86 results on '"Dan Mishmar"'
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2. Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
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Lana Meshnik, Dan Bar-Yaacov, Dana Kasztan, Tali Neiger, Tal Cohen, Mor Kishner, Itay Valenci, Sara Dadon, Christopher J. Klein, Jeffery M. Vance, Yoram Nevo, Stephan Züchner, Ofer Ovadia, Dan Mishmar, and Anat Ben-Zvi
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C. elegans ,fzo-1 ,Heteroplasmy inheritance ,Mitofusin ,mtDNA ,PARKIN ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. Results We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. Conclusions Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy.
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- 2022
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3. Immune system cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation and rewiring toward glycolysis
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Hadar Medini, Amit Zirman, and Dan Mishmar
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Immune system ,Virology ,Genomics ,Science - Abstract
Summary: Mitochondria are pivotal for bioenergetics, as well as in cellular response to viral infections. Nevertheless, their role in COVID-19 was largely overlooked. Here, we analyzed available bulk RNA-seq datasets from COVID-19 patients and corresponding healthy controls (three blood datasets, N = 48 healthy, 119 patients; two respiratory tract datasets, N = 157 healthy, 524 patients). We found significantly reduced mtDNA gene expression in blood, but not in respiratory tract samples from patients. Next, analysis of eight single-cells RNA-seq datasets from peripheral blood mononuclear cells, nasopharyngeal samples, and Bronchoalveolar lavage fluid (N = 1,192,243 cells), revealed significantly reduced mtDNA gene expression especially in immune system cells from patients. This is associated with elevated expression of nuclear DNA-encoded OXPHOS subunits, suggesting compromised mitochondrial-nuclear co-regulation. This, together with elevated expression of ROS-response genes and glycolysis enzymes in patients, suggest rewiring toward glycolysis, thus generating beneficial conditions for SARS-CoV-2 replication. Our findings underline the centrality of mitochondrial dysfunction in COVID-19.
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- 2021
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4. mtDNA Chromatin-like Organization Is Gradually Established during Mammalian Embryogenesis
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Shani Marom, Amit Blumberg, Anshul Kundaje, and Dan Mishmar
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Science - Abstract
Summary: Unlike the nuclear genome, the mammalian mitochondrial genome (mtDNA) is thought to be coated solely by mitochondrial transcription factor A (TFAM), whose binding sequence preferences are debated. Therefore, higher-order mtDNA organization is considered much less regulated than both the bacterial nucleoid and the nuclear chromatin. However, our recently identified conserved DNase footprinting pattern in human mtDNA, which co-localizes with regulatory elements and responds to physiological conditions, likely reflects a structured higher-order mtDNA organization. We hypothesized that this pattern emerges during embryogenesis. To test this hypothesis, we analyzed assay for transposase-accessible chromatin sequencing (ATAC-seq) results collected during the course of mouse and human early embryogenesis. Our results reveal, for the first time, a gradual and dynamic emergence of the adult mtDNA footprinting pattern during embryogenesis of both mammals. Taken together, our findings suggest that the structured adult chromatin-like mtDNA organization is gradually formed during mammalian embryogenesis. : Biological Sciences; Developmental Genetics; Molecular Genetics; Developmental Biology Subject Areas: Biological Sciences, Developmental Genetics, Molecular Genetics, Developmental Biology
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- 2019
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5. Two Homogametic Genotypes – One Crayfish: On the Consequences of Intersexuality
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Tom Levy, Tomer Ventura, Giulio De Leo, Nufar Grinshpan, Faiza Amterat Abu Abayed, Rivka Manor, Amit Savaya, Menachem Y. Sklarz, Vered Chalifa-Caspi, Dan Mishmar, and Amir Sagi
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zoology ,genetics ,genotyping ,evolutionary biology ,Science - Abstract
Summary: In the Australian redclaw crayfish, Cherax quadricarinatus (WZ/ZZ system), intersexuals, although exhibiting both male and female gonopores, are functional males bearing a female genotype (WZ males). Therefore, the occurrence of the unusual homogametic WW females in nature is plausible. We developed W/Z genomic sex markers and used them to investigate the genotypic structure of experimental and native C. quadricarinatus populations in Australia. We discovered, for the first time, the natural occurrence of WW females in crustacean populations. By modeling population dynamics, we found that intersexuals contribute to the growth rate of crayfish populations in the short term. Given the vastly fragmented C. quadricarinatus habitat, which is characterized by drought-flood cycles, we speculate that intersexuals contribute to the fitness of this species since they lead to occasional increment in the population growth rate which potentially supports crayfish population restoration and establishment under extinction threats or colonization events.
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- 2020
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6. Higher Order Organization of the mtDNA: Beyond Mitochondrial Transcription Factor A
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Dan Mishmar, Rotem Levin, Mansur M. Naeem, and Neal Sondheimer
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ATAC-seq ,DNase-seq ,G-quadruplex ,higher order organization ,mtDNA ,mitochondrial transcription factor A ,Genetics ,QH426-470 - Abstract
The higher order organization of eukaryotic and prokaryotic genomes is pivotal in the regulation of gene expression. Specifically, chromatin accessibility in eukaryotes and nucleoid accessibility in bacteria are regulated by a cohort of proteins to alter gene expression in response to diverse physiological conditions. By contrast, prior studies have suggested that the mitochondrial genome (mtDNA) is coated solely by mitochondrial transcription factor A (TFAM), whose increased cellular concentration was proposed to be the major determinant of mtDNA packaging in the mitochondrial nucleoid. Nevertheless, recent analysis of DNase-seq and ATAC-seq experiments from multiple human and mouse samples suggest gradual increase in mtDNA occupancy during the course of embryonic development to generate a conserved footprinting pattern which correlate with sites that have low TFAM occupancy in vivo (ChIP-seq) and tend to adopt G-quadruplex structures. These findings, along with recent identification of mtDNA binding by known modulators of chromatin accessibility such as MOF, suggest that mtDNA higher order organization is generated by cross talk with the nuclear regulatory system, may have a role in mtDNA regulation, and is more complex than once thought.
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- 2019
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7. The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels
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Noam Shtolz and Dan Mishmar
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mitochondria ,mtDNA ,selection ,single cell ,single mitochondrion ,evolution ,Evolution ,QH359-425 ,Ecology ,QH540-549.5 - Abstract
Natural selection acts on the phenotype. Therefore, many mistakenly expect to observe its signatures only in the organism, while overlooking its impact on tissues, cells and subcellular compartments. This is particularly crucial in the case of the mitochondrial genome (mtDNA), which, unlike the nucleus, resides in multiple cellular copies that may vary in sequence (heteroplasmy) and quantity among tissues. Since the mitochondrion is a hub for cellular metabolism, ATP production, and additional activities such as nucleotide biosynthesis and apoptosis, mitochondrial dysfunction leads to both tissue-specific and systemic disorders. Therefore, strong selective pressures act to maintain mitochondrial function via removal of deleterious mutations via purifying (negative) selection. In parallel, selection also acts on the mitochondrion to allow adaptation of cells and organisms to new environments and physiological conditions (positive selection). Nevertheless, unlike the nuclear genetic information, the mitochondrial genetic system incorporates closely interacting bi-genomic factors (i.e., encoded by the nuclear and mitochondrial genomes). This is further complicated by the order of magnitude higher mutation rate of the vertebrate mtDNA as compared to the nuclear genome. Such mutation rate difference generates a generous mtDNA mutational landscape for selection to act, but also requires tight mito-nuclear co-evolution to maintain mitochondrial activities. In this essay we will consider the unique mitochondrial signatures of natural selection at the organism, tissue, cell, and single mitochondrion levels.
