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

Lookup NU author(s): Professor Patrick Chinnery, Dr David Samuels

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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 mution 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. © 2008 The American Society of Human Genetics.

Publication metadata

Author(s): Rajasimha HK, Chinnery PF, Samuels DC

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2008

Volume: 82

Issue: 2

Pages: 333-343

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2007.10.007

DOI: 10.1016/j.ajhg.2007.10.007

PubMed id: 18252214

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