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Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability.

ABSTRACT: BACKGROUND:The accumulation of mtDNA mutations in different tissues from various mouse models has been widely studied especially in the context of mtDNA mutation-driven ageing but has been confounded by the inherent limitations of the most widely used approaches. By implementing a method to sequence mtDNA without PCR amplification prior to library preparation, we map the full unbiased mtDNA mutation spectrum across six distinct brain regions from mice. RESULTS:We demonstrate that ageing-induced levels of mtDNA mutations (single nucleotide variants and deletions) reach stable levels at 50?weeks of age but can be further elevated specifically in the cortex, nucleus accumbens (NAc), and paraventricular thalamic nucleus (PVT) by expression of a proof-reading-deficient mitochondrial DNA polymerase, PolgD181A. The increase in single nucleotide variants increases the fraction of shared SNVs as well as their frequency, while characteristics of deletions remain largely unaffected. In addition, PolgD181A also induces an ageing-dependent accumulation of non-coding control-region multimers in NAc and PVT, a feature that appears almost non-existent in wild-type mice. CONCLUSIONS:Our data provide a novel view of the spatio-temporal accumulation of mtDNA mutations using very limited tissue input. The differential response of brain regions to a state of replication instability provides insight into a possible heterogenic mitochondrial landscape across the brain that may be involved in the ageing phenotype and mitochondria-associated disorders.

SUBMITTER: Bagge EK

PROVIDER: S-EPMC7585204 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability.

Bagge Emilie Kristine EK Fujimori-Tonou Noriko N Kubota-Sakashita Mie M Kasahara Takaoki T Kato Tadafumi T

BMC biology 20201023 1

<h4>Background</h4>The accumulation of mtDNA mutations in different tissues from various mouse models has been widely studied especially in the context of mtDNA mutation-driven ageing but has been confounded by the inherent limitations of the most widely used approaches. By implementing a method to sequence mtDNA without PCR amplification prior to library preparation, we map the full unbiased mtDNA mutation spectrum across six distinct brain regions from mice.<h4>Results</h4>We demonstrate that ...[more]

PMID: 33097039

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Project description:BACKGROUND:The licensed doctor misdistribution is one of the major challenges faced by China. However, this subject remains underexplored as spatial distribution characteristics (such as spatial clustering patterns) have not been fully mapped out by existing studies. To fill the void, this study aims to explore the spatio-temporal dynamics and spatial clustering patterns of different subtypes of licensed doctors (i.e., clinicians, traditional Chinese medicine doctors, dentists, public health doctors, general practitioners) in China. METHODS:Data on the licensed doctor quantity and population during 2012-2016 was obtained from the National Health (and Family Planning) Yearbook. Functional boxplots were used to visualize and compare the temporal trends of densities of different subtypes of licensed doctors. This study adopted two complementary spatial statistics (space-time scan statistics and Moran's I statistics) to explore the spatio-temporal dynamics and spatial clustering patterns of licensed doctor distribution in China. The former was used to explore the spatial variations in the temporal trends of licensed doctor density during 2012-2016, and the latter was adopted to explore the spatial changing patterns of licensed doctor distribution during the research period. RESULTS:The results show that the densities of almost all subtypes of licensed doctors displayed upward trends during 2012-2016, though some provincial units were left behind. Besides, spatial distribution characteristics varied across different subtypes of licensed doctors, with the low-low cluster area of general practitioners being the largest. CONCLUSIONS:The misdistribution of licensed doctors is a global problem and China is no exception. In order to achieve a balanced distribution of licensed doctors, the government is suggested to introduce a series of measures, such as deliberative policy design and effective human resource management initiatives to educate, recruit, and retain licensed doctors and prevent a brain drain of licensed doctors from disadvantaged units.

Dataset Information

Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability.

Publications

Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability.

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