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- 2019
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8. Correction: Mitochondrial 16S rRNA Is Methylated by tRNA Methyltransferase TRMT61B in All Vertebrates.
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Dan Bar-Yaacov, Idan Frumkin, Yuka Yashiro, Takeshi Chujo, Yuma Ishigami, Yonatan Chemla, Amit Blumberg, Orr Schlesinger, Philipp Bieri, Basil Greber, Nenad Ban, Raz Zarivach, Lital Alfonta, Yitzhak Pilpel, Tsutomu Suzuki, and Dan Mishmar
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Biology (General) ,QH301-705.5 - Abstract
[This corrects the article DOI: 10.1371/journal.pbio.1002557.].
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- 2017
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9. Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns.
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Tal Cohen, Liron Levin, and Dan Mishmar
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Genetics ,QH426-470 - Abstract
Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world.
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- 2016
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10. Mitochondrial 16S rRNA Is Methylated by tRNA Methyltransferase TRMT61B in All Vertebrates.
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Dan Bar-Yaacov, Idan Frumkin, Yuka Yashiro, Takeshi Chujo, Yuma Ishigami, Yonatan Chemla, Amit Blumberg, Orr Schlesinger, Philipp Bieri, Basil Greber, Nenad Ban, Raz Zarivach, Lital Alfonta, Yitzhak Pilpel, Tsutomu Suzuki, and Dan Mishmar
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Biology (General) ,QH301-705.5 - Abstract
The mitochondrial ribosome, which translates all mitochondrial DNA (mtDNA)-encoded proteins, should be tightly regulated pre- and post-transcriptionally. Recently, we found RNA-DNA differences (RDDs) at human mitochondrial 16S (large) rRNA position 947 that were indicative of post-transcriptional modification. Here, we show that these 16S rRNA RDDs result from a 1-methyladenosine (m1A) modification introduced by TRMT61B, thus being the first vertebrate methyltransferase that modifies both tRNA and rRNAs. m1A947 is conserved in humans and all vertebrates having adenine at the corresponding mtDNA position (90% of vertebrates). However, this mtDNA base is a thymine in 10% of the vertebrates and a guanine in the 23S rRNA of 95% of bacteria, suggesting alternative evolutionary solutions. m1A, uridine, or guanine may stabilize the local structure of mitochondrial and bacterial ribosomes. Experimental assessment of genome-edited Escherichia coli showed that unmodified adenine caused impaired protein synthesis and growth. Our findings revealed a conserved mechanism of rRNA modification that has been selected instead of DNA mutations to enable proper mitochondrial ribosome function.
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- 2016
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11. LEMONS - A Tool for the Identification of Splice Junctions in Transcriptomes of Organisms Lacking Reference Genomes.
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Liron Levin, Dan Bar-Yaacov, Amos Bouskila, Michal Chorev, Liran Carmel, and Dan Mishmar
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Medicine ,Science - Abstract
RNA-seq is becoming a preferred tool for genomics studies of model and non-model organisms. However, DNA-based analysis of organisms lacking sequenced genomes cannot rely on RNA-seq data alone to isolate most genes of interest, as DNA codes both exons and introns. With this in mind, we designed a novel tool, LEMONS, that exploits the evolutionary conservation of both exon/intron boundary positions and splice junction recognition signals to produce high throughput splice-junction predictions in the absence of a reference genome. When tested on multiple annotated vertebrate mRNA data, LEMONS accurately identified 87% (average) of the splice-junctions. LEMONS was then applied to our updated Mediterranean chameleon transcriptome, which lacks a reference genome, and predicted a total of 90,820 exon-exon junctions. We experimentally verified these splice-junction predictions by amplifying and sequencing twenty randomly selected genes from chameleon DNA templates. Exons and introns were detected in 19 of 20 of the positions predicted by LEMONS. To the best of our knowledge, LEMONS is currently the only experimentally verified tool that can accurately predict splice-junctions in organisms that lack a reference genome.
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- 2015
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12. Mitochondrial DNA variation, but not nuclear DNA, sharply divides morphologically identical chameleons along an ancient geographic barrier.
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Dan Bar Yaacov, Karmit Arbel-Thau, Yael Zilka, Ofer Ovadia, Amos Bouskila, and Dan Mishmar
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Medicine ,Science - Abstract
The Levant is an important migration bridge, harboring border-zones between Afrotropical and palearctic species. Accordingly, Chameleo chameleon, a common species throughout the Mediterranean basin, is morphologically divided in the southern Levant (Israel) into two subspecies, Chamaeleo chamaeleon recticrista (CCR) and C. c. musae (CCM). CCR mostly inhabits the Mediterranean climate (northern Israel), while CCM inhabits the sands of the north-western Negev Desert (southern Israel). AFLP analysis of 94 geographically well dispersed specimens indicated moderate genetic differentiation (PhiPT = 0.097), consistent with the classical division into the two subspecies, CCR and CCM. In contrast, sequence analysis of a 637 bp coding mitochondrial DNA (mtDNA) fragment revealed two distinct phylogenetic clusters which were not consistent with the morphological division: one mtDNA cluster consisted of CCR specimens collected in regions northern of the Jezreel Valley and another mtDNA cluster harboring specimens pertaining to both the CCR and CCM subspecies but collected southern of the Jezreel Valley. AMOVA indicated clear mtDNA differentiation between specimens collected northern and southern to the Jezreel Valley (PhiPT = 0.79), which was further supported by a very low coalescent-based estimate of effective migration rates. Whole chameleon mtDNA sequencing (∼17,400 bp) generated from 11 well dispersed geographic locations revealed 325 mutations sharply differentiating the two mtDNA clusters, suggesting a long allopatric history further supported by BEAST. This separation correlated temporally with the existence of an at least 1 million year old marine barrier at the Jezreel Valley exactly where the mtDNA clusters meet. We discuss possible involvement of gender-dependent life history differences in maintaining such mtDNA genetic differentiation and suggest that it reflects (ancient) local adaptation to mitochondrial-related traits.
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- 2012
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13. The Impact of Darwinian Evolution on Medicine: The Maternal Side of the Story
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Dan Mishmar
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evolutionary medicine ,mitochondria ,next-generation sequencing ,disease ,Medicine ,Medicine (General) ,R5-920 - Abstract
Complex disorders are common in the human population and are caused by interplay between genetic and environmental factors. Therefore the quest for the genetic basis of such disorders has much similarity to deciphering the genetic basis of macro-evolutionary processes, such as speciation. Here I discuss conceptual connections between the principles underlying and processes occurring in disease and evolution. Special focus is given to the tremendous mitochondrial genetic variability in the population and within individuals and the impact of both types of variability on evolutionary processes and diseases.
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- 2010
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14. Gene expression patterns of oxidative phosphorylation complex I subunits are organized in clusters.
