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Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.
Freyer C, Cree LM, Mourier A, Stewart JB, Koolmeister C, Milenkovic D, Wai T, Floros VI, Hagström E, Chatzidaki EE, Wiesner RJ, Samuels DC, Larsson NG, Chinnery PF
(2012) Nat Genet 44: 1282-5
MeSH Terms: Animals, DNA Polymerase gamma, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Female, Fertility, Genetic Heterogeneity, Genome, Mitochondrial, Germ-Line Mutation, Mice, Mice, Inbred C57BL, Oocytes, RNA, RNA, Mitochondrial, RNA, Transfer, Met
Show Abstract · Added December 12, 2013
A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base-pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNA(Met) mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.
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15 MeSH Terms
Multiple mutations of the first gene of a dimeric tRNA gene abolish in vitro tRNA gene transcription.
Nichols M, Bell J, Klekamp MS, Weil PA, Söll D
(1989) J Biol Chem 264: 17084-90
MeSH Terms: Cloning, Molecular, Endopeptidases, Mutation, Promoter Regions, Genetic, RNA Polymerase III, RNA, Fungal, RNA, Transfer, RNA, Transfer, Met, RNA, Transfer, Ser, Regulatory Sequences, Nucleic Acid, Saccharomyces cerevisiae, Schizosaccharomyces, Transcription Factor TFIIIB, Transcription Factors, Transcription Factors, TFIII, Transcription, Genetic
Show Abstract · Added March 5, 2014
Eukaryotic tRNA expression initiates with transcription by RNA polymerase III and requires two additional protein factors and two regions within the tRNA gene (the 5'-internal control region (ICR) or A-box and the 3'-ICR or B-box). Using a reconstituted Saccharomyces cerevisiae RNA polymerase III system, the transcription of various 5'-ICR, 3'-ICR, and double mutation alleles of the Schizosaccharomyces pombe sup3-e dimeric tRNA gene were studied. The sup3-e tRNA locus consists of an upstream serine tRNA gene and a downstream initiator methionine tRNA gene which are transcribed as a dimeric precursor and processed to give two tRNAs. Only the ICRs of the tRNA(Ser) gene are active in directing dimeric gene transcription. Mutations in the 3'-ICR of the tRNA(Ser) gene reduce transcription of the dimer more than those in the 5'-ICR. Mutations in the 5'-ICR were found which greatly increased or decreased transcription of the dimer, while base changes in the 3'-ICR were only found to decrease transcription. This suggests a modulatory role for the 5'-ICR in transcription regulation. Mutation of the methionine tRNA gene ICR has little effect on sup3-e transcription, and no detectable transcripts initiate from the methionine tRNA gene when the tRNA(Ser) gene promoter is inactivated by mutation. Comparison with transcription studies of other mutant tRNA genes suggests that nucleotides sites within the ICRs, such as nucleotides 8, 10, 13, 18, and 19 in the 5'-ICR and 48, 53, 56, 57, and 58 in the 3'-ICR, appear to have evolved universal importance for RNA polymerase III transcription in eukaryotes. Thus these ICR sequences may play a critical role in regulation of tRNA expression.
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16 MeSH Terms