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Neal Sondheimer - One of the best experts on this subject based on the ideXlab platform.

  • nuclear genome wide associations with mitochondrial Heteroplasmy
    Science Advances, 2021
    Co-Authors: Priyanka Nandakumar, Chao Tian, Jared Oconnell, David A Hinds, Andrew D Paterson, Neal Sondheimer
    Abstract:

    The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of Heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of Heteroplasmy itself is deleterious. However, mitochondrial Heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial Heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of Heteroplasmy. GWAS identified 20 loci for Heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial Heteroplasmy has a heritable nuclear component.

  • g quadruplex mediated reduction of a pathogenic mitochondrial Heteroplasmy
    Human Molecular Genetics, 2019
    Co-Authors: Mansur M. Naeem, Rathena Maheshan, Sheila R Costford, Azizia Wahedi, Marko Trajkovski, Janez Plavec, Liliya A Yatsunyk, Grzegorz L Ciesielski, Brett A Kaufman, Neal Sondheimer
    Abstract:

    Disease-associated variants in mitochondrial DNA (mtDNA) are frequently heteroplasmic, a state of co-existence with the wild-type genome. Because Heteroplasmy correlates with the severity and penetrance of disease, improvement in the ratio between these genomes in favor of the wild-type, known as Heteroplasmy shifting, is potentially therapeutic. We evaluated known pathogenic mtDNA variants and identified those with the potential for allele-specific differences in the formation of non-Watson-Crick G-quadruplex (GQ) structures. We found that the Leigh syndrome (LS)-associated m.10191C variant promotes GQ formation within local sequence in vitro. Interaction of this sequence with a small molecule GQ-binding agent, berberine hydrochloride, further increased GQ stability. The GQ formed at m.10191C differentially impeded the processivity of the mitochondrial DNA polymerase gamma (Pol γ) in vitro, providing a potential means to favor replication of the wild-type allele. We tested the potential for shifting Heteroplasmy through the cyclical application of two different mitochondria-targeted GQ binding compounds in primary fibroblasts from patients with m.10191T>C Heteroplasmy. Treatment induced alternating mtDNA depletion and repopulation and was effective in shifting Heteroplasmy towards the non-pathogenic allele. Similar treatment of pathogenic heteroplasmies that do not affect GQ formation did not induce Heteroplasmy shift. Following treatment, heteroplasmic m.10191T>C cells had persistent improvements and Heteroplasmy and a corresponding increase in maximal mitochondrial oxygen consumption. This study demonstrates the potential for using small-molecule GQ-binding agents to induce genetic and functional improvements in m.10191T>C Heteroplasmy.

  • Heteroplasmy Shifting as Therapy for Mitochondrial Disorders.
    Mitochondria in Health and in Sickness, 2019
    Co-Authors: Mansur M. Naeem, Neal Sondheimer
    Abstract:

    Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of Heteroplasmy, with coexistence of pathogenic and wild type mtDNA. The load of Heteroplasmy, defined as the relative amount of pathogenic mtDNA to wild type mtDNA, corresponds to timing and symptom severity. Thus, changing the Heteroplasmy load may lead to a shift in disease onset and symptom severity. Here we review techniques aimed at preventing inheritance of pathogenic mtDNA via mitochondrial replacement therapy (MRT) and strategies geared toward shifting of Heteroplasmy in individuals with active mitochondrial disease. MRT strategies seek to create embryos with the nuclear genetic makeup of the intended parents and wild type mtDNA from a donor in order to avoid known maternal pathogenic variants. Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.

