scholarly journals Quasi-Mendelian Paternal Inheritance of mitochondrial DNA: A notorious artifact, or anticipated mtDNA behavior?

2019 ◽  
Author(s):  
Sofia Annis ◽  
Zoe Fleischmann ◽  
Mark Khrapko ◽  
Melissa Franco ◽  
Kevin Wasko ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Selective Advantage ◽  
Somatic Tissue ◽  
Biparental Inheritance ◽  
Mtdna Copy Number ◽  
Mendelian Segregation ◽  
Paternal Haplotype ◽  
Mtdna Haplotype

AbstractA recent report by Luo et al (2018) in PNAS (DOI:10.1073/pnas.1810946115) presented evidence of biparental inheritance of mitochondrial DNA. The pattern of inheritance, however, resembled that of a nuclear gene. The authors explained this peculiarity with Mendelian segregation of a faulty gatekeeper gene that permits survival of paternal mtDNA in the oocyte. Three other groups (Vissing, 2019; Lutz-Bonengel and Parson, 2019; Salas et al, 2019), however, posited the observation was an artifact of inheritance of mtDNA nuclear pseudogenes (NUMTs), present in the father’s nuclear genome. We present justification that both interpretations are incorrect, but that the original authors did, in fact, observe biparental inheritance of mtDNA. Our alternative model assumes that because of initially low paternal mtDNA copy number these copies are randomly partitioned into nascent cell lineages. The paternal mtDNA haplotype must have a selective advantage, so ‘seeded’ cells will tend to proceed to fixation of the paternal haplotype in the course of development. We use modeling to emulate the dynamics of paternal genomes and predict their mode of inheritance and distribution in somatic tissue. The resulting offspring is a mosaic of cells that are purely maternal or purely paternal – including in the germline. This mosaicism explains the quasi-Mendelian segregation of the paternal mDNA. Our model is based on known aspects of mtDNA biology and explains all of the experimental observations outlined in Luo et. al., including maternal inheritance of the grand-paternal mtDNA.

199 EVIDENCE FOR A NOVEL PERTURBATION IN CLONED FETUSES: MITOCHONDRIAL DNA DEPLETION

2007 ◽  
Vol 19 (1) ◽  
pp. 216
Author(s):  
S. Hiendleder ◽  
D. Bebbere ◽  
S. E. Ulbrich ◽  
V. Zakhartchenko ◽  
M. Weppert ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Real Time ◽  
Nuclear Gene ◽  
Complement C3 ◽  
Mtdna Copy Number ◽  
Vitro Fertilization ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Dna Depletion

