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Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations.

ABSTRACT: The dynamics of the cellular proportion of mutant mtDNA molecules is crucial for mitochondrial diseases. Cellular populations of mitochondria are under homeostatic control, but the details of the control mechanisms involved remain elusive. Here, we use stochastic modelling to derive general results for the impact of cellular control on mtDNA populations, the cost to the cell of different mtDNA states, and the optimisation of therapeutic control of mtDNA populations. This formalism yields a wealth of biological results, including that an increasing mtDNA variance can increase the energetic cost of maintaining a tissue, that intermediate levels of heteroplasmy can be more detrimental than homoplasmy even for a dysfunctional mutant, that heteroplasmy distribution (not mean alone) is crucial for the success of gene therapies, and that long-term rather than short intense gene therapies are more likely to beneficially impact mtDNA populations.

SUBMITTER: Hoitzing H

PROVIDER: S-EPMC6615642 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations.

Hoitzing Hanne H Gammage Payam A PA Haute Lindsey Van LV Minczuk Michal M Johnston Iain G IG Jones Nick S NS

PLoS computational biology 20190626 6

The dynamics of the cellular proportion of mutant mtDNA molecules is crucial for mitochondrial diseases. Cellular populations of mitochondria are under homeostatic control, but the details of the control mechanisms involved remain elusive. Here, we use stochastic modelling to derive general results for the impact of cellular control on mtDNA populations, the cost to the cell of different mtDNA states, and the optimisation of therapeutic control of mtDNA populations. This formalism yields a wealt ...[more]

PMID: 31242175

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Project description:The study of genetic information can reveal a reconstruction of human population's history. We sequenced the entire mtDNA control region (positions 16.024 to 576 following Cambridge Reference Sequence, CRS) of 605 individuals from seven Mesoamerican indigenous groups and one Aridoamerican from the Greater Southwest previously defined, all of them in present Mexico. Samples were collected directly from the indigenous populations, the application of an individual survey made it possible to remove related or with other origins samples. Diversity indices and demographic estimates were calculated. Also AMOVAs were calculated according to different criteria. An MDS plot, based on FST distances, was also built. We carried out the construction of individual networks for the four Amerindian haplogroups detected. Finally, barrier software was applied to detect genetic boundaries among populations. The results suggest: a common origin of the indigenous groups; a small degree of European admixture; and inter-ethnic gene flow. The process of Mesoamerica's human settlement took place quickly influenced by the region's orography, which development of genetic and cultural differences facilitated. We find the existence of genetic structure is related to the region's geography, rather than to cultural parameters, such as language. The human population gradually became fragmented, though they remained relatively isolated, and differentiated due to small population sizes and different survival strategies. Genetic differences were detected between Aridoamerica and Mesoamerica, which can be subdivided into "East", "Center", "West" and "Southeast". The fragmentation process occurred mainly during the Mesoamerican Pre-Classic period, with the Otomí being one of the oldest groups. With an increased number of populations studied adding previously published data, there is no change in the conclusions, although significant genetic heterogeneity can be detected in Pima and Huichol groups. This result may be explained because populations historically assigned as belonging to the same group were, in fact, different indigenous populations.

Dataset Information

Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations.

Publications

Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations.

Similar Datasets

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