  • lack of relationship between mitochondrial Heteroplasmy or variation and childhood obesity
    International Journal of Obesity, 2012
    Co-Authors: Struan F A Grant, Jack E Tirone, Hakon Hakonarson, J Glessner, Jonathan P Bradfield, Jianhua Zhao, Robert I Berkowitz, Neal Sondheimer
    Abstract:

    Mitochondrial electron transport has a central role in regulating energy supply within a cell. We hypothesized that mitochondrial variants or increased levels of mitochondrial Heteroplasmy could be associated with common childhood obesity through their effects on mitochondrial function. To investigate this question, we queried two genome-wide genotyped childhood obesity datasets, consisting of 1080 European-American (EA) obese children (defined as BMI ≥ 95th percentile) together with 2500 EA lean controls (defined as BMI<50th percentile) and 1479 African-American (AA) obese children and 1575 AA lean controls. Association was not observed between childhood obesity and any of the assayed mitochondrial polymorphisms in either ethnicity. We also found no observable differences in Heteroplasmy between each obese and non-obese group. Finally, we analyzed the quantitative mitochondrial genotype cells generated, whether they exceeded the Heteroplasmy threshold or not. With this more lenient test, we found six positions with a significant difference between EA cases and controls (P<1 × 10(-4)). However, when evaluating the AA data set, no differences were noted at these sites, suggesting that our initial observations were because of chance rather than a meaningful relationship to childhood obesity. As such, it is unlikely that common mitochondrial polymorphisms or Heteroplasmy have a role in childhood obesity.

  • neutral mitochondrial Heteroplasmy and the influence of aging
    Human Molecular Genetics, 2011
    Co-Authors: Neal Sondheimer, Catherine Glatz, Jack E Tirone, Matthew A Deardorff, Abba M Krieger, Hakon Hakonarson
    Abstract:

    The development and maintenance of mitochondrial Heteroplasmy has important consequences for both health and heredity. Previous studies using pathogenic mutations have shown considerable variability between maternally related individuals and studies of several D-loop polymorphisms have suggested a relationship between Heteroplasmy and somatic aging. To broadly explore the variation of human Heteroplasmy and to clarify the dynamics of somatic Heteroplasmy over the course of lifespan, we analyzed mitochondrial sequence variation across a range of ages. We utilized array-generated single-nucleotide polymorphism data that were well correlated with independent measures of Heteroplasmy. Significant levels of Heteroplasmy were identified at 0.24% of sites evaluated. By examining mother–child pairs, we found that Heteroplasmy was inherited (30%) but could occur de novo in offspring or, conversely, be present in mothers but eliminated in their children (70%). Cumulatively, mitochondrial Heteroplasmy across the genome increased significantly with advanced age (r = 0.224, P =8 × 10−30). Surprisingly, changes in Heteroplasmy were not uniform with some sites demonstrating a loss of variation (increased homoplasmy) with aging. These data suggest that both mutation and selective pressure affect blood mitochondrial DNA sequence over the course of the human lifespan and reveal the unexpectedly dynamic nature of human Heteroplasmy.

Walther Parson - One of the best experts on this subject based on the ideXlab platform.

  • mitochondrial dna Heteroplasmy in the emerging field of massively parallel sequencing
    Forensic Science International-genetics, 2015
    Co-Authors: Rebecca S Just, Jodi A Irwin, Walther Parson
    Abstract:

    Long an important and useful tool in forensic genetic investigations, mitochondrial DNA (mtDNA) typing continues to mature. Research in the last few years has demonstrated both that data from the entire molecule will have practical benefits in forensic DNA casework, and that massively parallel sequencing (MPS) methods will make full mitochondrial genome (mtGenome) sequencing of forensic specimens feasible and cost-effective. A spate of recent studies has employed these new technologies to assess intraindividual mtDNA variation. However, in several instances, contamination and other sources of mixed mtDNA data have been erroneously identified as Heteroplasmy. Well vetted mtGenome datasets based on both Sanger and MPS sequences have found authentic point Heteroplasmy in approximately 25% of individuals when minor component detection thresholds are in the range of 10–20%, along with positional distribution patterns in the coding region that differ from patterns of point Heteroplasmy in the well-studied control region. A few recent studies that examined very low-level Heteroplasmy are concordant with these observations when the data are examined at a common level of resolution. In this review we provide an overview of considerations related to the use of MPS technologies to detect mtDNA Heteroplasmy. In addition, we examine published reports on point Heteroplasmy to characterize features of the data that will assist in the evaluation of future mtGenome data developed by any typing method.

