Inferring signatures of time-varying mutational mechanisms during antibody affinity maturation

During adaptive immune responses, B cells produce antibodies that recognize pathogen-derived antigens. B cells undergo affinity maturation, an iterative process of mutation and selection that generates lineages of increasingly effective antibody variants. Recent studies suggest that this mutation process is affinity-dependent rather than uniform. High-affinity B cells undergoing clonal expansion appear to acquire fewer mutations per division, possibly due to a shortened window of mutator activity that preserves beneficial genotypes (Pae et al. 2025; Merkenschlager et al. 2025) and may confer an evolutionary advantage (Pyo et al. 2025). If these dynamics reflect changes in underlying mutational mechanisms, they should produce detectable shifts in mutational spectra. However, current methods for quantifying mutation patterns assume constant mutational processes and thus cannot capture these dynamics (e.g. Yaari et al. 2013), leaving their temporal variation poorly understood. Here, we investigate time-varying mutation spectra along B cell lineages from repertoire sequencing data by modeling mutation as an inhomogeneous Poisson process. We quantify temporal changes in mutation spectra and identify mutational signatures active during specific stages of affinity maturation, pointing to dynamic regulation of mutagenesis as an evolutionary mechanism in adaptive immune responses.