Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA

Jenuth, Jack P.; Peterson, Alan C.; Fu, Katherine; Shoubridge, Eric A.

doi:10.1038/ng1096-146

Cited by 530 publications

(465 citation statements)

References 29 publications

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“…The most well studied one carried two different normal mtDNA obtained by cytoplast transfer into one cell-embryo [34]. These two different normal mtDNA were found to be actively segregated for during the animal lifespan, in a non-random fashion as one genotype was favored in kidney and liver while the other one was favored in blood and spleen [35].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed.Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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“…In the female germline, this phenomenon is thought to be accelerated by a bottleneck, in which only a small, random sample of the mtDNA molecules in the parent cell passes through and contributes to the entire population of mtDNA molecules in daughter cells, thus increasing the variance of heteroplasmy in the successive generations of individuals. 15,16 These phenomena can expose the mutation to selection by increasing the degree of heteroplasmy, or remove the mutation by decreasing the heteroplasmy.…”

Section: Relative Fitness Of 3243a > G Carriers Ymentioning

confidence: 99%

Relative fitness of carriers of the mitochondrial DNA mutation 3243A > G

Moilanen

Majamaa

2001

Eur J Hum Genet

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Deleterious point mutations in mitochondrial DNA (mtDNA) have been found in many human populations and always at a low frequency suggesting that they are under strong negative selection. It is assumed that this selection is caused by reduced genetic fitness of mutation carriers, but the fitness of carriers of any mtDNA mutation has not been determined. We estimated the reproductive disadvantage caused by the mitochondrial DNA mutation 3243A > G in a population-based group of female carriers (n = 32). The person-years method, Kaplan-Meier survival analysis and population statistics were used to estimate net reproduction rates of the mutation carriers and the general population. We found that women with 3243A > G reproduced at the same rate as women in the general population, suggesting that on average host-level selection against women harbouring the 3243A > G mutation is not strong. European Journal of Human Genetics (2001) 9, 59-62.

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“…This is largely because of the unsuccessful attempts to introduce exogenous DNA to mitochondria, which has prevented generation of in vivo disease models. Heteroplasmic mice carrying two normal mtDNA variants (18) or randomly occurring mutations isolated from somatic tissues (19)(20)(21)(22) have been generated by cytoplast fusion to zygotes. Further, random mtDNA mutagenesis has been induced by manipulating nuclear-encoded mtDNA maintenance genes (23)(24)(25)(26).…”

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Tissue- and cell-type–specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model

Hämäläinen

Manninen

Koivumäki

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

189

169

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Mitochondrial DNA (mtDNA) mutations manifest with vast clinical heterogeneity. The molecular basis of this variability is mostly unknown because the lack of model systems has hampered mechanistic studies. We generated induced pluripotent stem cells from patients carrying the most common human disease mutation in mtDNA, m.3243A>G, underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. During reprogramming, heteroplasmic mtDNA showed bimodal segregation toward homoplasmy, with concomitant changes in mtDNA organization, mimicking mtDNA bottleneck during epiblast specification. Induced pluripotent stem cell-derived neurons and various tissues derived from teratomas manifested cell-type specific respiratory chain (RC) deficiency patterns. Similar to MELAS patient tissues, complex I defect predominated. Upon neuronal differentiation, complex I specifically was sequestered in perinuclear PTEN-induced putative kinase 1 (PINK1) and Parkin-positive autophagosomes, suggesting active degradation through mitophagy. Other RC enzymes showed normal mitochondrial network distribution. Our data show that cellular context actively modifies RC deficiency manifestation in MELAS and that autophagy is a significant component of neuronal MELAS pathogenesis. mitochondria | disease modeling

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Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA

Cited by 530 publications

References 29 publications

Unsolved issues related to human mitochondrial diseases

Unsolved issues related to human mitochondrial diseases

Relative fitness of carriers of the mitochondrial DNA mutation 3243A > G

Tissue- and cell-type–specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model

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