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Yael Garbian, Ofer Ovadia, Sarah Dadon, and Dan Mishmar
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Medicine ,Science - Abstract
After the radiation of eukaryotes, the NUO operon, controlling the transcription of the NADH dehydrogenase complex of the oxidative phosphorylation system (OXPHOS complex I), was broken down and genes encoding this protein complex were dispersed across the nuclear genome. Seven genes, however, were retained in the genome of the mitochondrion, the ancient symbiote of eukaryotes. This division, in combination with the three-fold increase in subunit number from bacteria (N = approximately 14) to man (N = 45), renders the transcription regulation of OXPHOS complex I a challenge. Recently bioinformatics analysis of the promoter regions of all OXPHOS genes in mammals supported patterns of co-regulation, suggesting that natural selection favored a mechanism facilitating the transcriptional regulatory control of genes encoding subunits of these large protein complexes. Here, using real time PCR of mitochondrial (mtDNA)- and nuclear DNA (nDNA)-encoded transcripts in a panel of 13 different human tissues, we show that the expression pattern of OXPHOS complex I genes is regulated in several clusters. Firstly, all mtDNA-encoded complex I subunits (N = 7) share a similar expression pattern, distinct from all tested nDNA-encoded subunits (N = 10). Secondly, two sub-clusters of nDNA-encoded transcripts with significantly different expression patterns were observed. Thirdly, the expression patterns of two nDNA-encoded genes, NDUFA4 and NDUFA5, notably diverged from the rest of the nDNA-encoded subunits, suggesting a certain degree of tissue specificity. Finally, the expression pattern of the mtDNA-encoded ND4L gene diverged from the rest of the tested mtDNA-encoded transcripts that are regulated by the same promoter, consistent with post-transcriptional regulation. These findings suggest, for the first time, that the regulation of complex I subunits expression in humans is complex rather than reflecting global co-regulation.
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- 2010
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15. Ancient mtDNA genetic variants modulate mtDNA transcription and replication.
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Sarit Suissa, Zhibo Wang, Jason Poole, Sharine Wittkopp, Jeanette Feder, Timothy E Shutt, Douglas C Wallace, Gerald S Shadel, and Dan Mishmar
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Genetics ,QH426-470 - Abstract
Although the functional consequences of mitochondrial DNA (mtDNA) genetic backgrounds (haplotypes, haplogroups) have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are "evolutionary silent hitchhikers". We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74%) and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%). The variant defining Caucasian haplogroup J (C295T) increased the binding of TFAM (Electro Mobility Shift Assay) and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1), a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds) harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mtDNA haplogroup-defining control region mutations, paving the path towards assessing the functionality of both fixed and un-fixed genetic variants in the mitochondrial genome.
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- 2009
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16. Chapter 12. Genes as Jewish History?: Human Population Genetics in the Service of Historians
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Noa Sophie Kohler and Dan Mishmar
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- 2022
17. Predicting 3D protein structures in light of evolution
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Dan Mishmar, Shimon Bershtein, and Daniel Kleiner
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Experimental evolution ,Protein structure ,Ecology ,Computer science ,In silico ,Ecology (disciplines) ,Proteins ,Computational biology ,Protein structure prediction ,Ecology, Evolution, Behavior and Systematics - Abstract
Recent advances in AI-based 3D protein structure prediction could help address health-related questions, but may also have far-reaching implications for evolution. Here we discuss the advantages and limitations of high-quality 3D structural predictions by AlphaFold2 in unravelling the relationship between protein properties and their impact on fitness, and emphasize the need to integrate in silico structural predictions with functional genomic studies.
- Published
- 2021
18. Immune system cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation and rewiring toward glycolysis
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Amit Zirman, Hadar Medini, and Dan Mishmar
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Mitochondrial DNA ,Multidisciplinary ,Science ,Oxidative phosphorylation ,Genomics ,Mitochondrion ,Biology ,Peripheral blood mononuclear cell ,Article ,Immune system ,Virology ,Gene expression ,Immunology ,Glycolysis ,Gene - Abstract
Mitochondria are pivotal for bioenergetics, as well as in cellular response to viral infections. Nevertheless, their role in COVID-19 was largely overlooked. Here, we analyzed available bulk RNA-seq datasets from COVID-19 patients and corresponding healthy controls (three blood datasets, N = 48 healthy, 119 patients; two respiratory tract datasets, N = 157 healthy, 524 patients). We found significantly reduced mtDNA gene expression in blood, but not in respiratory tract samples from patients. Next, analysis of eight single-cells RNA-seq datasets from peripheral blood mononuclear cells, nasopharyngeal samples, and Bronchoalveolar lavage fluid (N = 1,192,243 cells), revealed significantly reduced mtDNA gene expression especially in immune system cells from patients. This is associated with elevated expression of nuclear DNA-encoded OXPHOS subunits, suggesting compromised mitochondrial-nuclear co-regulation. This, together with elevated expression of ROS-response genes and glycolysis enzymes in patients, suggest rewiring toward glycolysis, thus generating beneficial conditions for SARS-CoV-2 replication. Our findings underline the centrality of mitochondrial dysfunction in COVID-19., Graphical abstract, Immune system; Virology; Genomics
- Published
- 2021
19. An enhanced MITOMAP with a global mtDNA mutational phylogeny.
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Eduardo Ruiz-Pesini, Marie T. Lott, Vincent Procaccio, Jason C. Poole, Marty C. Brandon, Dan Mishmar, Christina Yi, James Kreuziger, Pierre Baldi, and Douglas C. Wallace
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- 2007
- Full Text
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20. Corrigendum: Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
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Gilad Barshad, Amit Blumberg, Tal Cohen, and Dan Mishmar
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Genetics ,Genetics (clinical) - Published
- 2022
21. Human mitochondrial RNA modifications associate with tissue-specific changes in gene expression, and are affected by sunlight and UV exposure
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Tal Cohen, Hadar Medini, Chen Mordechai, Alal Eran, and Dan Mishmar
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RNA, Mitochondrial ,Genetics ,Sunlight ,Humans ,RNA ,Gene Expression ,DNA, Mitochondrial ,Genetics (clinical) - Abstract
RNA-DNA differences (RDD) have previously been identified in the human mitochondrial RNA (mt-RNA) transcripts, yet their functional impact is poorly understood. By analyzing 4928 RNA-seq samples from 23 body sites, we found that mtDNA gene expression negatively correlated with the levels of both m
- Published
- 2021
22. Coordination of mitochondrial and nuclear gene-expression regulation in health, evolution, and disease
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Omer Papier, Gavriel Minor, Hadar Medini, and Dan Mishmar
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Physiology ,Physiology (medical) - Published
- 2022
23. Mitochondrial gene expression in single cells shape pancreatic beta cells' sub-populations and explain variation in insulin pathway
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Tal Cohen, Hadar Medini, and Dan Mishmar
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0301 basic medicine ,Cell type ,Mitochondrial DNA ,Evolution ,Science ,Gene Expression ,Alpha (ethology) ,Cell Count ,030209 endocrinology & metabolism ,Biology ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin-Secreting Cells ,Gene expression ,Genetics ,Animals ,Humans ,Insulin ,Beta (finance) ,Pancreas ,Gene ,Multidisciplinary ,Glucagon ,Molecular biology ,Mitochondria ,Computational biology and bioinformatics ,Nuclear DNA ,030104 developmental biology ,Mutation ,Medicine ,Beta cell ,Signal Transduction - Abstract
Mitochondrial gene expression is pivotal to cell metabolism. Nevertheless, it is unknown whether it diverges within a given cell type. Here, we analysed single-cell RNA-seq experiments from human pancreatic alpha (N = 3471) and beta cells (N = 1989), as well as mouse beta cells (N = 1094). Cluster analysis revealed two distinct human beta cells populations, which diverged by mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded oxidative phosphorylation (OXPHOS) gene expression in healthy and diabetic individuals, and in newborn but not in adult mice. Insulin gene expression was elevated in beta cells with higher mtDNA gene expression in humans and in young mice. Such human beta cell populations also diverged in mitochondrial RNA mutational repertoire, and in their selective signature, thus implying the existence of two previously overlooked distinct and conserved beta cell populations. While applying our approach to human alpha cells, two sub-populations of cells were identified which diverged in mtDNA gene expression, yet these cellular populations did not consistently diverge in nDNA OXPHOS genes expression, nor did they correlate with the expression of glucagon, the hallmark of alpha cells. Thus, pancreatic beta cells within an individual are divided into distinct groups with unique metabolic-mitochondrial signature.