The reported mtDNA turnover and plasticity of mtDNA copy number in mammalian zygotes and early embryos (McConnel and Petrie 2004 Reprod. Biomed. Online 9, 418–424) have revealed a potential for adverse effects of in vitro embryo techniques on mtDNA and mitochondrial function. We explored the effects of in vitro fertilization (IVF) and somatic cell nuclear transfer cloning (NT) on relative mtDNA amount and phenotype in viable bovine fetuses recovered 80 days after the initiation of embryonic development (Hiendleder et al. 2004 Biol. Reprod. 71, 217–223). We sampled brain, liver, and skeletal muscle to represent all 3 embryonic germ layers, and compared IVF-fetuses (n = 24), NT-fetuses (n = 23), and fetuses generated by in vivo insemination (controls, n = 24). This experimental approach allowed us to distinguish abnormalities specific to cloning from more general consequences of in vitro embryo manipulation. We analyzed relative mtDNA amounts by real-time quantitative PCR (qPCR) and amplified a segment of the mtDNA control region that was normalized against the nuclear gene complement C3. ANOVA (SPSS 13.0) of qPCR data and phenotypic parameters revealed significant effects of fetus group on mtDNA amount in liver (P < 0.05) and muscle (P < 0.01), and on fetus (P < 0.001), heart (P < 0.001), and liver (P < 0.001) weights. The mtDNA amount in all tissues from IVF-fetuses was normal, but mtDNA levels in liver (-23%; P < 0.05) and muscle (-24%; P < 0.01) of NT-fetuses were significantly lower than in controls. Fetuses derived from IVF- or NT-embryos were similar in weight and displayed fetal overgrowth (+19% and +22%; P < 0.001), but only the NT-fetuses were affected by disproportionate hepatomegaly and cardiomegaly with 31% and 49% increases (ANCOVA; P < 0.001) in their respective organ weights. This further partitioned NT-fetuses from IVF-fetuses and identified symptoms that are also encountered in mitochondrial DNA depletion syndromes (MDDS): a phenotypically heterogeneous group of human disorders characterized by loss of mtDNA from various tissues during development and associated respiratory chain dysfunction. The MDDS phenotypes have mainly been classified into a hepatocerebral (MIM 251880) or myopathic (MIM 609560) form, and neonates and infants display a spectrum of abnormalities, including hepatomegaly and cardiomegaly, that are similar or identical to phenotypic abnormalities commonly encountered in cloned mammals. Reduced mtDNA amounts in NT-fetuses could stem from perturbation of mtDNA during the reported turnover period, or be a secondary effect of epigenetic change in nuclear-encoded genes involved in mtDNA replication and stability. Mitochondrial transcription factor A (TFAM) is regulated by CpG methylation in vitro, but our real-time RT-PCR quantification of TFAM transcript in liver and muscle of a subset of NT- and control fetuses failed to detect significant differences (P > 0.10). In conclusion, our observed reduction of mtDNA amount in cloned fetuses provides the molecular basis for a mitochondrial perspective on pathological phenotypes of cloned mammals, and may explain similarities to mitochondrial disease in human.

Geographic distribution and seasonal variation of mitochondrial DNA haplotypes in the aphid Rhopalosiphum padi (Hemiptera: Aphididae)

1997 ◽  
Vol 87 (2) ◽  
pp. 161-167 ◽  
Author(s):  
D. Martinez-Torres ◽  
A. Moya ◽  
P.D.N. Hebert ◽  
J.-C. Simon
Keyword(s):  
Mitochondrial Dna ◽  
Seasonal Variation ◽  
Gene Flow ◽  
Temperature Regime ◽  
Rhopalosiphum Padi ◽  
Nuclear Gene ◽  
Selective Advantage ◽  
Nuclear Markers ◽  
Host Alternation ◽  
Dna Diversity

AbstractThis study examines the spatial and seasonal patterning of mitochondrial DNA diversity in French populations of the bird cherry-oat aphid, Rhopalosiphum padi (Linnaeus), on both its primary and secondary hosts. Our results confirm the presence of two major mitochondrial lineages that are generally associated with the breeding system variation (cyclic and obligate parthenogenesis) shown by this species. The strength of this relationship varies regionally, being most evident in the south and west. Cyclically parthenogenetic populations show no significant regional or seasonal genetic divergence reflecting high levels of gene flow, possibly promoted by their obligate host-alternation. However, obligately parthenogenetic populations show a north-south cline in the distribution of the dominant haplotypes. This pattern might result from a selective advantage of some obligately parthenogenetic lineages under cold temperature regime. Alternatively, this cline might be established by a gradient in the intensity of nuclear gene flow between cyclically and obligately parthenogenetic populations mediated by androcyclic males. The discrimination between these possible explanations will require extending analysis to include hypervariable nuclear markers.

scholarly journals Extensive Variation in Nuclear Mitochondrial DNA Content Between the Genomes of Phytophthora sojae and Phytophthora ramorum

2006 ◽  
Vol 19 (12) ◽  
pp. 1329-1336 ◽  
Author(s):  
Konstantinos Krampis ◽  
Brett M. Tyler ◽  
Jeffrey L. Boore
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Genome ◽  
Sequence Divergence ◽  
Nuclear Gene ◽  
Phytophthora Sojae ◽  
Phytophthora Ramorum ◽  
Mtdna Sequences ◽  
Sequence Comparisons ◽  
Mitochondrial Dna Content ◽  
Mitochondrial Dnas

