Replication Errors Made During Oogenesis Lead to Detectable De Novo mtDNA Mutations in Zebrafish Oocytes with a Low mtDNA Copy Number

Auke B C Otten, Alphons P M Stassen, Michiel Adriaens, Mike Gerards, Richard G J Dohmen, Adriana J Timmer, Sabina J V Vanherle, Rick Kamps, Iris B W Boesten, Jo M Vanoevelen, Marc Muller, Bert Smeets

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Of all pathogenic mitochondrial DNA (mtDNA) mutations in humans, similar to 25% is de novo, although the occurrence in oocytes has never been directly assessed. We used next-generation sequencing to detect point mutations directly in the mtDNA of 3-15 individual mature oocytes and three somatic tissues from eight zebrafish females. Various statistical and biological filters allowed reliable detection of de novo variants with heteroplasmy >= 1.5%. In total, we detected 38 de novo base substitutions, but no insertions or deletions. These 38 de novo mutations were present in 19 of 103 mature oocytes, indicating that similar to 20% of the mature oocytes carry at least one de novo mutation with heteroplasmy >= 1.5%. This frequency of de novo mutations is close to that deducted from the reported error rate of polymerase gamma, the mitochondrial replication enzyme, implying that mtDNA replication errors made during oogenesis are a likely explanation. Substantial variation in the mutation prevalence among mature oocytes can be explained by the highly variable mtDNA copy number, since we previously reported that similar to 20% of the primordial germ cells have a mtDNA copy number of

Original languageEnglish
Pages (from-to)1423-1431
Number of pages9
JournalGenetics
Volume204
Issue number4
DOIs
Publication statusPublished - Dec 2016

Keywords

  • mitochondrial DNA
  • de novo mutations
  • next-generation sequencing
  • zebrafish
  • oogenesis
  • DNA-POLYMERASE-GAMMA
  • MITOCHONDRIAL-DNA
  • RAPID SEGREGATION
  • POINT MUTATIONS
  • READ ALIGNMENT
  • GENETIC DRIFT
  • HETEROPLASMY
  • BOTTLENECK
  • GERMLINE
  • INHERITANCE

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