Article

Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A→G Mutation in Blood

Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 02/2008; 82(2):333-43. DOI: 10.1016/j.ajhg.2007.10.007
Source: PubMed

ABSTRACT The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.

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    • "In the NZB mouse model, the rate of selection is currently held to be independent of initial heteroplasmy, and constant with time (Battersby et al., 2003). The human A3243G mtDNA mutation is lost continually from the blood of patients (Rahman et al., 2001; Rajasimha et al., 2008). To find out whether mtDNA dynamics change during organismal development or stay constant at all times, we applied an appropriate population genetic model for mtDNA segregation in our data. "
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    • "Mutation load in several easily accessible tissues must be considered. Since mtDNA heteroplasmy may change with age in blood [8]. This is partly supported by our findings of motor-predominant axonal neuropathy in mother of our patient in whom heteroplasmy level was found within interval of 68–96% (blood-hair follicles) in contrast with totally asymptomatic mother from previous case harboring higher mutation load (85%) in blood, however other tissues remained uninvestigated. "
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    • "This tissue dependance has been suggested to result from a replicative disadvantage of cells harboring a high mutant load, thus promoting ''mutation epuration'' from fast regenerating tissues. Should such a biological process operate prenatally, it could be missed out within the ''short'' course of a pregnancy, by reference to the very slow decrease of mean mutation level in adult white blood cells [Rajasimha et al., 2008], thus reflecting the apparent intertissue mutant load stability throughout the prenatal period. Alternatively, cell proliferation rate would be identical among all tissues throughout intrauterine life, and would become tissue dependent from a fairly late postnatal period. "
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