Fragments of mitochondrial DNA (mtDNA) transferred to the nuclear genome are called nuclear mitochondrial DNAs (NUMTs). We report here a comparison of NUMT content between genomes from two species of the same genus. Analysis of the genomes of Phytophthora sojae and P. ramorum revealed large differences in the NUMT content of the two genomes: 16.27 × 10−3 and 2.28 × 10−3% of each genome, respectively. Substantial differences also exist between the two species in the sizes of the NUMTs found in each genome, with ranges of 20 to 405 bp for P. sojae and 19 to 137 bp for P. ramorum. Furthermore, in P. sojae, fragments from the mitochondrial genes rns, rnl, cox1, and nad (various subunits) are found most frequently, whereas P. ramorum NUMTs most often originate from the cox3, rps14, nad4, and nad5 genes. The large differences in the presumptive mtDNA insertions suggest that the insertions occurred subsequent to the divergence of the two species, and this is supported by sequence comparisons among the NUMTs and the mtDNA sequences of the two species. P. sojae mtDNA sequences inserted in the nuclear genome appear to have been altered as a result of insertions, deletions, inversions, and translocations and provide insights into active mechanisms of sequence divergence in this plant pathogen. No clear examples were found of NUMTs forming functional nuclear genes or of NUMTs inserted into exons or introns of any nuclear gene.

Progress in mitochondrial epigenetics

2013 ◽  
Vol 4 (4) ◽  
pp. 381-389 ◽  
Author(s):  
Hari Manev ◽  
Svetlana Dzitoyeva
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Expression Patterns ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Methylation Pattern ◽  
Mitochondrial Activity ◽  
Epigenetic Mechanisms ◽  
Molecular Events ◽  
Recent Developments

AbstractMitochondria, intracellular organelles with their own genome, have been shown capable of interacting with epigenetic mechanisms in at least four different ways. First, epigenetic mechanisms that regulate the expression of nuclear genome influence mitochondria by modulating the expression of nuclear-encoded mitochondrial genes. Second, a cell-specific mitochondrial DNA content (copy number) and mitochondrial activity determine the methylation pattern of nuclear genes. Third, mitochondrial DNA variants influence the nuclear gene expression patterns and the nuclear DNA (ncDNA) methylation levels. Fourth and most recent line of evidence indicates that mitochondrial DNA similar to ncDNA also is subject to epigenetic modifications, particularly by the 5-methylcytosine and 5-hydroxymethylcytosine marks. The latter interaction of mitochondria with epigenetics has been termed ‘mitochondrial epigenetics’. Here we summarize recent developments in this particular area of epigenetic research. Furthermore, we propose the term ‘mitoepigenetics’ to include all four above-noted types of interactions between mitochondria and epigenetics, and we suggest a more restricted usage of the term ‘mitochondrial epigenetics’ for molecular events dealing solely with the intra-mitochondrial epigenetics and the modifications of mitochondrial genome.

scholarly journals Plasticity of Mitochondrial DNA Inheritance and its Impact on Nuclear Gene Transcription in Yeast Hybrids

2018 ◽  
Author(s):  
Sarah K. Hewitt ◽  
Kobchai Duangrattanalert ◽  
Tim Burgis ◽  
Leo A.H. Zeef ◽  
Daniela Delneri
Keyword(s):  
Mitochondrial Dna ◽  
Expression Profiles ◽  
Hybrid Cell ◽  
Carbon Sources ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
The Other ◽  
Cellular Functions ◽  
Hybrid Fitness ◽  
Selection Of

AbstractMitochondrial DNA (mtDNA) in budding yeast is biparentally inherited, but colonies rapidly lose one type of parental mtDNA, becoming homoplasmic. Therefore, hybrids between different yeast species possess two homologous nuclear genomes, but only one type of mitochondrial DNA. We hypothesise that the choice of mtDNA retention is influenced by its contribution to hybrid fitness in different environments, and that the allelic expression of the two nuclear sub-genomes is affected by the presence of different mtDNAs in hybrids. Here, we crossedSaccharomyces cerevisiaewithS. uvarumunder different environmental conditions and examined the plasticity of the retention of mtDNA in each hybrid. We showed that on fermentable carbon sources at warm temperatures each parental mtDNA was equally likely to be retained, while at colder temperatures, hybrids preferentially retained mtDNA derived fromS. uvarum. On a non-fermentable carbon source, hybrids retainedS. cerevisiaemtDNA, independent of temperature. By acquiring transcriptome data and co-expression profiles for hybrids harbouring different mtDNA in a selection of environments, we found a clear pattern of concerted allelic transcription of one or the other sub-genome for specific biological pathways, supporting the notion that the hybrid cell works preferentially with one set of parental alleles or the other according to specific cellular functions. We argue that the type of mtDNA retained in hybrids affects the expression of the nuclear genome and the organism fitness in different environments, and therefore may have a role in driving the evolution of the hybrid nuclear genome in terms of gene retention and loss.

