Hypermutator

A hypermutator is a cell lineage with an elevated mutation rate compared with typical strains. This phenotype arises when DNA repair systems are compromised or when cells increase the activity of error-prone DNA synthesis. Hypermutators have been described in bacteria, fungi, and cancer cells, and they can accelerate adaptation under stress while also increasing the load of deleterious mutations.

In bacteria, the most common cause is loss of function in the mismatch repair system (MutS, MutL, MutH). Without efficient mismatch repair, replication errors accumulate, raising base substitutions and frameshift events. This mutator state is often accompanied by activation of the SOS response and upregulation of error-prone polymerases such as DinB (Pol IV) and UmuC/UmuD’ (Pol V), further increasing mutagenesis. Hypermutator populations can rapidly evolve antibiotic resistance or other traits that help survival under stress, though they may experience fitness costs when stress subsides.

In eukaryotes, hypermutator phenotypes occur in cancer and can arise from mismatch repair deficiency (loss of MLH1, MSH2, MSH6, PMS2) leading to microsatellite instability, or from mutations in DNA polymerase proofreading domains (such as POLE and POLD1), which produce ultramutated tumors. These high mutation burdens can influence tumor evolution and responses to therapies, including immunotherapies.

Detection and implications: Mutation rates are typically expressed as mutations per genome per generation and are estimated via genome sequencing or specialized assays. Hypermutator lineages promote rapid genetic diversification, affecting treatment strategies in infectious diseases and informing therapeutic decisions in cancer by linking mutational burden to potential benefits from immune-based therapies.