Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins

Avital, Gal; Buchshtav, Mor; Zhidkov, Ilia; Tuval, Jeanette; Dadon, Sara; Rubin, Eitan; Glass, Dan; Spector, Timothy D.; Mo, Dan

doi:10.1093/hmg/dds245

Cited by 83 publications

(92 citation statements)

References 40 publications

(50 reference statements)

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“…pointing to the ubiquitous occurrence of heteroplasmy (4) and are in remarkable agreement with a recent analysis of the 1,000 Genomes Project data (19) as well as several smaller-scale studies (5,11,(32)(33)(34)) (Dataset S1, Table S14). …”

Section: Estimating the Size Of The Germ-line Mtdna Bottleneck And Musupporting

confidence: 89%

“…For deleterious heteroplasmies such a change may transform alleles that are benign at low frequency in a mother into diseasecausing alleles when at a high frequency in her child. Our study estimates the mtDNA germ-line bottleneck to be small (30)(31)(32)(33)(34)(35) and documents a positive association between the number of child heteroplasmies and maternal age at fertilization, enabling prediction of transmission of disease-causing variants and informing mtDNA evolution. Data deposition: The sequences reported in this paper have been deposited in the Sequence Read Archive, www.ncbi.nlm.nih.gov/sra (accession no.…”

Section: Significancementioning

confidence: 65%

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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.

212

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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Section: Estimating the Size Of The Germ-line Mtdna Bottleneck And Musupporting

confidence: 89%

Section: Significancementioning

confidence: 65%

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.

212

324

View full text Add to dashboard Cite

show abstract

“…Considering that heteroplasmy [11,40,44,45,107] and gene duplication of mitochondrial genes [46][47][48] are pervasive across taxa, the intraindividual level provides a new frontier for exploration of the evolutionary and medical significance of the mitonuclear interaction. A very striking example of the potential for intraindividual mitonuclear interaction was found in mice with artificially induced heteroplasmy between two wild-type mtDNAs, that of the Balb/cByJ mouse and that of the NZB/ BINJ mouse [108].…”

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

“…Heteroplasmy [44,45], gene duplication of nuclear-encoded mitochondrial genes [48,116], as well as the genetic footprint of adaptive selection in mitochondrial gene trees [117][118][119] are pervasive in humans, and all of these factors have the potential to fuel mitonuclear interactions for key phenotypes, as outlined above. Thus, the coevolutionary processes underpinning the mitonuclear interaction may provide tangible insights into our understanding of the origins of mitochondrial disease, and ultimately help us to predict incidences and severity of disease expression.…”

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Wolff

Ladoukakis

Enrı́quez

et al. 2014

Phil. Trans. R. Soc. B

196

218

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Fundamental biological processes hinge on coordinated interactions between genes spanning two obligate genomes—mitochondrial and nuclear. These interactions are key to complex life, and allelic variation that accumulates and persists at the loci embroiled in such intergenomic interactions should therefore be subjected to intense selection to maintain integrity of the mitochondrial electron transport system. Here, we compile evidence that suggests that mitochondrial–nuclear (mitonuclear) allelic interactions are evolutionarily significant modulators of the expression of key health-related and life-history phenotypes, across several biological scales—within species (intra- and interpopulational) and between species. We then introduce a new frontier for the study of mitonuclear interactions—those that occur within individuals, and are fuelled by the mtDNA heteroplasmy and the existence of nuclear-encoded mitochondrial gene duplicates and isoforms. Empirical evidence supports the idea of high-resolution tissue- and environment-specific modulation of intraindividual mitonuclear interactions. Predicting the penetrance, severity and expression patterns of mtDNA-induced mitochondrial diseases remains a conundrum. We contend that a deeper understanding of the dynamics and ramifications of mitonuclear interactions, across all biological levels, will provide key insights that tangibly advance our understanding, not only of core evolutionary processes, but also of the complex genetics underlying human mitochondrial disease.

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“…In addition, mtDNA exhibits intracellular variability (heteroplasmy), the extent of which differs across individuals (Goto et al 2011;Avital et al 2012). Moreover, in many organisms (vertebrates and invertebrates), RNA editing contributes a third layer of sequence diversity in the mitochondria (Reichert et al 1998).…”

mentioning

confidence: 99%

RNA–DNA differences in human mitochondria restore ancestral form of 16S ribosomal RNA

et al. 2013

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RNA transcripts are generally identical to the underlying DNA sequences. Nevertheless, RNA–DNA differences (RDDs) were found in the nuclear human genome and in plants and animals but not in human mitochondria. Here, by deep sequencing of human mitochondrial DNA (mtDNA) and RNA, we identified three RDD sites at mtDNA positions 295 (C-to-U), 13710 (A-to-U, A-to-G), and 2617 (A-to-U, A-to-G). Position 2617, within the 16S rRNA, harbored the most prevalent RDDs (>30% A-to-U and ∼15% A-to-G of the reads in all tested samples). The 2617 RDDs appeared already at the precursor polycistrone mitochondrial transcript. By using traditional Sanger sequencing, we identified the A-to-U RDD in six different cell lines and representative primates (Gorilla gorilla, Pongo pigmaeus, and Macaca mulatta), suggesting conservation of the mechanism generating such RDD. Phylogenetic analysis of more than 1700 vertebrate mtDNA sequences supported a thymine as the primate ancestral allele at position 2617, suggesting that the 2617 RDD recapitulates the ancestral 16S rRNA. Modeling U or G (the RDDs) at position 2617 stabilized the large ribosomal subunit structure in contrast to destabilization by an A (the pre-RDDs). Hence, these mitochondrial RDDs are likely functional.

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Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins

Cited by 83 publications

References 40 publications

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

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

Mitonuclear interactions: evolutionary consequences over multiple biological scales

RNA–DNA differences in human mitochondria restore ancestral form of 16S ribosomal RNA

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