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| Item Type: | Preprint |
|---|---|
| Title: | Codon affinity in mitochondrial DNA shapes evolutionary and somatic fitness |
| Creators Name: | Lareau, C.A., Yin, Y., Gutierrez, J.C., Dhindsa, R.S., Gribling-Burrer, A.S., Hsieh, Y.H., Nitsch, L., Buquicchio, F.A., Abay, T., Zielinski, S., Stickels, R.R., Ulirsch, J.C., Yan, P., Wang, F., Miao, Z., Sandor, K., Daniel, B., Liu, V., Wang, Q., Hu, F., Smith, K.R., Deevi, S.V.V., Maschmeyer, P., Petrovski, S., Smyth, R.P., Greenleaf, W.J., Kundaje, A., Munschauer, M., Ludwig, L.S. and Satpathy, A.T. |
| Abstract: | Somatic variation contributes to biological heterogeneity by modulating cellular proclivity to differentiate, expand, adapt, or die. While large-scale sequencing efforts have revealed the foundational role of somatic variants to drive human tumor evolution, our understanding of the contribution of mutations to modulate cellular fitness in non-malignant contexts remains understudied. Here, we identify a mosaic synonymous variant (m.7076A>G) in the mitochondrial DNA (mtDNA) encoded cytochrome c-oxidase subunit 1 gene (MT-CO1, p.Gly391=), which was present at homoplasmy in 47% of immune cells from a healthy donor. Using single-cell multi-omics, we discover highly specific selection against the m.7076G mutant allele in the CD8+ effector memory T cell compartment in vivo, reminiscent of selection observed for pathogenic mtDNA alleles1,2 and indicative of lineage-specific metabolic requirements. While the wildtype m.7076A allele is translated via Watson-Crick-Franklin base-pairing, the anticodon diversity of the mitochondrial transfer RNA pool is limited, requiring wobble-dependent translation of the m.7076G mutant allele. Notably, mitochondrial ribosome profiling revealed altered codon-anticodon affinity at the wobble position as evidenced by stalled translation of the synonymous m.7076G mutant allele encoding for glycine. Generalizing this observation, we provide a new ontogeny of the 8,482 synonymous variants in the human mitochondrial genome that enables interpretation of functional mtDNA variation. Specifically, via inter- and intra-species evolutionary analyses, population-level complex trait associations, and the occurrence of germline and somatic mtDNA mutations from large-scale sequencing studies, we demonstrate that synonymous variation impacting codon:anticodon affinity is actively evolving across the entire mitochondrial genome and has broad functional and phenotypic effects. In summary, our results introduce a new ontogeny for mitochondrial genetic variation and support a model where organismal principles can be discerned from somatic evolution via single-cell genomics. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2023.04.23.537997 |
| Date: | 23 April 2023 |
| Official Publication: | https://doi.org/10.1101/2023.04.23.537997 |
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