MITOCHONDRIAL MUTATIONAL SPECTRA IN HUMAN-CELLS AND TISSUES

We have found that human organs such as colon, lung, and muscle, as we ll as their derived tumors, share nearly all mitochondrial hotspot poi nt mutations. Seventeen hotspots, primarily G --> A and A --> G transi tions, have been identified in the mitochondrial sequence of base pair s 10,030-10,130. Mutant fractions increase with tile number of cell ge nerations in a human IS cell line, TK6, indicating that they are herit able changes, The mitochondrial point mutation rate appears to he more than two orders of magnitude higher than the nuclear point mutation r ate in TK6 cells and in human tissues. The similarity of the hotspot s ets in vivo and in vitro leads us to conclude that human mitochondrial point mutations in the sequence studied are primarily spontaneous in origin and arise either from DNA replication error or reactions of DNA with endogenous metabolites, The predominance of transition mutations and the high number of hotspots in this short sequence resembles spec tra produced by DNA polymerases in vitro.