A Sticky Multinomial Mixture Model of Strand-Coordinated Mutational Processes in Cancer

The characterization of mutational processes in terms of their signatures of activity relies, to the most part, on the assumption that mutations in a given cancer genome are independent of one another. Recently, it was discovered that certain segments of mutations, termed processive groups, occur on the same DNA strand and are generated by a single process or signature. Here we provide a first probabilistic model of mutational signatures that accounts for their observed stickiness and strand-coordination. The model conditions on the observed strand for each mutation, and allows the same signature to generate a run of mutations. We show that this model provides a more accurate description of the properties of mutagenic processes than independent-mutation models or strand oblivous models, achieving substantially higher likelihood on held-out data. We apply this model to characterize the processivity of mutagenic processes across multiple types of cancer in terms of replication and transcriptional strand-coordination.