  • evidence for frequent and tissue specific sequence Heteroplasmy in human mitochondrial dna
    Mitochondrion, 2015
    Co-Authors: Walther Parson, Jana Naue, Steffen Horer, Timo Sanger, Christina Strobl, Petra Hatzergrubwieser, Sabine Lutzbonengel
    Abstract:

    Mitochondrial point Heteroplasmy is a common event observed not only in patients with mitochondrial diseases but also in healthy individuals. We here report a comprehensive investigation of Heteroplasmy occurrence in human including the whole mitochondrial control region from nine different tissue types of 100 individuals. Sanger sequencing was used as a standard method and results were supported by cloning, minisequencing, and massively parallel sequencing. Only 12% of all individuals showed no Heteroplasmy, whereas 88% showed at least one heteroplasmic position within the investigated tissues. In 66% of individuals up to 8 positions were affected. The highest relative number of heteroplasmies was detected in muscle and liver (79%, 69%), followed by brain, hair, and heart (36.7%-30.2%). Lower percentages were observed in bone, blood, lung, and buccal cells (19.8%-16.2%). Accumulation of position-specific heteroplasmies was found in muscle (positions 64, 72, 73, 189, and 408), liver (position 72) and brain (partial deletion at position 71). Deeper analysis of these specific positions in muscle revealed a non-random appearance and position-specific dependency on age. MtDNA Heteroplasmy frequency and its potential functional importance have been underestimated in the past and its occurrence is ubiquitous and dependent at least on age, tissue, and position-specific mutation rates.

  • investigation of Heteroplasmy in the human mitochondrial dna control region a synthesis of observations from more than 5000 global population samples
    Journal of Molecular Evolution, 2009
    Co-Authors: Jodi A Irwin, Jessica L Saunier, Harald Niederstatter, Katharine M Strouss, Kimberly A Sturk, Toni M Diegoli, Anita Brandstatter, Walther Parson, Thomas J Parsons
    Abstract:

    Instances of point and length Heteroplasmy in the mitochondrial DNA control region were compiled and analyzed from over 5,000 global human population samples. These data represent observations from a large and broad population sample, representing nearly 20 global populations. As expected, length Heteroplasmy was frequently observed in the HVI, HVII and HVIII C-stretches. Length Heteroplasmy was also observed in the AC dinucleotide repeat region, as well as other locations. Point Heteroplasmy was detected in approximately 6% of all samples, and while the vast majority of heteroplasmic samples comprised two molecules differing at a single position, samples exhibiting two and three mixed positions were also observed in this data set. In general, the sites at which Heteroplasmy was most commonly observed correlated with reported control region mutational hotspots. However, for some sites, observations of Heteroplasmy did not mirror established mutation rate data, suggesting the action of other mechanisms, both selective and neutral. Interestingly, these data indicate that the frequency of Heteroplasmy differs between particular populations, perhaps reflecting variable mutation rates among different mtDNA lineages and/or artifacts of particular population groups. The results presented here contribute to our general understanding of mitochondrial DNA control region Heteroplasmy and provide additional empirical information on the mechanisms contributing to mtDNA control region mutation and evolution.

Xavier Estivill - One of the best experts on this subject based on the ideXlab platform.

  • Estivill X. Detection of unrecognized low-level mtDNA Heteroplasmy may explain the variable phenotypic expressivity of apparently homoplasmic mtDNA mutations. Hum Mutat 2008
    2020
    Co-Authors: Ester Ballana, Nancy Govea, Rafael De Cid, Cecilia Garcia, Carles Arribas, Jordi Rosell, Xavier Estivill
    Abstract:

