High-resolution genomic analysis of human mitochondrial RNA sequence variation

Science. 2014 Apr 25;344(6182):413-5. doi: 10.1126/science.1251110.


Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • DNA, Mitochondrial / chemistry
  • DNA, Mitochondrial / genetics
  • Female
  • Genetic Variation*
  • Genome, Mitochondrial*
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Methylation
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Single Nucleotide
  • RNA / chemistry
  • RNA / genetics*
  • RNA / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA, Mitochondrial
  • RNA, Transfer / chemistry
  • RNA, Transfer / genetics*
  • RNA, Transfer / metabolism
  • Ribonuclease P / genetics*
  • Ribonuclease P / metabolism
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Transcriptome


  • DNA, Mitochondrial
  • RNA, Mitochondrial
  • RNA
  • RNA, Transfer
  • PRORP protein, human
  • Ribonuclease P