Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
21
06
2022
accepted:
20
03
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
13
5
2024
Statut:
aheadofprint
Résumé
The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.
Identifiants
pubmed: 38741018
doi: 10.1038/s41588-024-01724-8
pii: 10.1038/s41588-024-01724-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Susan G. Komen (Susan G. Komen Breast Cancer Foundation)
ID : SAC220206
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P30-CA008748
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R37-CA276200
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R37-CA276200
Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : RM1-HG011014
Organisme : U.S. Department of Defense (United States Department of Defense)
ID : W81XWH-18-1-0318
Informations de copyright
© 2024. The Author(s).
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