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

@article{Cree2008ARO,
  title={A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes},
  author={Lynsey M. Cree and David C. Samuels and Susana Lopes and Harsha Karur Rajasimha and Passorn Wonnapinij and Jeffrey R Mann and H M Dahl and Patrick F. Chinnery},
  journal={Nature Genetics},
  year={2008},
  volume={40},
  pages={249-254}
}
Mammalian mitochondrial DNA (mtDNA) is inherited principally down the maternal line, but the mechanisms involved are not fully understood. Females harboring a mixture of mutant and wild-type mtDNA (heteroplasmy) transmit a varying proportion of mutant mtDNA to their offspring. In humans with mtDNA disorders, the proportion of mutated mtDNA inherited from the mother correlates with disease severity. Rapid changes in allele frequency can occur in a single generation. This could be due to a marked… 
The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes
TLDR
By directly tracking the evolution of mtDNA genotypic variance during oogenesis, it is shown that the genetic bottleneck occurs during postnatal folliculogenesis and not during embryonic oogenesis.
Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos
TLDR
It is shown that mtDNA copy number is reduced and non-synonymous mt DNA mutations are eliminated to prevent mtDNA mutation accumulation in germ cells during human primordial germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller’s ratchet.
New Evidence Confirms That the Mitochondrial Bottleneck Is Generated without Reduction of Mitochondrial DNA Content in Early Primordial Germ Cells of Mice
TLDR
Clear evidence is provided to confirm that no remarkable reduction in mt DNA content occurs in PGCs and reinforce that the bottleneck is generated without reduction of mtDNA content in germ cells.
Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them
TLDR
New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own.
Developmentally-orchestrated mitochondrial processes prime the selective inheritance against harmful mitochondrial DNA mutations
TLDR
It is demonstrated that mitochondrial fission, together with the lack of mtDNA replication in germarium region 2A, effectively segregates mtDNA into individual organelles and the Balbiani body has a minor role in mtDNA selective inheritance by supplying healthy mitochondria to the pole plasm.
The mitochondrial DNA genetic bottleneck: inheritance and beyond.
TLDR
Key recent findings are reviewed, ways forward are suggested that will hopefully advance the understanding of the role of mtDNA in human disease, and how the bottleneck is controlled during development are suggested.
Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro
TLDR
Differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.
Variation in germ line mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission
TLDR
It is shown that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline, and high percentages of mtDNA genomes with the tRNAMet mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 42 REFERENCES
The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells
TLDR
The mitochondrial bottleneck is not due to a drastic decline in mtDNA copy number in early oogenesis but rather to a small effective number of segregation units for mtDNA in mouse germ cells, which provides new information formtDNA segregation models and for understanding the recurrence risks for mt DNA diseases.
Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA
TLDR
It is shown that the pattern of segregation can be explained by random genetic drift ocurring in early oogenesis, and that the effective number of segregating units for mtDNA is ∼200 in mice, which provides the basis for estimating recurrence risks for mitochondrial disease due to pathogenic mt DNA mutations and for predicting the rate of fixation of neutral mtDNA mutations in maternal lineages.
Mitochondrial gene segregation in mammals: is the bottleneck always narrow?
TLDR
It is suggested here that the segregation of mitochondrial genes may be more complex than initially envisaged, and that models need to be developed that account for both rapid and slow segregation.
Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop
TLDR
The nucleotide sequence of all or part of the D-loop region in 14 maternally related Holstein cows is determined to help answer the question of how individual variant mtDNA molecules resulting from mutational events can come to dominate the large intracellular mtDNA population so rapidly.
Skewed segregation of the mtDNA nt 8993 (T-->G) mutation in human oocytes.
TLDR
Oocytes from a woman with heteroplasmic expression of the mtDNA nt 8993 (T-->G) mutation are studied, and it is found that subsequent mature oocytes may contain predominantly wild-type or mutant mitochondrial genomes.
Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy.
TLDR
Among families with Leber hereditary optic neuroretinopathy, a maternal lineage is found with individuals heteroplasmic for a single nucleotide change, and the results show that rapid segregation can occur but also that the level of heteroplasmy can be maintained from one generation to another.
Germline bottlenecks and the evolutionary maintenance of mitochondrial genomes.
TLDR
It is shown that a bottleneck increases the efficacy of selection against deleterious mutations by increasing the variance in fitness among eukaryotic hosts, and that, over a longer time scale, a bottleneck acts to slow the progression of the ratchet.
Heteroplasmic point mutations in the human mtDNA control region.
TLDR
The data from this study, together with unpublished data from other populations, are used to estimate the frequency of site heteroplasmy in normal human populations, and it is calculated that the rate of mutation and fixation in the first hypervariable segment of the human mtDNA control region is between 1.2 and 2.7 x 10(-6) per site per generation.
...
1
2
3
4
5
...