Ontology highlight
ABSTRACT:
PROVIDER: PRJNA863572 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Sarda orientalis isolate CF-2 cytochrome b (cytb) gene, partial cds mitochondrial Raw sequence reads
| PRJNA541341 | ENA
Project description:Somatic variation contributes to biological heterogeneity by modulating the 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 somatic variation to modulate cellular fitness in non-malignant contexts remains understudied. Here, we identify a somatic synonymous variant (m.7076A>G) in the mitochondrial DNA (mtDNA) encoded cytochrome c-oxidase subunit 1 gene (COX1), 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 alleles and indicative of lineage-specific metabolic vulnerabilities. Due to the limited transfer RNA (tRNA) pool in mitochondria, the m.7076G mutant allele requires wobble-dependent translation whereas the wildtype m.7076A allele can translate via Watson-Crick-Franklin (WCF) base-pairing. Mitochondrial ribosome profiling revealed that the synonymous m.7076G mutant allele altered codon-anticodon affinity by 33% at the wobble position, stalling translation at the glycine residue within COX1 encoded at m.7076. Leveraging population-based sequencing analyses, we identify evidence of synonymous somatic variants in tumor genomes and dozens of germline variants associated with complex diseases, suggesting broad functional effects of synonymous variation altering codon affinity across the mitochondrial genome. Together, these results provide a new ontogeny for mitochondrial genetic variation and elucidate a framework whereby somatic variation can impact cell state transitions in a lineage-specific manner.
2024-10-31 | GSE216911 | GEO
Project description:Somatic variation contributes to biological heterogeneity by modulating the 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 somatic variation to modulate cellular fitness in non-malignant contexts remains understudied. Here, we identify a somatic synonymous variant (m.7076A>G) in the mitochondrial DNA (mtDNA) encoded cytochrome c-oxidase subunit 1 gene (COX1), 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 alleles and indicative of lineage-specific metabolic vulnerabilities. Due to the limited transfer RNA (tRNA) pool in mitochondria, the m.7076G mutant allele requires wobble-dependent translation whereas the wildtype m.7076A allele can translate via Watson-Crick-Franklin (WCF) base-pairing. Mitochondrial ribosome profiling revealed that the synonymous m.7076G mutant allele altered codon-anticodon affinity by 33% at the wobble position, stalling translation at the glycine residue within COX1 encoded at m.7076. Leveraging population-based sequencing analyses, we identify evidence of synonymous somatic variants in tumor genomes and dozens of germline variants associated with complex diseases, suggesting broad functional effects of synonymous variation altering codon affinity across the mitochondrial genome. Together, these results provide a new ontogeny for mitochondrial genetic variation and elucidate a framework whereby somatic variation can impact cell state transitions in a lineage-specific manner.
2024-10-31 | GSE216903 | GEO
Project description:The prokaryotic translation elongation factor P (EF-P), and the eukaryotic/archeal counterparts eIF5A/aIF5A, are proteins that serve a crucial role in mitigating ribosomal stalling during the translation of specific sequences, notably those containing consecutive proline residues. Although mitochondrial DNA-encoded proteins synthesized by mitochondrial ribosomes also contain polyproline stretches, an EF-P/eIF5A mitochondrial counterpart remains unidentified. Here, we show that the missing factor is the translational activator of COX1 (TACO1), a protein causative of a juvenile form of neurodegenerative Leigh's syndrome associated with cytochrome c oxidase deficiency. By using a combination of metabolic labeling, puromycin release, and ribosome profiling experiments, we show that TACO1 is required for the rapid synthesis of the poly-proline rich COX1 and COX3 proteins, while its requirement is negligible for other proteins. In agreement with a role in translation rate regulation, we show that TACO1 cooperates with the N-terminal extension of the large ribosomal subunit bL27m to provide stability to the peptidyl-transferase center during elongation, and that excess TACO1 enhances overall translation rate. We conclude that TACO1 is a Translation Accelerator and propose it as a promising target to regulate mitochondrial protein synthesis in disease scenarios.
2024-09-06 | PXD051090 | Pride