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Published December 1, 1992 | Published
Journal Article Open

Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy


The segregation of mutant and wild-type mtDNA was investigated in transformants constructed by transferring human mitochondria from individuals belonging to four pedigrees with the MELAS encephalomyopathy-associated mtDNA mutation (MELAS is mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) into human mtDNA-less (rho-degrees) cells. Five of 13 clonal cell lines containing mixtures of wild-type and mutant mtDNAs were found to undergo a rapid shift of their genotype toward the pure mutant type. The other 8 cell lines, which included 6 exhibiting nearly homoplasmic mutant mtDNA, on the contrary, maintained a stable genotype. Subcloning experiments and growth rate measurements clearly indicated that an intracellular replicative advantage of mutant mtDNA was mainly responsible for the dramatic shift toward the mutant genotype observed in the unstable cell lines.

Additional Information

© 1992 by the National Academy of Sciences. Contributed by Giuseppe Attardi, August 10, 1992. We are very grateful to Dr. M. King for isolating the 2S transformants, to N.-G. Larsson for providing the clone pTZ18/K4, and to Dr. Ronald Butow for valuable discussion. The technical assistance of Ms. S. T. Lai, B. Keeley, Linda McKee, A. Drew, and L. Tefo is gratefully acknowledged. These investigations were supported by the National Institutes of Health Grants GM-11726 to G.A. and AR38231 to O.H., Muscular Dystrophy Association Grant 37826 to G.A. and A.C., a Gosney Fellowship to M.Y., and a Fellowship from the Associazione per la Promozione delle Richerche Neurologiche to A.M. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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