The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes

  title={The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes},
  author={Timothy Wai and Daniella Teoli and Eric A. Shoubridge},
  journal={Nature Genetics},
In mammals, mitochondrial DNA (mtDNA) sequence variants are observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte. [] Key Method By directly tracking the evolution of mtDNA genotypic variance during oogenesis, we show that the genetic bottleneck occurs during postnatal folliculogenesis and not during embryonic oogenesis.

New Evidence Confirms That the Mitochondrial Bottleneck Is Generated without Reduction of Mitochondrial DNA Content in Early Primordial Germ Cells of Mice

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.

The mitochondrial DNA genetic bottleneck: inheritance and beyond.

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.

Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos

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.

Selective propagation of functional mtDNA during oogenesis restricts the transmission of a deleterious mitochondrial variant

These findings establish a previously uncharacterized developmental mechanism for the selective amplification of wild-type mtDNA, which may be evolutionarily conserved to limit the transmission of deleterious mutations.

No recombination of mtDNA after heteroplasmy for 50 generations in the mouse maternal germline

No germline recombination after transmission of mtDNA under genetically and evolutionary relevant conditions in mammals is found and a method based on cloning of single mtDNA molecules in the λ phage, without prior PCR amplification, followed by subsequent mutation analysis is validated.

Role of mitochondrial DNA replication during differentiation of reprogrammed stem cells.

The only method to overcome the problems of heteroplasmy in SCNT embryos is to completely deplete the donor cell of its mtDNA prior to SCNT, as interspecies SCNT (iSCNT) genetic divergence contributes to developmental failure.

The Strength and Timing of the Mitochondrial Bottleneck in Salmon Suggests a Conserved Mechanism in Vertebrates

The results confirm the presence of a mitochondrial bottleneck in fish, and show that segregation of mtDNA variation is effectively complete by the end of oogenesis, and suggest the mechanism underlying the mtDNA bottleneck is conserved in these distant vertebrates both in terms of it magnitude and timing.

Variation in germ line mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission

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.

Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro

Differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.



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

It is shown that the partitioning of mtDNA molecules into different cells before and after implantation, followed by the segregation of replicating mtDNA between proliferating primordial germ cells, is responsible for the different levels of heteroplasmy seen in the offspring ofheteroplasmic female mice.

The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells

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

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.

Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop

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.

Nuclear genetic control of mitochondrial DNA segregation

It is shown that this phenotype segregates in F2 mice from a genetic cross (BALB/c × CAST/Ei) and that it maps to at least three quantitative-trait loci (QTLs) and is the first genetic evidence for nuclear control of mammalian mtDNA segregation.

Organization and dynamics of human mitochondrial DNA

It is demonstrated that nucleoids and respiratory complexes are mobile and diffuse efficiently into mitochondria previously devoid of mtDNA, and fusion-mediated exchange and intramitochondrial mobility of endogenous mitochondrial components are not rate-limiting for intermitochondrial complementation.

Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides.

It is concluded that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.

Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA

This study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.

Mitochondrial DNA copy number in bovine oocytes and somatic cells.

Germline passage of mitochondria: quantitative considerations and possible embryological sequelae.

It is proposed that maintaining the integrity of mitochondrial inheritance is such a strong evolutionary imperative that features of ovarian follicular formation, function, and loss could be expected to have been primarily adapted to this special purpose.