GENOTYPIC SELECTION OF MITOCHONDRIAL AND ONCOGENIC MUTATIONS IN HUMANTISSUE SUGGESTS MECHANISMS OF AGE-RELATED PATHOPHYSIOLOGY

The invention of the polymerase chain reaction (PCR) has facilitated t he development of a new class of assays to quantify human somatic muta tions in vivo, based on genotypic selection of mutants at the DNA leve l rather than phenotypic selection of mutants at the cell level. Use o f these assays has provided new perspectives on the timing, location a nd distribution of somatic mutagenesis in mitochondrial genes and in o ncogenes of the aging human body. This descriptive information has led to the inference and development of new models for age-related pathop hysiology and oncogenesis. Mutations of mitochondrial genes rise rapid ly with age to frequencies a thousand fold higher than those of nuclea r genes. Genotypic selection analysis has revealed that mitochondrial mutations accumulate predominantly in non-mitotic cells whose age-depe ndent loss is associated with pathology. Random mitochondrial mutation is most likely to inactive Complex I, a deficiency of which induces m itochondrial superoxide formation and cell death. Genotypic selection of oncogenic mutations at the BCL2 and p53 loci has revealed that the cell specificity of oncogenic mutations in persons without cancer corr elates well with sites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors. Quantitativ e variation in human BCL2 mutation frequency is extensive, and BCL2 mu tation frequency rises with age, concordant with increased risk for ly mphoma. The clonality and persistence of BCL2 mutations suggests two s pecific testable mechanisms of lymphomagenesis. BCL2 mutation frequenc y rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin exposed to sunlight than in unexposed skin. Thus, in add ition to their likely relevance to future cancer risk, the dose-respon se relationship between exposure and oncogenic mutations indicates pro mise for their future use as in vivo biodosimeters of human exposure t o carcinogens.