Mutation

A mutation is a transmissible or heritable change in the nucleotide sequence of the genetic material of a cell or virus. Mutations are either spontaneous, occurring naturally due to errors in DNA or RNA replication, or induced by external agents. When identifying the etiology of a disease and the factors that alter a person's risk for disease, epidemiologists must often determine the unique contributions of environmental and genetic factors. Increasingly, we are made aware of the importance of mutations in the development of disease and the evolution of pathogens.

Mutations are often involved in the etiology of diseases attributed to host genetic factors. Mutations of the breast cancer susceptibility genes BRCA1 or BRCA2 result in an increased risk of developing breast cancer or ovarian cancer and account for up to half of hereditary breast cancers. It is believed that these genes normally play a role in repairing breaks in double-stranded DNA induced by radiation and that mutations in these genes hinder this mechanism, resulting in DNA replication errors and cancer. The effect of host mutations need not be deleterious as certain mutations confer protection from disease. A mutant variant of the chemokine receptor 5 resulting from a 32 base pair deletion (CCR5Δ32) is associated with nearly complete resistance to HIV-1 infection in homozygous individuals and partial resistance with delayed disease progression in heterozygous individuals. CCR5 is a necessary coreceptor for HIV-1 infection; individuals with at least one mutant allele do not express the receptor on their cell surfaces and are thereby protected.

Mutations acquired by pathogens may alter infectivity and virulence, and therefore, affect disease in the host. Influenza virus lacks a proofreading mechanism and thus allows errors during replication to remain undetected and uncorrected, resulting in an accumulation of point mutations and the ultimate emergence of a new antigenic variant. This process is [Page 705]referred to as antigenic drift and is the reason why the human influenza vaccine must be updated on an annual basis. Avian influenza viruses undergo limited antigenic drift in their aquatic bird reservoirs; however, the accumulation of mutations becomes more pronounced when the virus spreads through domestic poultry, and continued accumulation could support human-to-human transmission as witnessed with the 1918 Spanish influenza pandemic.

Epidemiologists are recognizing with increasing frequency the contributions of genetic factors such as mutations in the development of both chronic and communicable diseases.