High-resolution genomic analysis of human mitochondrial RNA sequence variation.
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.
CHU Sainte-Justine Research Centre, Department of Pediatrics, Faculty of Medicine, Université de Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada.
Alan
A
Hodgkinson
Youssef
Y
Idaghdour
Elias
E
Gbeha
Jean-Christophe
JC
Grenier
Elodie
E
Hip-Ki
Vanessa
V
Bruat
Jean-Philippe
JP
Goulet
Thibault
T
de Malliard
Philip
P
Awadalla
D000328:Adult; D000368:Aged; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D054629:Genome, Mitochondrial; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043262:Ribonuclease P / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012313:RNA; D012343:RNA, Transfer; C545252:PRORP protein, human; D043262:Ribonuclease P