A single-tube multiplex qPCR assay for mitochondrial DNA (mtDNA) copy number assessment

2019 ◽  
Vol 44 (6) ◽  
pp. 769-777 ◽  
Author(s):  
Hasan Basri Kiliç ◽  
Bengisu Kevser Bulduk ◽  
Y. Çetin Kocaefe
Keyword(s):  
18S Rdna ◽  
Copy Number ◽  
Molecular Beacon ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Single Copy ◽  
Mtdna Copy Number ◽  
Single Tube ◽  
Multiplex Qpcr ◽  
Copy Sequence

Abstract Objective Detection of mtDNA copy number is required for diagnosis of mtDNA depletion. Multiplex quantification of mtDNA in blood samples was claimed via normalizing to a nuclear single copy gene using qPCR. This is not possible in high mtDNA samples due to template abundance. Multiplex qPCR assays cannot be normalized to single copy sequences of the nuclear genome. Methods mtDNA quantification was tested normalizing to a single copy nuclear gene via singleplex and multiplex reactions. Failure in normalization directed to design and test targeting multi-copy 18S rDNA gene with success. mtDNA quantification was standardized both in separate and multiplexed single-tube reactions based on molecular beacon technology. Results mtDNA copy number assessment cannot be normalized to a single copy sequence in high-copy-number tissues. However, normalizing mtDNA to the nuclear 18S rDNA multiple copy sequence is amenable to be standardized in single tube. When compared, multiplexing exhibited higher resolution power for quantification of mtDNA in various samples from the most abundant to the scant ones. Conclusion We describe a multiplex assay that can be translated as a standard technique for single-tube quantification of mtDNA copy number. Our findings show higher accuracy and reproducibility over canonical approach, reducing cost and error rate.

Mitochondrial Genotype Affects Fitness in Drosophila simulans

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 187-194 ◽  
Author(s):  
Avis C James ◽  
J William O Ballard
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Variation ◽  
Life History ◽  
Geographic Distribution ◽  
Life History Traits ◽  
Nuclear Genome ◽  
Drosophila Simulans ◽  
Wild Type ◽  
Mitochondrial Genotype ◽  
Mtdna Haplotype

Abstract Drosophila simulans is known to harbor three distinct mitochondrial DNA (mtDNA) haplotype groups (siI, -II, and -III) with nearly 3.0% interhaplotypic divergence but <0.06% intrahaplotypic diversity. With the large amount of genetic variation in this system, the potential power to detect intraspecific fitness differences in fly lines that carry distinct haplotypes is great. We test three life-history traits on fly lines with known sequence differences in the mtDNA genome after controlling the nuclear genome by backcrossing. We find that flies with the siI haplotype are fastest developing and have the lowest probability of surviving to three experimental periods (2–6, 12–17, and 34–39 days of age). Wild-type males with siIII mtDNA were more active while disruption of specific coadapted nucleo-mitochondrial complexes caused a significant decrease in activity. These results are discussed in the context of the geographic distribution of each haplotype.

scholarly journals Elimination of rNMPs from mitochondrial DNA has no effect on its stability

2020 ◽  
Vol 117 (25) ◽  
pp. 14306-14313
Author(s):  
Paulina H. Wanrooij ◽  
Phong Tran ◽  
Liam J. Thompson ◽  
Gustavo Carvalho ◽  
Sushma Sharma ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Life Span ◽  
Genome Stability ◽  
Nuclear Genome ◽  
Dna Strand Breaks ◽  
Mtdna Copy Number ◽  
Timely Manner ◽  
Strand Breaks ◽  
Progressive Loss ◽  
Dna Strand

Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent inSAMHD1−/−mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.

