High-Resolution Genomic Analysis of Human Mitochondrial RNA Sequence Variation

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Science  25 Apr 2014:
Vol. 344, Issue 6182, pp. 413-415
DOI: 10.1126/science.1251110

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RNA Heteroplasmy

Like nuclear DNA, the mitochondrial genome has to be posttranscriptionally modified to function properly; however, among individuals, mitochondrial RNA (mtRNA) transcripts vary in ways that are poorly understood. Hodgkinson et al. (p. 413) looked at mtRNA editing events and posttranscriptional methylation in more than 700 individuals. Interestingly, variation at the ninth position within transfer RNAs showed a high frequency of variation that, in some cases, is genetically attributable.


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.

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