    Communicated by Garry R. Cutting Mitochondrial DNA (mtDNA) mutations are an important cause of human disease. Most mtDNA mutations are found in Heteroplasmy, in which the proportion of mutant vs. wild-type species is believed to explain some of the observed high phenotypic heterogeneity. However, homoplasmic mutations also observe phenotypic heterogeneity, which may be in part due to undetected low levels of Heteroplasmy. In the present report, we have developed two assays, using DHPLC and Pyrosequencing (Biotage AB, Uppsala, Sweden), for reliably and accurately detecting low-level mtDNA Heteroplasmy. Using these assays we have identified a three-generation family segregating two mtDNA mutations in Heteroplasmy: the deafness-related m.1555A4G mutation in the 12S rRNA gene (MTRNR1) and a new variant (m.15287T4C) in the cytochrome b gene (MTCYB). Both heteroplasmic mtDNA mutations are transmitted through generations in a random manner, thus showing differences in mutation load between siblings within the family. In addition, the developed assays were also used to screen a group of deaf subjects of unknown etiology for the presence of Heteroplasmy for both mtDNA variants. Two additional heteroplasmic m.1555A4G samples, previously considered as homoplasmic, and two deaf subjects carrying m.15287T4C variant were identified, thus confirming the high specificity and reliability of the approach. The development of assays for reliably detecting low-level Heteroplasmy, together with the study of heteroplasmic mtDNA transmission, are essential steps for a better knowledge and clinical management of mtDNA diseases. Hum Mutat 29(2), [248][249][250][251][252][253][254][255][256][257] 2008

  • detection of unrecognized low level mtdna Heteroplasmy may explain the variable phenotypic expressivity of apparently homoplasmic mtdna mutations
    Human Mutation, 2008
    Co-Authors: Ester Ballana, Nancy Govea, Rafael De Cid, Cecilia Garcia, Carles Arribas, Jordi Rosell, Xavier Estivill
    Abstract:

    Genetics Unit, Pompeu Fabra University (UPF), Barcelona, Catalonia, SpainCommunicated by Garry R. CuttingMitochondrial DNA (mtDNA) mutations are an important cause of human disease. Most mtDNA mutationsare found in Heteroplasmy, in which the proportion of mutant vs. wild-type species is believed to explain some ofthe observed high phenotypic heterogeneity. However, homoplasmic mutations also observe phenotypicheterogeneity, which may be in part due to undetected low levels of Heteroplasmy. In the present report, we havedeveloped two assays, using DHPLC and Pyrosequencing (Biotage AB, Uppsala, Sweden), for reliably andaccurately detecting low-level mtDNA Heteroplasmy. Using these assays we have identified a three-generationfamily segregating two mtDNA mutations in Heteroplasmy: the deafness-related m.1555A4G mutation in the12S rRNA gene (MTRNR1) and a new variant (m.15287T4C) in the cytochrome b gene (MTCYB). Bothheteroplasmic mtDNA mutations are transmitted through generations in a random manner, thus showingdifferences in mutation load between siblings within the family. In addition, the developed assays were also usedto screen a group of deaf subjects of unknown etiology for the presence of Heteroplasmy for both mtDNAvariants. Two additional heteroplasmic m.1555A4G samples, previously considered as homoplasmic, and twodeaf subjects carrying m.15287T4C variant were identified, thus confirming the high specificity and reliabilityof the approach. The development of assays for reliably detecting low-level Heteroplasmy, together with thestudy of heteroplasmic mtDNAtransmission, are essential steps for a better knowledge and clinical managementof mtDNA diseases. Hum Mutat 29(2), 248–257, 2008.

Maria Pilar Aluja - One of the best experts on this subject based on the ideXlab platform.