Development of a mito-CRISPR system for generating mitochondrial DNA-deleted strain in Saccharomyces cerevisiae

2020 ◽  
Vol 85 (4) ◽  
pp. 895-901
Author(s):  
Takamitsu Amai ◽  
Tomoka Tsuji ◽  
Mitsuyoshi Ueda ◽  
Kouichi Kuroda
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Dna ◽  
Ethidium Bromide ◽  
Nuclear Genome ◽  
Target Sequence ◽  
Guide Rna ◽  
Crispr System ◽  
Mitochondrial Target ◽  
Gene Treatment ◽  
Mtdna Deletion

ABSTRACT Mitochondrial dysfunction can occur in a variety of ways, most often due to the deletion or mutation of mitochondrial DNA (mtDNA). The easy generation of yeasts with mtDNA deletion is attractive for analyzing the functions of the mtDNA gene. Treatment of yeasts with ethidium bromide is a well-known method for generating ρ° cells with complete deletion of mtDNA from Saccharomyces cerevisiae. However, the mutagenic effects of ethidium bromide on the nuclear genome cannot be excluded. In this study, we developed a “mito-CRISPR system” that specifically generates ρ° cells of yeasts. This system enabled the specific cleavage of mtDNA by introducing Cas9 fused with the mitochondrial target sequence at the N-terminus and guide RNA into mitochondria, resulting in the specific generation of ρ° cells in yeasts. The mito-CRISPR system provides a concise technology for deleting mtDNA in yeasts.

scholarly journals Risk of cardiac manifestations in adult mitochondrial disease caused by nuclear genetic defects

Open Heart ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. e001510
Author(s):  
Albert Zishen Lim ◽  
Daniel M Jones ◽  
Matthew G D Bates ◽  
Andrew M Schaefer ◽  
John O'Sullivan ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Laboratory Data ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Left Ventricular ◽  
Adult Patients ◽  
Limited Information ◽  
Cardiac Abnormalities ◽  
Cardiac Manifestations

ObjectiveRegular cardiac surveillance is advocated for patients with primary mitochondrial DNA disease. However, there is limited information to guide clinical practice in mitochondrial conditions caused by nuclear DNA defects. We sought to determine the frequency and spectrum of cardiac abnormalities identified in adult mitochondrial disease originated from the nuclear genome.MethodsAdult patients with a genetically confirmed mitochondrial disease were identified and followed up at the national clinical service for mitochondrial disease in Newcastle upon Tyne, UK (January 2009 to December 2018). Case notes, molecular genetics reports, laboratory data and cardiac investigations, including serial electrocardiograms and echocardiograms, were reviewed.ResultsIn this cohort-based observational study, we included 146 adult patients (92 women) (mean age 53.6±18.7 years, 95% CI 50.6 to 56.7) with a mean follow-up duration of 7.9±5.1 years (95% CI 7.0 to 8.8). Eleven different nuclear genotypes were identified: TWNK, POLG, RRM2B, OPA1, GFER, YARS2, TYMP, ETFDH, SDHA, TRIT1 and AGK. Cardiac abnormalities were detected in 14 patients (9.6%). Seven of these patients (4.8%) had early-onset cardiac manifestations: hypertrophic cardiomyopathy required cardiac transplantation (AGK; n=2/2), left ventricular (LV) hypertrophy and bifascicular heart block (GFER; n=2/3) and mild LV dysfunction (GFER; n=1/3, YARS2; n=1/2, TWNK; n=1/41). The remaining seven patients had acquired heart disease most likely related to conventional cardiovascular risk factors and presented later in life (14.6±12.8 vs 55.1±8.9 years, p<0.0001).ConclusionsOur findings demonstrate that the risk of cardiac involvement is genotype specific, suggesting that routine cardiac screening is not indicated for most adult patients with nuclear gene-related mitochondrial disease.

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