A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes

Cree, Lynsey M.; Samuels, David C.; Lopes, Susana Chuva de Sousa; Rajasimha, Harsha; Wonnapinij, Passorn; Mann, Jeffrey R.; Dahl, Hans Henrik M.; Chinnery, Patrick F.

doi:10.1038/ng.2007.63

Cited by 443 publications

(489 citation statements)

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“…Transmission of heteroplasmic normal genotypes has shown that the bottleneck was due to low mtDNA copy number in oogonia but also to preferential amplification of mtDNA subpopulations during folliculogenesis [41,42].…”

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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“…However, this ratio does not necessarily reflect the extent of paternal leakage in the developing embryo. The mtDNA content remains constant during early embryogenesis (Cao et al, 2007;Cree et al, 2008) and mitochondria are apportioned to arising cells in a random fashion. Because most of these cells form extraembryonic tissues (Hogan et al, 1986), only a subset of all cells and consequently mtDNAs present in the zygote will ultimately contribute to the embryo proper (Fleming et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Lost in the zygote: the dilution of paternal mtDNA upon fertilization

Wolff¹,

Gemmell²

2008

Heredity

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The mechanisms by which paternal inheritance of mitochondrial DNA (mtDNA) (paternal leakage) and, subsequently, recombination of mtDNA are prevented vary in a speciesspecific manner with one mechanism in common: paternally derived mtDNA is assumed to be vastly outnumbered by maternal mtDNA in the zygote. To date, this dilution effect has only been described for two mammalian species, human and mouse. Here, we estimate the mtDNA content of chinook salmon oocytes to evaluate the dilution effect operating in another vertebrate; the first such study outside a mammalian system. Employing real-time PCR, we determined the mtDNA content of chinook salmon oocytes to be 3.2 Â 10 9 ± 1.0 Â 10 9 , and recently, we determined the mtDNA content of chinook salmon sperm to be 5.73 ± 2.28 per gamete. Accordingly, the ratio of paternal-to-maternal mtDNA if paternal leakage occurs is estimated to be 1:5.5 Â 10 8 . This contribution of paternal mtDNA to the overall mtDNA pool in salmon zygotes is three to five orders of magnitude smaller than those revealed for the mammalian system, strongly suggesting that paternal inheritance of mtDNA per offspring will be much less likely in this system than in mammals.

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“…(b) Purifying selection appears to play a major role but the issue of positive selection remains unresolved. (c) Random genetic drift is also a prominent feature of human mitochondrial genetics, largely due to the germline bottleneck (Cree et al, 2008). There is a conundrum, because, according to standard population genetic models, drift tends to minimize or diminish the effects of purifying selection.…”

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confidence: 99%