  • frequency and pattern of Heteroplasmy in the complete human mitochondrial genome
    PLOS ONE, 2013
    Co-Authors: Amanda Ramos, Cristina Santos, Luis Alvarez, Ligia Mateiu, Maria Del Mar Gonzalez, Luisa Azevedo, A Amorim, Maria Pilar Aluja
    Abstract:

    Determining the levels of human mitochondrial Heteroplasmy is of utmost importance in several fields. In spite of this, there are currently few published works that have focused on this issue. In order to increase the knowledge of mitochondrial DNA (mtDNA) Heteroplasmy, the main goal of this work is to investigate the frequency and the mutational spectrum of Heteroplasmy in the human mtDNA genome. To address this, a set of nine primer pairs designed to avoid co-amplification of nuclear DNA (nDNA) sequences of mitochondrial origin (NUMTs) was used to amplify the mitochondrial genome in 101 individuals. The analysed individuals represent a collection with a balanced representation of genders and mtDNA haplogroup distribution, similar to that of a Western European population. The results show that the frequency of heteroplasmic individuals exceeds 61%. The frequency of point Heteroplasmy is 28.7%, with a widespread distribution across the entire mtDNA. In addition, an excess of transitions in Heteroplasmy were detected, suggesting that genetic drift and/or selection may be acting to reduce its frequency at population level. In fact, Heteroplasmy at highly stable positions might have a greater impact on the viability of mitochondria, suggesting that purifying selection must be operating to prevent their fixation within individuals. This study analyses the frequency of Heteroplasmy in a healthy population, carrying out an evolutionary analysis of the detected changes and providing a new perspective with important consequences in medical, evolutionary and forensic fields.

  • frequency and pattern of Heteroplasmy in the control region of human mitochondrial dna
    Journal of Molecular Evolution, 2008
    Co-Authors: Cristina Santos, Blanca Sierra, Luis Alvarez, Amanda Ramos, Elisabet Fernandez, Ramon Nogues, Maria Pilar Aluja
    Abstract:

    In this work, we present the results of the screening of human mitochondrial DNA (mtDNA) Heteroplasmy in the control region of mtDNA from 210 unrelated Spanish individuals. Both hypervariable regions of mtDNA were amplified and sequenced in order to identify and quantify point and length Heteroplasmy. Of the 210 individuals analyzed, 30% were fully homoplasmic and the remaining presented point and/or length Heteroplasmy. The prevalent form of Heteroplasmy was length Heteroplasmy in the poly(C) tract of the hypervariable region II (HVRII), followed by length Heteroplasmy in the poly(C) tract of hypervariable region I (HVRI) and, finally, point Heteroplasmy, which was found in 3.81% of the individuals analyzed. Moreover, no significant differences were found in the proportions of the different kinds of Heteroplasmy in the population when blood and buccal cell samples were compared. The pattern of Heteroplasmy in HVRI and HVRII presents important differences. Moreover, the mutational profile in Heteroplasmy seems to be different from the mutational pattern detected in population. The results suggest that a considerable number of mutations and, particularly, transitions that appear in Heteroplasmy are probably eliminated by drift and/or by selection acting at different mtDNA levels of organization. Taking as a whole the results reported in this work, it is mandatory to perform a broad-scale screening of Heteroplasmy to better establish the Heteroplasmy profile which would be important for medical, evolutionary, and forensic proposes.

Cristina M Kenney - One of the best experts on this subject based on the ideXlab platform.

  • low frequency mitochondrial dna Heteroplasmy snps in blood retina and rpe choroid of age related macular degeneration subjects
    PLOS ONE, 2021
    Co-Authors: Shari R Atilano, Nitin Udar, Timothy A Satalich, Viraat Udar, Marilyn Chwa, Cristina M Kenney
    Abstract:

