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Tissue-specific apparent mtDNA heteroplasmy and its relationship with ageing and mtDNA gene expression

Wengert, S.; Giannoulis, X.; Kreitmaier, P.; Kautz, P.; Ludwig, L. S.; Prokisch, H.; Casale, F. P.; Heinig, M.; Cai, N.

2024-12-16 genomics
10.1101/2024.12.11.627989 bioRxiv
Show abstract

Heteroplasmy in the mitochondrial DNA (mtDNA) accumulates with age, but how much it occurs in tissues and how it affects function and physiology is not well-studied. Here we present a comprehensive tissue-specific map of mtDNA heteroplasmy and mtRNA modifications, and their relationships with age and mitochondrial gene expression. We propose a robust variant calling pipeline for mtDNA heteroplasmy and mtRNA modifications using bulk RNAseq data from 49 tissues in GTEx, and a calibrated phenotype association framework for both types of variants. We identify 109 associations between them and donor age, and 784 associations with tissue-specific mtDNA gene expression. Of these, 7 and 18 show cell-type specificity within tissue. In addition, we find 9 instances where these variations mediate donor age effects on mtDNA gene expression. Finally, we confirm previously identified relationships between mt-tRNA modifications and gene expression on their 5, but read- and gene-level investigations reveal previously unmodeled complexities.

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