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: 10.93). 02/2008; 82(2):333-43. DOI: 10.1016/j.ajhg.2007.10.007
Source: PubMed


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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    • "This parameter value was set at b = 0.66 based on 87 human mother–offspring pairs (Lott et al., 1990; Ciafaloni et al., 1992; Larsson et al., 1992; Martinuzzi et al., 1992; Tatuch et al., 1992; Zhu et al., 1992; Hammans et al., 1993, 1995; Piccolo et al., 1993; Howell et al., 1994; Santorelli et al., 1994; Harding et al., 1995; Houstek et al., 1995; Makelabengs et al., 1995; Black et al., 1996; Mak et al., 1996; Carelli et al., 1997; Uziel et al., 1997; Olsson et al., 1998; Onishi et al., 1998; Tanaka et al., 1998; Chinnery et al., 1999; White et al., 1999; Lien et al., 2001; Porto et al., 2001; Hurvitz et al., 2002; Wong et al., 2002; Kaplanova et al., 2004; Enns et al., 2006; Phasukkijwatana et al., 2006), including the following mutations: m.3243A>G (15 pairs), m.83446A>G (10 pairs), m.11778G>A (23 pairs), m.3460G>A (15 pairs), m.9883T>C (10 pairs) and m.8993T>G (14 pairs). Data from the A3243G mutation taken from blood samples were adjusted to correct for the known decrease in the A3243G mutation level in blood with age (Rajasimha et al., 2008). Of course, these pathogenic variants cause a range of different phenotypes, which could in principle affect the inheritance of that variant. "
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    • "The mtDNAs in the simulation were copied with no preference to either wild-type or mutant. For simulation details see [46], [47]. The simulated cells were divided and the mtDNA molecules were individually randomly distributed to the two daughter cells. "
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