- Published
- 2021
24. Two Homogametic Genotypes – One Crayfish: On the Consequences of Intersexuality
- Author
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Amir Sagi, Amit Savaya, Faiza Amterat Abu Abayed, Vered Chalifa-Caspi, Nufar Grinshpan, Dan Mishmar, Tom Levy, Giulio A. De Leo, Menachem Y. Sklarz, Tomer Ventura, and Rivka Manor
- Subjects
0301 basic medicine ,Population ,Zoology ,02 engineering and technology ,Article ,03 medical and health sciences ,Cherax quadricarinatus ,Genotype ,Colonization ,genetics ,education ,lcsh:Science ,education.field_of_study ,Multidisciplinary ,Extinction ,biology ,zoology ,evolutionary biology ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Crayfish ,Crustacean ,030104 developmental biology ,genotyping ,lcsh:Q ,0210 nano-technology ,Heterogametic sex - Abstract
Summary In the Australian redclaw crayfish, Cherax quadricarinatus (WZ/ZZ system), intersexuals, although exhibiting both male and female gonopores, are functional males bearing a female genotype (WZ males). Therefore, the occurrence of the unusual homogametic WW females in nature is plausible. We developed W/Z genomic sex markers and used them to investigate the genotypic structure of experimental and native C. quadricarinatus populations in Australia. We discovered, for the first time, the natural occurrence of WW females in crustacean populations. By modeling population dynamics, we found that intersexuals contribute to the growth rate of crayfish populations in the short term. Given the vastly fragmented C. quadricarinatus habitat, which is characterized by drought-flood cycles, we speculate that intersexuals contribute to the fitness of this species since they lead to occasional increment in the population growth rate which potentially supports crayfish population restoration and establishment under extinction threats or colonization events., Graphical Abstract, Highlights • Two sexes and four sexual genotypes are consequences of crayfish intersexuality • W/Z genomic sex markers were developed for the Australian redclaw crayfish • Homogametic WW females were found for the first time in crayfish populations • Intersexuals may contribute to fitness by increasing population growth rate, zoology; genetics; genotyping; evolutionary biology
- Published
- 2020
25. Mitochondria Are Fundamental for the Emergence of Metazoans: On Metabolism, Genomic Regulation, and the Birth of Complex Organisms
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Tal Cohen, Hadar Medini, and Dan Mishmar
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0303 health sciences ,Genome ,Intracellular parasite ,Cell ,Embryonic Development ,Mitochondrion ,Biology ,Chromatin remodeling ,Chromatin ,Cell biology ,Epigenesis, Genetic ,Mitochondria ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Genetics ,medicine ,Transcriptional regulation ,Animals ,Humans ,Epigenetics ,030217 neurology & neurosurgery ,Function (biology) ,030304 developmental biology - Abstract
Out of many intracellular bacteria, only the mitochondria and chloroplasts abandoned their independence billions of years ago and became endosymbionts within the host eukaryotic cell. Consequently, one cannot grow eukaryotic cells without their mitochondria, and the mitochondria cannot divide outside of the cell, thus reflecting interdependence. Here, we argue that such interdependence underlies the fundamental role of mitochondrial activities in the emergence of metazoans. Several lines of evidence support our hypothesis: ( a) Differentiation and embryogenesis rely on mitochondrial function; ( b) mitochondrial metabolites are primary precursors for epigenetic modifications (such as methyl and acetyl), which are critical for chromatin remodeling and gene expression, particularly during differentiation and embryogenesis; and ( c) mitonuclear coregulation adapted to accommodate both housekeeping and tissue-dependent metabolic needs. We discuss the evolution of the unique mitochondrial genetic system, mitochondrial metabolites, mitonuclear coregulation, and their critical roles in the emergence of metazoans and in human disorders.
- Published
- 2020
26. Mitochondrial and insulin gene expression in single cells shape pancreatic beta cells’ population divergence
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Dan Mishmar, Tal Cohen, and Hadar Medini
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Cell type ,education.field_of_study ,Mitochondrial DNA ,Population ,Gene expression ,Biology ,Beta cell ,education ,Beta (finance) ,Gene ,Nuclear DNA ,Cell biology - Abstract
Mitochondrial gene expression is pivotal to cell metabolism. Nevertheless, it is unknown whether it diverges within a given cell type. Here, we analysed single-cell RNA-seq experiments from ∼4600 human pancreatic alpha and beta cells, as well as ∼900 mouse beta cells. Cluster analysis revealed two distinct human beta cells populations, which diverged by mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded oxidative phosphorylation (OXPHOS) gene expression in healthy and diabetic individuals, and in newborn but not in adult mice. Insulin gene expression was elevated in beta cells with higher mtDNA gene expression in humans and in young mice. Such human beta cell populations also diverged in mt-RNA mutational repertoire, and in their selective signature, thus implying the existence of two previously overlooked distinct and conserved beta cell populations. While applying our approach to alpha cells, two sub-populations of cells were identified which diverged in mtDNA gene expression, yet these cellular populations did not consistently diverge in nDNA OXPHOS genes expression, nor did they correlate with the expression of glucagon, the hallmark of alpha cells. Thus, pancreatic beta cells within an individual are divided into distinct groups with unique metabolic-mitochondrial signature.
- Published
- 2020
27. Mitochondrial DNA associations with East Asian metabolic syndrome
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Dan Mishmar, Douglas C. Wallace, Olga Derbeneva, Larry N. Singh, Dimitra Chalkia, Lee-Ming Chuang, Yi-Cheng Chang, Xiaogang Liu, Ping H. Wang, and Maria Lvova
- Subjects
Male ,0301 basic medicine ,Pedigree chart ,Eastern ,medicine.disease_cause ,Biochemistry ,Haplogroup ,Gene duplication ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic Syndrome ,Genetics ,Mutation ,mtDNA ,Asia, Eastern ,Diabetes ,Single Nucleotide ,Middle Aged ,humanities ,Mitochondrial ,Mitochondria ,Pedigree ,Phenotype ,Female ,Type 2 ,Physical Chemistry (incl. Structural) ,Adult ,Cybrids ,Mitochondrial DNA ,Asia ,Biophysics ,Biology ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Asian People ,Diabetes Mellitus ,medicine ,Humans ,Obesity ,Polymorphism ,Risk factor ,Metabolic and endocrine ,Nutrition ,nutritional and metabolic diseases ,DNA ,social sciences ,Cell Biology ,medicine.disease ,eye diseases ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Haplotypes ,Case-Control Studies ,Biochemistry and Cell Biology ,Metabolic syndrome ,Human mitochondrial DNA haplogroup - Abstract
Mitochondrial dysfunction has repeatedly been reported associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), as have mitochondrial DNA (mtDNA) tRNA and duplication mutations and mtDNA haplogroup lineages. We identified 19 Taiwanese T2DM and MS pedigrees from Taiwan, with putative matrilineal transmission, one of which harbored the pathogenic mtDNA tRNALeu(UUR) nucleotide (nt) 3243A>G mutation on the N9a3 haplogroup background. We then recruited three independent Taiwanese cohorts, two from Taipei (N = 498, mean age 52 and N = 1002, mean age 44) and one from a non-urban environment (N = 501, mean age 57). All three cohorts were assessed for an array of metabolic parameters, their mtDNA haplogroups determined, and the haplogroups correlated with T2DM/MS phenotypes. Logistic regression analysis revealed that mtDNA haplogroups D5, F4, and N9a conferred T2DM protection, while haplogroups F4 and N9a were risk factors for hypertension (HTN), and F4 was a risk factor for obesity (OB). Additionally, the 5263C>T (ND2 A165V) variant commonly associated with F4 was associated with hypertension (HTN). Cybrids were prepared with macro-haplogroup N (defined by variants m.ND3 10398A (114T) and m.ATP6 8701A (59T)) haplogroups B4 and F1 mtDNAs and from macro-haplogroup M (variants m.ND3 10398G (114A) and m.ATP6 8701G (59A)) haplogroup M9 mtDNAs. Additionally, haplogroup B4 and F1 cybrids were prepared with and without the mtDNA variant in ND1 3394T>C (Y30H) reported to be associated with T2DM. Assay of mitochondria complex I in these cybrids revealed that macro-haplogroup N cybrids had lower activity than M cybrids, that haplogroup F cybrids had lower activity than B4 cybrids, and that the ND1 3394T>C (Y30H) variant reduced complex I on both the B4 and F1 background but with very different cumulative effects. These data support the hypothesis that functional mtDNA variants may contribute to the risk of developing T2DM and MS.
