair errors happening at any time). The fact that the signature is the same for both suggests that the same polymerase is involved. The authors call this a mutational funnel, since multiple mutation types converge on this one signature; the unidentified polymerase is the “funneling polymerase.” One of my favorite observations explained by their model is this: SBS5 signatures occur in very different genomic locations in neurons (which never divide) versus glial cells (which do). This distribution makes sense when we consider the two processes that enter the funnel: one occurs exclusively during DNA replication.
I recommend you read the preprint, to learn about mutations and their analysis, but also to enjoy some scientific writing that is among the best I have ever seen. Here is just one example:
A key prediction of the model is therefore that in the regime of high cumulative damage and frequent cell divisions, the same source of damage will give rise to two types of mutational signatures, one due to unrepaired lesions and the other to repair errors (green area in Figure 2B). Across cells, the number of mutations contributed by signatures of unrepaired damage should be correlated with one another and with signatures of repair errors (Figure 2E). Moreover, if the same polymerase is occasionally recruited for different damage types and if it synthesizes over neighboring nucleotides that result in a comparable spectrum of misincorporations, then distinct sources of damage will result in a similar signature of collateral mutagenesis. In that sense, and in contrast to the usual interpretation of mutational signatures, collateral mutagenesis will behave as a “funnel”, in which different sources of damage pour into the same mutational output.
Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature
In bioRxiv, 1 September 2025
From the group of Molly Przeworski at Columbia University.
Snippet by Stephen Matheson
Image credit: Figure 2 from Spisak et al. cited above (CC BY).