After 4 fantastic years of research, together with @caina89.bsky.social & Matthias Heinig, I’m thrilled to share the first tissue specific map of apparent mtDNA heteroplasmy in humans and their relationships with donor age and mtDNA gene expr across 49 tissues! www.biorxiv.org/content/10.1... - ThreadSky

simon-wengert.bsky.social • 71 days ago

After 4 fantastic years of research, together with @caina89.bsky.social & Matthias Heinig, I’m thrilled to share the first tissue specific map of apparent mtDNA heteroplasmy in humans and their relationships with donor age and mtDNA gene expr across 49 tissues!

https://www.biorxiv.org/content/10.1101/2024.12.11.627989v1

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simon-wengert.bsky.social•71 days ago

1/7 How much does mtDNA heteroplasmy vary between tissues? How much of it is
transcribed to RNA and how much are mtRNAs modified post-transcription? We investigate how these variations change with age, and how they affect mtDNA gene expression in a tissue-specific manner.

simon-wengert.bsky.social•71 days ago

2/7 We first assess the landscape of both types of variations across tissues: for mtDNA heteroplasmy, we identify those with putatively somatic and inherited origins, and for mtRNA modifications, we find significant enrichments in CNS as compared to other tissues.

simon-wengert.bsky.social•71 days ago

3/7 Since the detection of both variations are affected by RNAseq coverage, we develop a calibrated association testing framework that accounts for coverage effects. Using it, we identify 109 assocs of mtDNA hets and mtRNA mods with donor age, 7 of which are cell type specific.

simon-wengert.bsky.social•71 days ago

4/7 Next, we apply the framework to test for relationships with mtDNA encoded poly-A transcript levels, and find 784 effects across tissues (# 576 mtDNA hets; # 208 mtRNA mods). We find that 18 of these are cell type specific, suggesting potentially common effects across cells.

simon-wengert.bsky.social•71 days ago

5/7 There are 10 sites (9 mtDNA het, 1 mtRNA mod) linked to both donor age and mtDNA gene exp. To learn how age, gene exp and het/mod are related, we perform a mediation analysis using partial corr, and find the variations are consistently mediating the effect of age on gene exp.

simon-wengert.bsky.social•71 days ago

6/7 Finally, we zoom in on p9 mt-tRNA mod levels to test their impact on mitochondrial transcript processing. We replicate prev assocs between them in blood, test this in all 48 tissues, and further test whether cuts on the 5’ of p9 mods mediate this effect using read-level data.

anavinuela.bsky.social•70 days ago

Congratulations Simon!! 🎉🎊Lovely to finally seeing this out.

simon-wengert.bsky.social•70 days ago

Thanks so much @anavinuela.bsky.social, glad you like it!! :)

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