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- 2018
28. Mitochondrial DNA Transcription and Its Regulation: An Evolutionary Perspective
- Author
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Shani Marom, Gilad Barshad, Tal Cohen, and Dan Mishmar
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0301 basic medicine ,Mitochondrial DNA ,Transcription, Genetic ,POLRMT ,Telomere-Binding Proteins ,Biology ,Mitochondrion ,DNA, Mitochondrial ,Genome ,Shelterin Complex ,Evolution, Molecular ,Mitochondrial Proteins ,03 medical and health sciences ,Transcription (biology) ,Genetics ,Transcriptional regulation ,Animals ,Humans ,Transcription factor ,DNA-Directed RNA Polymerases ,TFAM ,Mitochondria ,DNA-Binding Proteins ,030104 developmental biology ,Gene Expression Regulation ,Transcription Factors - Abstract
The bacterial heritage of mitochondria, as well as its independent genome [mitochondrial DNA (mtDNA)] and polycistronic transcripts, led to the view that mitochondrial transcriptional regulation relies on an evolutionarily conserved, prokaryotic-like system that is separated from the rest of the cell. Indeed, mtDNA transcription was previously thought to be governed by a few dedicated direct regulators, namely, the mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERF1). Recent findings have, however, revealed that known nuclear gene expression regulators are also involved in mtDNA transcription and have identified novel transcriptional features consistent with adaptation of the mitochondria to the regulatory environment of the precursor of the eukaryotic cell. Finally, whereas mammals follow the human mtDNA transcription pattern, other organisms notably diverge in terms of mtDNA transcriptional regulation. Hence, mtDNA transcriptional regulation is likely more evolutionary diverse than once thought.
- Published
- 2018
29. Higher Order Organization of the mtDNA: Beyond Mitochondrial Transcription Factor A
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Neal Sondheimer, Mansur M. Naeem, Dan Mishmar, and Rotem Levin
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0301 basic medicine ,Mitochondrial DNA ,lcsh:QH426-470 ,ATAC-seq ,DNase-seq ,Review ,Biology ,Genome ,mitochondrial transcription factor A ,03 medical and health sciences ,0302 clinical medicine ,higher order organization ,Genetics ,Nucleoid ,Genetics (clinical) ,Mitochondrial nucleoid ,Regulation of gene expression ,G-quadruplex ,mtDNA ,TFAM ,Cell biology ,Chromatin ,lcsh:Genetics ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine - Abstract
The higher order organization of eukaryotic and prokaryotic genomes is pivotal in the regulation of gene expression. Specifically, chromatin accessibility in eukaryotes and nucleoid accessibility in bacteria are regulated by a cohort of proteins to alter gene expression in response to diverse physiological conditions. By contrast, prior studies have suggested that the mitochondrial genome (mtDNA) is coated solely by mitochondrial transcription factor A (TFAM), whose increased cellular concentration was proposed to be the major determinant of mtDNA packaging in the mitochondrial nucleoid. Nevertheless, recent analysis of DNase-seq and ATAC-seq experiments from multiple human and mouse samples suggest gradual increase in mtDNA occupancy during the course of embryonic development to generate a conserved footprinting pattern which correlate with sites that have low TFAM occupancy in vivo (ChIP-seq) and tend to adopt G-quadruplex structures. These findings, along with recent identification of mtDNA binding by known modulators of chromatin accessibility such as MOF, suggest that mtDNA higher order organization is generated by cross talk with the nuclear regulatory system, may have a role in mtDNA regulation, and is more complex than once thought.
- Published
- 2019
- Full Text
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30. The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels
- Author
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Dan Mishmar and Noam Shtolz
- Subjects
0106 biological sciences ,0301 basic medicine ,Mitochondrial DNA ,Mutation rate ,Nuclear gene ,lcsh:Evolution ,selection ,Mitochondrion ,Biology ,010603 evolutionary biology ,01 natural sciences ,Genome ,03 medical and health sciences ,Negative selection ,lcsh:QH540-549.5 ,evolution ,lcsh:QH359-425 ,Ecology, Evolution, Behavior and Systematics ,Genetics ,Natural selection ,Ecology ,mtDNA ,single mitochondrion ,Heteroplasmy ,single cell ,mitochondria ,030104 developmental biology ,lcsh:Ecology - Abstract
Natural selection acts on the phenotype. Therefore, many mistakenly expect to observe its signatures only in the organism, while overlooking its impact on tissues, cells and subcellular compartments. This is particularly crucial in the case of the mitochondrial genome (mtDNA), which, unlike the nucleus, resides in multiple cellular copies that may vary in sequence (heteroplasmy) and quantity among tissues. Since the mitochondrion is a hub for cellular metabolism, ATP production, and additional activities such as nucleotide biosynthesis and apoptosis, mitochondrial dysfunction leads to both tissue-specific and systemic disorders. Therefore, strong selective pressures act to maintain mitochondrial function via removal of deleterious mutations via purifying (negative) selection. In parallel, selection also acts on the mitochondrion to allow adaptation of cells and organisms to new environments and physiological conditions (positive selection). Nevertheless, unlike the nuclear genetic information, the mitochondrial genetic system incorporates closely interacting bi-genomic factors (i.e., encoded by the nuclear and mitochondrial genomes). This is further complicated by the order of magnitude higher mutation rate of the vertebrate mtDNA as compared to the nuclear genome. Such mutation rate difference generates a generous mtDNA mutational landscape for selection to act, but also requires tight mito-nuclear co-evolution to maintain mitochondrial activities. In this essay we will consider the unique mitochondrial signatures of natural selection at the organism, tissue, cell, and single mitochondrion levels.
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- 2019
31. Disease-causing mutations in subunits of OXPHOS complex I affect certain physical interactions
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Maya Schuldiner, Lihi Gal, Nicol Zlotinkov-Poznianski, Gilad Barshad, and Dan Mishmar
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Models, Molecular ,0301 basic medicine ,Mitochondrial DNA ,Protein combining ,lcsh:Medicine ,Context (language use) ,medicine.disease_cause ,Article ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Dihydrofolate reductase ,medicine ,Humans ,Genetic Predisposition to Disease ,Cloning, Molecular ,lcsh:Science ,Frameshift Mutation ,Gene ,Cell Nucleus ,Genetics ,Mutation ,Binding Sites ,Electron Transport Complex I ,Multidisciplinary ,biology ,Eukaryote ,lcsh:R ,High-throughput screening ,NADH Dehydrogenase ,Mitochondria ,Nuclear DNA ,030104 developmental biology ,biology.protein ,lcsh:Q ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Mitochondrial complex I (CI) is the largest multi-subunit oxidative phosphorylation (OXPHOS) protein complex. Recent availability of a high-resolution human CI structure, and from two non-human mammals, enabled predicting the impact of mutations on interactions involving each of the 44 CI subunits. However, experimentally assessing the impact of the predicted interactions requires an easy and high-throughput method. Here, we created such a platform by cloning all 37 nuclear DNA (nDNA) and 7 mitochondrial DNA (mtDNA)-encoded human CI subunits into yeast expression vectors to serve as both ‘prey’ and ‘bait’ in the split murine dihydrofolate reductase (mDHFR) protein complementation assay (PCA). We first demonstrated the capacity of this approach and then used it to examine reported pathological OXPHOS CI mutations that occur at subunit interaction interfaces. Our results indicate that a pathological frame-shift mutation in the MT-ND2 gene, causing the replacement of 126 C-terminal residues by a stretch of only 30 amino acids, resulted in loss of specificity in ND2-based interactions involving these residues. Hence, the split mDHFR PCA is a powerful assay for assessing the impact of disease-causing mutations on pairwise protein-protein interactions in the context of a large protein complex, thus offering a possible mechanistic explanation for the underlying pathogenicity.