    Purpose Mitochondrial (mt) DNA damage is associated with age-related macular degeneration (AMD) and other human aging diseases. This study was designed to quantify and characterize mtDNA low-frequency Heteroplasmy single nucleotide polymorphisms (SNPs) of three different tissues isolated from AMD subjects using Next Generation Sequencing (NGS) technology. Methods DNA was extracted from neural retina, [RPE+choroid] and blood from three deceased age-related macular degeneration (AMD) subjects. Entire mitochondrial genomes were analyzed for low-frequency Heteroplasmy SNPs using NGS technology that independently sequenced both mtDNA strands. This deep sequencing method (average sequencing depth of 30,000; range 1,000-100,000) can accurately differentiate low-frequency Heteroplasmy SNPs from DNA modification artifacts. Twenty-three 'hot-spot' Heteroplasmy mtDNA SNPs were analyzed in 222 additional blood samples. Results Germline homoplasmy SNPs that defined mtDNA haplogroups were consistent in the three tissues of each subject. Analyses of SNPs with T, m.1284T>C, m.1556C>T, m.7256C>T) were found in additional samples (n = 222). Five Heteroplasmy SNPs (m.4104A>G, m.5320C>T, m.5471G>A, m.5474A>G, m.5498A>G) declined with age. Two Heteroplasmy SNPs (m.13095T>C, m.13105A>G) increased in AMD compared to Normal samples. In the Heteroplasmy SNPs, very few transversion mutations (purine to pyrimidine or vice versa, associated with oxidative damage) were found and the majority were transition changes (purine to purine or pyrimidine to pyrimidine, associated with replication errors). Conclusion Within an individual, the blood, retina and [RPE+choroid] contained identical homoplasmy SNPs representing inherited germline mtDNA haplogroup. NGS methodology showed significantly more mtDNA Heteroplasmy SNPs in blood compared to retina and [RPE+choroid], suggesting the latter tissues have substantial protection. Significantly higher Heteroplasmy levels of m.13095T>C and m.13105A>G may represent potential AMD biomarkers. Finally, high levels of transition mutations suggest that accumulation of heteroplasmic SNPs may occur through replication errors rather than oxidative damage.

  • Low frequency mitochondrial DNA Heteroplasmy SNPs in blood, retina, and [RPE+choroid] of age-related macular degeneration subjects.
    'Public Library of Science (PLoS)', 2021
    Co-Authors: Shari R Atilano, Nitin Udar, Timothy A Satalich, Viraat Udar, Marilyn Chwa, Cristina M Kenney
    Abstract:

    PurposeMitochondrial (mt) DNA damage is associated with age-related macular degeneration (AMD) and other human aging diseases. This study was designed to quantify and characterize mtDNA low-frequency Heteroplasmy single nucleotide polymorphisms (SNPs) of three different tissues isolated from AMD subjects using Next Generation Sequencing (NGS) technology.MethodsDNA was extracted from neural retina, [RPE+choroid] and blood from three deceased age-related macular degeneration (AMD) subjects. Entire mitochondrial genomes were analyzed for low-frequency Heteroplasmy SNPs using NGS technology that independently sequenced both mtDNA strands. This deep sequencing method (average sequencing depth of 30,000; range 1,000-100,000) can accurately differentiate low-frequency Heteroplasmy SNPs from DNA modification artifacts. Twenty-three 'hot-spot' Heteroplasmy mtDNA SNPs were analyzed in 222 additional blood samples.ResultsGermline homoplasmy SNPs that defined mtDNA haplogroups were consistent in the three tissues of each subject. Analyses of SNPs with T, m.1284T>C, m.1556C>T, m.7256C>T) were found in additional samples (n = 222). Five Heteroplasmy SNPs (m.4104A>G, m.5320C>T, m.5471G>A, m.5474A>G, m.5498A>G) declined with age. Two Heteroplasmy SNPs (m.13095T>C, m.13105A>G) increased in AMD compared to Normal samples. In the Heteroplasmy SNPs, very few transversion mutations (purine to pyrimidine or vice versa, associated with oxidative damage) were found and the majority were transition changes (purine to purine or pyrimidine to pyrimidine, associated with replication errors).ConclusionWithin an individual, the blood, retina and [RPE+choroid] contained identical homoplasmy SNPs representing inherited germline mtDNA haplogroup. NGS methodology showed significantly more mtDNA Heteroplasmy SNPs in blood compared to retina and [RPE+choroid], suggesting the latter tissues have substantial protection. Significantly higher Heteroplasmy levels of m.13095T>C and m.13105A>G may represent potential AMD biomarkers. Finally, high levels of transition mutations suggest that accumulation of heteroplasmic SNPs may occur through replication errors rather than oxidative damage