The neglected genome

Pesole, Graziano; Allen, John F.; Lane, Nick; Martin, William; Rand, David M.; Schatz, Gottfried; Saccone, Cecilia

doi:10.1038/embor.2012.57

Cited by 43 publications

(35 citation statements)

References 16 publications

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“…Their small genomes have been the subject of increasing attention, and there is evidence that mitochondrial genetic variation can affect evolutionary trajectories and shape the expression of life-history traits considered to be key human health indicators [1,2]. However, it is not understood how genetic variation across a diminutive genome, which in most species harbors only about a dozen protein-coding genes, can exert broadscale effects on the organismal phenotype [2,3]. Such effects are particularly puzzling given that the mitochondrial genes involved are under strong evolutionary constraint and that mitochondrial gene expression is highly conserved across diverse taxa [4].…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging

et al. 2015

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Mitochondria underpin energy conversion in eukaryotes. Their small genomes have been the subject of increasing attention, and there is evidence that mitochondrial genetic variation can affect evolutionary trajectories and shape the expression of life-history traits considered to be key human health indicators [1, 2]. However, it is not understood how genetic variation across a diminutive genome, which in most species harbors only about a dozen protein-coding genes, can exert broad-scale effects on the organismal phenotype [2, 3]. Such effects are particularly puzzling given that the mitochondrial genes involved are under strong evolutionary constraint and that mitochondrial gene expression is highly conserved across diverse taxa [4]. We used replicated genetic lines in the fruit fly, Drosophila melanogaster, each characterized by a distinct and naturally occurring mitochondrial haplotype placed alongside an isogenic nuclear background. We demonstrate that sequence variation within the mitochondrial DNA (mtDNA) affects both the copy number of mitochondrial genomes and patterns of gene expression across key mitochondrial protein-coding genes. In several cases, haplotype-mediated patterns of gene expression were gene-specific, even for genes from within the same transcriptional units. This invokes post-transcriptional processing of RNA in the regulation of mitochondrial genetic effects on organismal phenotypes. Notably, the haplotype-mediated effects on gene expression could be traced backward to the level of individual nucleotides and forward to sex-specific effects on fertility and longevity. Our study thus elucidates how small-scale sequence changes in the mitochondrial genome can achieve broad-scale regulation of health-related phenotypes and even contribute to sex-related differences in longevity.

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Section: Discussionmentioning

confidence: 99%

Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging

et al. 2015

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“…emerging nuclear genome, and a system to import proteins back into the mitochondrial organelle (Rand et al, 2004;Ballard and Rand, 2005;Pesole et al, 2012). As an outcome of this coadaptation the mitochondria and cytosol have established circuits of signaling that ensure homeostasis through cellular plasticity in response to altered environmental conditions.…”

Section: Divergent Mitochondrial Genotypes On a Common Nuclear Backgrmentioning

confidence: 99%

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Villa-Cuesta

Holmbeck

Rand

2014

Journal of Cell Science

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Downregulation of the mammalian target of rapamycin (mTOR) pathway by its inhibitor rapamycin is emerging as a potential pharmacological intervention that mimics the beneficial effects of dietary restriction. Modulation of mTOR has diverse effects on mitochondrial metabolism and biogenesis, but the role of the mitochondrial genotype in mediating these effects remains unknown. Here, we use novel mitochondrial genome replacement strains in Drosophila to test the hypothesis that genes encoded in mitochondrial DNA (mtDNA) influence the mTOR pathway. We show that rapamycin increases mitochondrial respiration and succinate dehydrogenase activity, decreases H 2 O 2 production and generates distinct shifts in the metabolite profiles of isolated mitochondria versus whole Drosophila. These effects are disabled when divergent mitochondrial genomes from D. simulans are placed into a common nuclear background, demonstrating that the benefits of rapamycin to mitochondrial metabolism depend on genes encoded in the mtDNA. Rapamycin is able to enhance mitochondrial respiration when succinate dehydrogenase activity is blocked, suggesting that the beneficial effects of rapamycin on these two processes are independent. Overall, this study provides the first evidence for a link between mitochondrial genotype and the effects of rapamycin on mitochondrial metabolic pathways.

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“…In mammals, mtDNA mutates at high rates and is maternally inherited, making it a popular marker in evolutionary genetics (2). Despite its importance, mtDNA has drifted away from the spotlight eclipsed by nuclear DNA studies (3), and there are still gaps in our understanding of the basic aspects of human mtDNA biology. The lack of cures for diseases caused by mtDNA mutations makes it critical to understand how these mutations arise and are transmitted between generations.…”

mentioning

confidence: 99%

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

Rebolledo‐Jaramillo¹,

Su²,

Stoler³

et al. 2014

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

218

324

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The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germline mtDNA bottleneck at only ∼30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10 −8 (interquartile range from 4.2 × 10 −9 to 4.1 × 10) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome. mitochondria | heteroplasmy

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The neglected genome

Abstract: The mitochondrial genome, though tiny, is vital to life. Modern high‐throughput investigations should pay closer attention to this minute genetic treasure trove.

Cited by 43 publications

References 16 publications

Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging

Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

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