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- 2019
32. Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions at different rates across generations
- Author
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Neiger T, Dan Mishmar, Lana Meshnik, Kasztan D, Tal Cohen, Christopher J. Klein, Anat Ben-Zvi, Yoram Nevo, Sara Dadon, Mor Kishner, Jeffery M. Vance, Dan Bar-Yaacov, Itay Valenci, and Stephan Züchner
- Subjects
Genetics ,Mitochondrial DNA ,Mutation ,Mutant ,Biology ,medicine.disease_cause ,Heteroplasmy ,Parkin ,Complementation ,symbols.namesake ,mitochondrial fusion ,Mendelian inheritance ,symbols ,medicine - Abstract
Deleterious and intact mitochondrial DNA (mtDNA) mutations frequently co-exist (heteroplasmy). Such mutations likely survive and are inherited due to complementation via the intra-cellular mitochondrial network. Hence, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. To test this hypothesis, we assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin. Firstly, these animals displayed severe embryonic lethality and developmental delay. Strikingly, these phenotypes were relieved during subsequent generations in association with complete ΔmtDNA removal. Moreover, the rates of deletion loss negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. While introducing the ΔmtDNA into a fzo-1;pdr-1 (PARKIN ortholog) double mutant, we observed skew in the mendelian distribution of progeny, in contrast to normal distribution in the ΔmtDNA;fzo-1 mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. This underlines the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. Finally, while investigating heteroplasmy patterns in three Charcot-Marie-Tooth disease type 2A pedigrees, which carry a mutated mitofusin 2, we found a single potentially deleterious heteroplasmic mutation, whose levels were selectively reduced in the patient versus healthy maternal relatives. Taken together our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection, while inherited from generation to generation.
- Published
- 2019
33. Corrigendum: Initiation of mtDNA transcription is followed by pausing, and diverges across human cell types and during evolution
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Amit Blumberg, Edward J. Rice, Anshul Kundaje, Charles G. Danko, and Dan Mishmar
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Research ,Genetics ,Genetics (clinical) - Abstract
Mitochondrial DNA (mtDNA) genes are long known to be cotranscribed in polycistrones, yet it remains impossible to study nascent mtDNA transcripts quantitatively in vivo using existing tools. To this end, we used deep sequencing (GRO-seq and PRO-seq) and analyzed nascent mtDNA-encoded RNA transcripts in diverse human cell lines and metazoan organisms. Surprisingly, accurate detection of human mtDNA transcription initiation sites (TISs) in the heavy and light strands revealed a novel conserved transcription pausing site near the light-strand TIS. This pausing site correlated with the presence of a bacterial pausing sequence motif, with reduced SNP density, and with a DNase footprinting signal in all tested cells. Its location within conserved sequence block 3 (CSBIII), just upstream of the known transcription–replication transition point, suggests involvement in such transition. Analysis of nonhuman organisms enabled de novo mtDNA sequence assembly, as well as detection of previously unknown mtDNA TIS, pausing, and transcription termination sites with unprecedented accuracy. Whereas mammals (Pan troglodytes, Macaca mulatta, Rattus norvegicus, and Mus musculus) showed a human-like mtDNA transcription pattern, the invertebrate pattern (Drosophila melanogaster and Caenorhabditis elegans) profoundly diverged. Our approach paves the path toward in vivo, quantitative, reference sequence-free analysis of mtDNA transcription in all eukaryotes.
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- 2019
34. Disease-causing mutations in subunits of OXPHOS complex I affect their physical interactions
- Author
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Gilad Barshad, Maya Schuldiner, Dan Mishmar, Lihi Gal, and Nicol Zlotinkov-Poznianski
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Cloning ,Genetics ,Mutation ,Mitochondrial DNA ,biology ,Chemistry ,Protein combining ,Context (language use) ,medicine.disease_cause ,Nuclear DNA ,Dihydrofolate reductase ,medicine ,biology.protein ,Gene - Abstract
Mitochondrial complex I (C1) is the largest multi-subunit oxidative phosphorylation (OXPHOS) protein complex. Recent availability of a high-resolution human C1 structure, and from two non-human mammals, enabled predicting the impact of mutations on interactions involving each of the 44 C1 subunits. However, experimentally assessing the impact of the predicted interactions requires an easy and high-throughput method. Here, we created such a platform by cloning all 37 nuclear DNA (nDNA) and 7 mitochondrial DNA (mtDNA)-encoded human C1 subunits into yeast expression vectors to serve as both 'prey' and 'bait' in the split murine dihydrofolate reductase (mDHFR) protein complementation assay (PCA). We first demonstrated the capacity of this approach and then used it to examine reported pathological OXPHOS C1 mutations that occur at subunit interaction interfaces. Our results indicate that a pathological frame-shift mutation in the MT-ND2 gene, causing the replacement of 126 C-terminal residues by a stretch of only 30 amino acids, resulted in loss of specificity in ND2-based interactions involving these residues. Hence, the split mDHFR PCA is a powerful assay for assessing the impact of disease-causing mutations on pairwise protein-protein interactions in the context of a large protein complex, thus revealing the mechanism underlying any associated pathogenicity.
- Published
- 2019
35. mtDNA eQTLs and the m1A 16S rRNA modification explain mtDNA tissue-specific gene expression pattern in humans
- Author
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Alal Eran, Chen Mordechai, Dan Mishmar, and Tal Cohen
- Subjects
Genetics ,Mitochondrial DNA ,RRNA modification ,Gene expression ,Expression quantitative trait loci ,Tissue-Specific Gene Expression ,Single-nucleotide polymorphism ,Biology ,16S ribosomal RNA ,Haplogroup - Abstract
Expression quantitative trait loci (eQTLs) are instrumental in genome-wide identification of regulatory elements, yet were overlooked in the mitochondrial DNA (mtDNA). By analyzing 5079 RNA-seq samples from 23 tissues we identified association of ancient mtDNA SNPs (haplogroups T2, L2, J2 and V) and recurrent SNPs (mtDNA positions 263, 750, 1438 and 10398) with tissue-dependent mtDNA gene-expression. Since the recurrent SNPs independently occurred in different mtDNA genetic backgrounds, they constitute the best candidates to be causal eQTLs. Secondly, the discovery of mtDNA eQTLs in both coding and non-coding mtDNA regions, propose the identification of novel mtDNA regulatory elements. Third, we identified association between low m1A 947 MT-RNR2 (16S) rRNA modification levels and altered mtDNA gene-expression in twelve tissues. Such association disappeared in skin which was exposed to sun, as compared to sun-unexposed skin from the same individuals, thus supporting the impact of UV on mtDNA gene expression. Taken together, our findings reveal that both mtDNA SNPs and mt-rRNA modification affect mtDNA gene expression in a tissue-dependent manner.
