Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
17 09 2020
17 09 2020
Historique:
received:
07
04
2020
accepted:
07
08
2020
entrez:
18
9
2020
pubmed:
19
9
2020
medline:
12
6
2021
Statut:
epublish
Résumé
Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns. These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
Sections du résumé
BACKGROUND
Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease.
RESULTS
To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns.
CONCLUSIONS
These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
Identifiants
pubmed: 32943091
doi: 10.1186/s13059-020-02138-5
pii: 10.1186/s13059-020-02138-5
pmc: PMC7500033
doi:
Substances chimiques
DNA, Mitochondrial
0
DNA Polymerase gamma
EC 2.7.7.7
POLG protein, human
EC 2.7.7.7
Types de publication
Evaluation Study
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
248Subventions
Organisme : NIEHS NIH HHS
ID : ES065078
Pays : United States
Organisme : NIEHS NIH HHS
ID : ES065080
Pays : United States
Organisme : NIEHS NIH HHS
ID : ES065070
Pays : United States
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800674
Pays : United Kingdom
Organisme : Department of Health
ID : PDF-2018-11-ST2-02
Pays : United Kingdom
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