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

Nat Genet. 2008 Feb;40(2):249-54. doi: 10.1038/ng.2007.63. Epub 2008 Jan 27.

Abstract

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 reduction in the number of mtDNA molecules being transmitted from mother to offspring (the mitochondrial genetic bottleneck), to the partitioning of mtDNA into homoplasmic segregating units, or to the selection of a group of mtDNA molecules to re-populate the next generation. Here we show 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 of heteroplasmic female mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Blastocyst / chemistry
  • Blastocyst / cytology
  • Blastomeres / chemistry
  • Cell Lineage
  • Computer Simulation
  • Crosses, Genetic
  • DNA Replication
  • DNA, Mitochondrial / chemistry*
  • DNA, Mitochondrial / genetics*
  • Embryo Transfer
  • Embryo, Mammalian / chemistry
  • Embryo, Mammalian / cytology
  • Embryonic Development*
  • Female
  • Gene Dosage
  • Gene Frequency
  • Genetic Markers
  • Genotype*
  • Green Fluorescent Proteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Microinjections
  • Mitochondria / chemistry*
  • Models, Genetic
  • Oocytes / chemistry
  • Polymorphism, Genetic
  • Pregnancy
  • Repressor Proteins / metabolism

Substances

  • DNA, Mitochondrial
  • Dppa3 protein, mouse
  • Genetic Markers
  • Repressor Proteins
  • Green Fluorescent Proteins