A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations

Fan, Weiwei; Waymire, Katrina G.; Narula, Navneet; Li, Peng; Rocher, Christophe; Coşkun, Pınar; Vannan, Mani A.; Narula, Jagat; MacGregor, Grant R.; Wallace, Douglas C.

doi:10.1126/science.1147786

Cited by 407 publications

(397 citation statements)

References 18 publications

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“…Intriguingly mice harboring low proportions of a deleterious MT-ND6 frame-shift mutation were shown to transmit less and less of the mutation in their successive progeny, which would implicate some on-going selection at the ovarian level [44].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed.Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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“…Given the high mtDNA mutation rate and the great importance and conservation of the mtDNA genes, the cumulative mtDNA genetic load should drive animal species to extinction. This paradox is resolved because the mammalian ovary encompasses a selective system that systematically eliminates those proto-oocyes that harbor the most severely deleterious mtDNA mutations (21,22). Consequently, only oocytes with mildly deleterious, neutral, or beneficial mtDNA variants are ovulated and can be transmitted into the next generation.…”

Section: Energy Environments and Subpopulation Radiationmentioning

confidence: 99%

Bioenergetics, the origins of complexity, and the ascent of man

Wallace

2010

Proc. Natl. Acad. Sci. U.S.A.

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116

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Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the informationgenerating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.C harles Darwin and Albert Russel Wallace hypothesized that the environment acts on individual variation via natural selection to create new species (1, 2). However, nothing in the concept of natural selection requires that biological systems should evolve toward ever greater complexity. Yet, throughout the more than 3.5 billion years of biological evolution (3), life has generated ever more complex forms. What, then, drives increasing biological complexity, and what are its implications for the ascent of man? Bioenergetics and the Origin of Biological ComplexityIn a thermodynamically isolated system, complex structures decay toward randomness. However, in nonequilibrium systems, the flow of energy through the system generates and sustains structural complexity, and nonhomogeneous structures embody information (4, 5).On Earth, the flux of energy through the biosphere is relatively constant. If the flow of energy were the only factor generating complexity, complexity would soon achieve a steady state between the production and decay of structure. Biology is not static, because the information embedded in biological structures can be encoded and duplicated by informational molecules, DNA and RNA. Therefore, bio...

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“…Indeed, nucleosome code has been found to have a negative impact on protein sequence variations [45,46]. Fifth, complex organisms can eliminate reproductive cells carrying severe mutations [47]. Also, embryos of complex organisms may die or be aborted before birth if they did not develop properly due to mutations.…”

Section: Epigenetic Restriction Of Genetic Diversitymentioning

confidence: 99%