دورية أكاديمية
Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging
| العنوان: | Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging |
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| المؤلفون: | Scott A. Lujan, Matthew J. Longley, Margaret H. Humble, Christopher A. Lavender, Adam Burkholder, Emma L. Blakely, Charlotte L. Alston, Grainne S. Gorman, Doug M. Turnbull, Robert McFarland, Robert W. Taylor, Thomas A. Kunkel, William C. Copeland |
| المصدر: | Genome Biology, Vol 21, Iss 1, Pp 1-34 (2020) |
| بيانات النشر: | BMC, 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Biology (General) LCC:Genetics |
| مصطلحات موضوعية: | Biology (General), QH301-705.5, Genetics, QH426-470 |
| الوصف: | Abstract 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1474-760X |
| Relation: | http://link.springer.com/article/10.1186/s13059-020-02138-5; https://doaj.org/toc/1474-760X |
| DOI: | 10.1186/s13059-020-02138-5 |
| URL الوصول: | https://doaj.org/article/15e2915608854379b2a6c820537c4ae2 |
| رقم الأكسشن: | edsdoj.15e2915608854379b2a6c820537c4ae2 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1474760X |
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| DOI: | 10.1186/s13059-020-02138-5 |