Fran SupekInstitut de Recerca Biomèdica (IRB Barcelona)

Local hypermutation is an unusual occurence of a cluster of nearby mutations that arose in a single event, which can severely damage genetic material. The best known type of local hypermutation, called a mutation shower or thunderstorm, can contain tens of closely spaced mutations. However, these spectacular mutational events occur only rarely. Nonetheless their existence suggests that other types of local hypermutation may be more widespread in genomes than previously appreciated.

We have developed a sensitive statistical framework, HyperClust, to detect mutation clustering in cancer genomes. The application of HyperClust to thousands of cancer genome sequences revealed a new type of localized hypermutation pattern that we named mutation fog. This can generate hundreds of mutations per cell and can occur in different human somatic tissues. Such mutations are unevenly distributed across the human chromosomes: they preferentially accumulate in the most important, euchromatic regions of the genome, where gene density is higher.

Surprisingly, this new hypermutation type is facilitated by a normal DNA repair process. When cells sense a mismatch in their DNA, they undergo a DNA repair reaction, in order to preserve genetic information. Remarkably, this reaction can become coupled with the APOBEC3A enzyme, which is normally used by human cells to defend against retrotransposons and viruses by damaging their nucleic acids. In some cases, when both the APOBEC enzyme and the DNA repair process are active at the same time, APOBEC is able to hijack the DNA repair process, generating the mutation fog.

Such APOBEC mutagenesis has a high propensity to generate impactful mutations in oncogenes and tumor suppressor genes, which can exceed that of other common carcinogens such as tobacco smoke and ultraviolet radiation. Because human cells direct their DNA repair capacity towards more important genomic regions, carcinogens that subvert DNA repair can be remarkably potent.

Mas-Ponte D & Supek F. 2020, ‘DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers.Nature Genetics ;52(9):958-968.