Hypermutation

Hypermutation refers to an unusually high rate of genetic mutation in a cell, tissue, or region, exceeding the baseline rate for that organism. It can arise from defects in DNA repair, exposure to mutagens, or as a regulated process in certain cell types. Hypermutation can be global or localized to specific loci.

In bacteria, a mutator phenotype increases mutation rates and promotes rapid evolution under stress. Loss of mismatch repair genes (for example mutS, mutL, mutH) or proofreading defects can create hypermutators. The bacterial SOS response can induce error-prone DNA polymerases, elevating mutations during DNA damage and aiding adaptation, though at the cost of more deleterious changes.

In the immune system, somatic hypermutation is a normal, targeted process that diversifies antibody genes in B cells. Activation-induced cytidine deaminase (AID) initiates mutations in immunoglobulin variable regions in germinal centers, driving affinity maturation. This hypermutation is tightly regulated to limit off-target effects.

In cancer, a hypermutated phenotype can result from mismatch repair deficiency, exposure to alkylating agents, or mutations in DNA polymerase proofreading domains such as POLE. Tumors with high mutational burden often produce neoantigens and may respond to immune checkpoint inhibitors, though outcomes vary.

Measurement is expressed as a mutation rate or as tumor mutational burden in oncology; in microbes, as mutations per genome per generation. Hypermutation affects evolution, therapy resistance, and immunogenicity.