- Published
- 2018
36. mtDNA in the crossroads of evolution and disease
- Author
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Dan Mishmar
- Subjects
0303 health sciences ,Mitochondrial DNA ,Cell Biology ,Disease ,Mitochondrion ,Biology ,humanities ,Mtdna mutations ,03 medical and health sciences ,0302 clinical medicine ,Human disease ,Evolutionary biology ,Allele ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Dan Mishmar recounts the first studies that used mitochondrial DNA (mtDNA) to trace the origin of humanity to Africa and that connected mtDNA mutations with a human disease.
- Published
- 2020
37. A common pattern of DNase I footprinting throughout the human mtDNA unveils clues for a chromatin-like organization
- Author
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Dan Mishmar, Charles G. Danko, Amit Blumberg, and Anshul Kundaje
- Subjects
0301 basic medicine ,Mitochondrial DNA ,DNA Footprinting ,Human mitochondrial genetics ,DNA, Mitochondrial ,Cell Line ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,Animals ,Humans ,Transcription factor ,Genetics (clinical) ,Deoxyribonucleases ,biology ,Genome, Human ,Research ,DNase-I Footprinting ,TFAM ,Footprinting ,Chromatin ,Mitochondria ,DNA-Binding Proteins ,G-Quadruplexes ,030104 developmental biology ,Histone ,Gene Expression Regulation ,biology.protein ,030217 neurology & neurosurgery ,HeLa Cells ,Transcription Factors - Abstract
Human mitochondrial DNA (mtDNA) is believed to lack chromatin and histones. Instead, it is coated solely by the transcription factor TFAM. We asked whether mtDNA packaging is more regulated than once thought. To address this, we analyzed DNase-seq experiments in 324 human cell types and found, for the first time, a pattern of 29 mtDNA Genomic footprinting (mt-DGF) sites shared by ∼90% of the samples. Their syntenic conservation in mouse DNase-seq experiments reflect selective constraints. Colocalization with known mtDNA regulatory elements, with G-quadruplex structures, in TFAM-poor sites (in HeLa cells) and with transcription pausing sites, suggest a functional regulatory role for such mt-DGFs. Altered mt-DGF pattern in interleukin 3-treated CD34+ cells, certain tissue differences, and significant prevalence change in fetal versus nonfetal samples, offer first clues to their physiological importance. Taken together, human mtDNA has a conserved protein–DNA organization, which is likely involved in mtDNA regulation.
- Published
- 2018
38. A common pattern of DNase-I footprinting throughout the human mtDNA unveils clues for a chromatin-like organization
- Author
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Charles G. Danko, Dan Mishmar, Anshul Kundaje, and Amit Blumberg
- Subjects
mtDNA control region ,Genetics ,Mitochondrial DNA ,Histone ,biology ,biology.protein ,Nucleoid ,TFAM ,Transcription factor ,Human mitochondrial genetics ,Chromatin - Abstract
Human mitochondrial DNA (mtDNA) is believed to lack chromatin and histones. Instead, it is coated solely by the transcription factor TFAM, which binds the mtDNA without sequence specificity and packs it into a bacterial-like nucleoid in a dose-dependent fashion. We asked whether mtDNA packaging is more regulated than once thought. As a first step to address this question, we analyzed mtDNA DNase-I-seq experiments in 324 different human cell types and found, for the first time, a pattern of 29 Genomic footprinting (DGF) sites throughout the mtDNA shared by ∼90% of the tested samples. Low SNP density at the DGF sites, and their conservation in mouse DNase-seq experiments, reflect strong selective constraints. Co-localization of the DGFs with known mtDNA regulatory elements and with recently-discovered transcription pausing sites, suggest a role for such DGFs in mtDNA transcription. Altered mtDNA DGF pattern in IL-3 treated CD+34 cells offer first clue to their physiological importance. Taken together, human mtDNA has a conserved and regulated protein-DNA organization, which is likely involved in regulation of mtDNA gene expression.
- Published
- 2017
39. Oxidative-phosphorylation genes from the mitochondrial and nuclear genomes co-express in all human tissues except for the ancient brain
- Author
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Dan Mishmar, Gilad Barshad, and Amit Blumberg
- Subjects
Genetics ,Mitochondrial DNA ,Gene cluster ,Gene expression ,CEBPB ,Transcriptional regulation ,Biology ,Gene ,Genome ,Nuclear DNA - Abstract
In humans, oxidative phosphorylation (OXPHOS), the cellular energy producer, harbors ∼90 nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded subunits. Although nDNA- and mtDNA-encoded OXPHOS proteins physically interact, their transcriptional regulation profoundly diverges, thus questioning their co-regulation. To address mtDNA-nDNA gene co-expression, we analyzed ∼8,500 RNA-seq Gene-Tissue-Expression (GTEx) experiments encompassing 48 human tissues. We found overall positive cross-tissue mtDNA-nDNA OXPHOS gene co-expression. Nevertheless, alternatively-spliced variants, as well as certain OXPHOS genes, did not converge into the main OXPHOS gene cluster, suggesting tissue-specific flavor of OXPHOS gene expression. Finally, unlike non-brain body sites, and neocortex and cerebellum (‘mammalian’ brain), negative mito-nuclear expression correlation was found in the hypothalamus, basal ganglia and amygdala (‘ancient brain’). Analyses of co-expression, DNase-seq and ChIP-seq experiments identified candidate RNA-binding genes and CEBPb as best explaining this phenomenon. We suggest that evolutionary convergence of the ‘mammalian’ brain into positive mtDNA-nDNA OXPHOS co-expression reflects adjustment to novel bioenergetics needs.
- Published
- 2017
40. MtDNA meta-analysis reveals both phenotype specificity and allele heterogeneity: a model for differential association
- Author
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Michael Friger, Dan Mishmar, and Shani Marom
- Subjects
Male ,0301 basic medicine ,Longevity ,Population ,Breast Neoplasms ,Biology ,Population stratification ,DNA, Mitochondrial ,Article ,White People ,Haplogroup ,Evolution, Molecular ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Humans ,Genetic Predisposition to Disease ,Allele ,education ,Allele frequency ,Alleles ,Genetic association ,Genetics ,education.field_of_study ,Multidisciplinary ,Genetic heterogeneity ,Haplotype ,Parkinson Disease ,Mitochondria ,Phenotype ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Haplotypes ,Female ,030217 neurology & neurosurgery - Abstract
Human mtDNA genetic variants have traditionally been considered markers for ancient population migrations. However, during the past three decades, these variants have been associated with altered susceptibility to various phenotypes, thus supporting their importance for human health. Nevertheless, mtDNA disease association has frequently been supported only in certain populations, due either to population stratification or differential epistatic compensations among populations. To partially overcome these obstacles, we performed meta-analysis of the multiple mtDNA association studies conducted until 2016, encompassing 53,975 patients and 63,323 controls. Our findings support the association of mtDNA haplogroups and recurrent variants with specific phenotypes such as Parkinson’s disease, type 2 diabetes, longevity, and breast cancer. Strikingly, our assessment of mtDNA variants’ involvement with multiple phenotypes revealed significant impact for Caucasian haplogroups H, J, and K. Therefore, ancient mtDNA variants could be divided into those that affect specific phenotypes, versus others with a general impact on phenotype combinations. We suggest that the mtDNA could serve as a model for phenotype specificity versus allele heterogeneity.
