Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers

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According to the so-called “tRNA punctuation model”, tRNA processing is key to generating all mature mitochondrial mRNAs. However, the process is difficult to study in vivo, since standard tools for genetic manipulation are not applicable to mitochondria. Here, we circumvent this problem by using a large compendium of naturally occurring genetic perturbations, derived from human tumor sequencing data. We identify somatic mitochondrial mutations across hundreds of human tumors using an approach that simultaneously takes advantage of both genomic and transcriptomic sequencing. This enables us to compare the allele frequency in DNA and RNA for each mutation. Our data reveals that some mutations in mitochondrial tRNAs are associated with strong accumulation of immature tRNA precursors, indicative of impaired tRNA mutaration. We find that intact tRNA secondary structure is a major requirement for correct maturation, and that mutations affecting tRNA folding can impair maturation of not only the affected tRNA, but also neighboring gene transcripts. Mutations in mitochondrial tRNAs underlie a range of disease conditions, and our findings may help to explain why mutations in the same tRNA can present different phenotypes. Our results additionally support that there is selective pressure against mutations affecting oxidative phosphorylation, showing that functional mitochondria are required in many tumor cells.

Vyšlo v časopise: Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005333
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005333

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