Codon affinity in mitochondrial DNA shapes evolutionary and somatic fitness
Summary Paragraph 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 compartmentin vivo, reminiscent of selection observed for pathogenic mtDNA alleles1, 2and 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 27. Apr. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lareau, Caleb A. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.04.23.537997 |
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| PPN (Katalog-ID): |
XBI039353028 |
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| 100 | 1 | |a Lareau, Caleb A. |e verfasserin |0 (orcid)0000-0003-4179-4807 |4 aut | |
| 245 | 1 | 0 | |a Codon affinity in mitochondrial DNA shapes evolutionary and somatic fitness |
| 264 | 1 | |c 2023 | |
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| 520 | |a Summary Paragraph 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 compartmentin vivo, reminiscent of selection observed for pathogenic mtDNA alleles1, 2and 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. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Yin, Yajie |0 (orcid)0000-0002-2220-005X |4 aut | |
| 700 | 1 | |a Gutierrez, Jacob C. |4 aut | |
| 700 | 1 | |a Dhindsa, Ryan S. |4 aut | |
| 700 | 1 | |a Gribling-Burrer, Anne-Sophie |4 aut | |
| 700 | 1 | |a Hsieh, Yu-Hsin |4 aut | |
| 700 | 1 | |a Nitsch, Lena |4 aut | |
| 700 | 1 | |a Buquicchio, Frank A. |4 aut | |
| 700 | 1 | |a Abay, Tsion |4 aut | |
| 700 | 1 | |a Zielinski, Sebastian |4 aut | |
| 700 | 1 | |a Stickels, Robert R. |4 aut | |
| 700 | 1 | |a Ulirsch, Jacob C. |4 aut | |
| 700 | 1 | |a Yan, Patrick |4 aut | |
| 700 | 1 | |a Wang, Fangyi |4 aut | |
| 700 | 1 | |a Miao, Zhuang |4 aut | |
| 700 | 1 | |a Sandor, Katalin |4 aut | |
| 700 | 1 | |a Daniel, Bence |4 aut | |
| 700 | 1 | |a Liu, Vincent |4 aut | |
| 700 | 1 | |a Wang, Quanli |4 aut | |
| 700 | 1 | |a Hu, Fengyuan |4 aut | |
| 700 | 1 | |a Smith, Katherine R. |4 aut | |
| 700 | 1 | |a Deevi, Sri V.V. |4 aut | |
| 700 | 1 | |a Maschmeyer, Patrick |4 aut | |
| 700 | 1 | |a Petrovski, Slavé |4 aut | |
| 700 | 1 | |a Smyth, Redmond P. |4 aut | |
| 700 | 1 | |a Greenleaf, William J. |4 aut | |
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| 700 | 1 | |a Satpathy, Ansuman T. |0 (orcid)0000-0002-5167-537X |4 aut | |
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