- Published
- 2017
41. The First Mitochondrial Genomics and Evolution SMBE-Satellite Meeting : A New Scientific Symbiosis
- Author
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Andrew Pomiankowski, Göran Arnqvist, Ronald S. Burton, Oren Ostersetzer-Biran, Dan Mishmar, Nick Lane, Dorothée Huchon, and Aleksandra Filipovska
- Subjects
0301 basic medicine ,Functional role ,Mitochondrial DNA ,Genomic data ,Complex disease ,Genomics ,mitochondrial DNA ,Biology ,Meeting Report ,Genome ,DNA, Mitochondrial ,Evolution, Molecular ,Evolutionsbiologi ,03 medical and health sciences ,evolution ,Genetics ,genomics ,Humans ,Clinical phenotype ,Ecology, Evolution, Behavior and Systematics ,Cell Nucleus ,Evolutionary Biology ,Molecular ,DNA ,Heteroplasmy ,Mitochondrial ,mitochondria ,030104 developmental biology ,Evolutionary biology ,Genome, Mitochondrial ,Biochemistry and Cell Biology ,Maternal Inheritance ,Developmental Biology - Abstract
The central role of the mitochondrion for cellular and organismal metabolism is well known, yet its functional role in evolution has rarely been featured in leading international conferences. Moreover, the contribution of mitochondrial genetics to complex disease phenotypes is particularly important, and although major advances have been made in the field of genomics, mitochondrial genomic data have in many cases been overlooked. Accumulating data and new knowledge support a major contribution of this maternally inherited genome, and its interactions with the nucleus, to both major evolutionary processes and diverse disease phenotypes. These advances encouraged us to assemble the first Mitochondrial Genomics and Evolution (MGE) meeting—an SMBE satellite and Israeli Science foundation international conference (Israel, September 2017). Here, we report the content and outcome of the MGE meeting (https://www.mge2017.com/; last accessed November 5, 2017).
- Published
- 2017
42. Correction: Mitochondrial 16S rRNA Is Methylated by tRNA Methyltransferase TRMT61B in All Vertebrates
- Author
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Amit Blumberg, Dan Mishmar, Orr Schlesinger, Nenad Ban, Yuma Ishigami, Basil J. Greber, Dan Bar-Yaacov, Tsutomu Suzuki, Idan Frumkin, Yonatan Chemla, Yuka Yashiro, Raz Zarivach, Lital Alfonta, Yitzhak Pilpel, Philipp Bieri, and Takeshi Chujo
- Subjects
0301 basic medicine ,Genetics ,03 medical and health sciences ,030104 developmental biology ,General Immunology and Microbiology ,QH301-705.5 ,General Neuroscience ,TRNA Methyltransferase ,Biology ,Biology (General) ,General Agricultural and Biological Sciences ,16S ribosomal RNA ,General Biochemistry, Genetics and Molecular Biology - Abstract
[This corrects the article DOI: 10.1371/journal.pbio.1002557.].
- Published
- 2017
43. Obituary: Prof. Lea Reshef
- Author
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Dan Mishmar and Oded Meyuhas
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,Structural Biology ,Chemistry ,05 social sciences ,Genetics ,Biophysics ,050301 education ,Cell Biology ,0503 education ,Molecular Biology ,Biochemistry - Published
- 2018
44. The First Chameleon Transcriptome: Comparative Genomic Analysis of the OXPHOS System Reveals Loss of COX8 in Iguanian Lizards
- Author
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Dan Mishmar, Amos Bouskila, and Dan Bar-Yaacov
- Subjects
chameleon ,Mitochondrial DNA ,Letter ,Nuclear gene ,oxidative phosphorylation ,Genome ,Deep sequencing ,Electron Transport Complex IV ,Evolution, Molecular ,Transcriptome ,Adenosine Triphosphate ,Genetics ,Animals ,Humans ,Chamaeleo chamaeleon ,Gene ,Ecology, Evolution, Behavior and Systematics ,biology ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Lizards ,Molecular Sequence Annotation ,biology.organism_classification ,Mitochondria ,Gene expression profiling ,transcriptome - Abstract
Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system.
- Published
- 2013
45. Functional Recurrent Mutations in the Human Mitochondrial Phylogeny: Dual Roles in Evolution and Disease
- Author
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Dan Mishmar, Liron Levin, Hadas Hawlena, Yotam Gurman, and Ilia Zhidkov
- Subjects
Nonsynonymous substitution ,Mitochondrial DNA ,selection ,mitochondrial DNA ,Biology ,medicine.disease_cause ,Human mitochondrial genetics ,DNA, Mitochondrial ,Conserved sequence ,Evolution, Molecular ,Phylogenetics ,Genetics ,medicine ,Humans ,recurrent nodal mutations ,Selection, Genetic ,Codon ,Gene ,Ecology, Evolution, Behavior and Systematics ,Phylogeny ,Mutation ,homoplasy ,Mitochondria ,RNA ,Synonymous substitution ,Research Article - Abstract
Mutations frequently reoccur in the human mitochondrial DNA (mtDNA). However, it is unclear whether recurrent mtDNA nodal mutations (RNMs), that is, recurrent mutations in stems of unrelated phylogenetic nodes, are functional and hence selectively constrained. To answer this question, we performed comprehensive parsimony and maximum likelihood analyses of 9,868 publicly available whole human mtDNAs revealing 1,606 single nodal mutations (SNMs) and 679 RNMs. We then evaluated the potential functionality of synonymous, nonsynonymous and RNA SNMs and RNMs. For synonymous mutations, we have implemented the Codon Adaptation Index. For nonsynonymous mutations, we assessed evolutionary conservation, and employed previously described pathogenicity score assessment tools. For RNA genes’ mutations, we designed a bioinformatic tool which compiled evolutionary conservation and potential effect on RNA structure. While comparing the functionality scores of nonsynonymous and RNA SNMs and RNMs with those of disease-causing mtDNA mutations, we found significant difference (P < 0.001). However, 24 RNMs and 67 SNMs had comparable values with disease-causing mutations reflecting their potential function thus being the best candidates to participate in adaptive events of unrelated lineages. Strikingly, some functional RNMs occurred in unrelated mtDNA lineages that independently altered susceptibility to the same diseases, thus suggesting common functionality. To our knowledge, this is the most comprehensive analysis of selective signatures in the mtDNA not only within proteins but also within RNA genes. For the first time, we discover virtually all positively selected RNMs in our phylogeny while emphasizing their dual role in past evolutionary events and in disease today.
- Published
- 2013
46. Mitochondrial 16S rRNA Is Methylated by tRNA Methyltransferase TRMT61B in All Vertebrates
- Author
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Lital Alfonta, Basil J. Greber, Tsutomu Suzuki, Dan Mishmar, Philipp Bieri, Dan Bar-Yaacov, Orr Schlesinger, Amit Blumberg, Yuma Ishigami, Nenad Ban, Idan Frumkin, Takeshi Chujo, Yuka Yashiro, Yonatan Chemla, Yitzhak Pilpel, and Raz Zarivach
- Subjects
0301 basic medicine ,Adenosine ,RNA, Mitochondrial ,Mitochondrion ,Biochemistry ,RRNA modification ,RNA, Ribosomal, 16S ,Mitochondrial ribosome ,Small interfering RNAs ,RNA Processing, Post-Transcriptional ,Biology (General) ,Energy-Producing Organelles ,Genetics ,tRNA Methyltransferases ,Nucleotides ,General Neuroscience ,Mitochondrial DNA ,Mitochondria ,Nucleic acids ,RNA, Bacterial ,Ribosomal RNA ,Transfer RNA ,Vertebrates ,General Agricultural and Biological Sciences ,Research Article ,Cell biology ,Cellular structures and organelles ,Forms of DNA ,QH301-705.5 ,Biology ,Bioenergetics ,Methylation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Extraction techniques ,23S ribosomal RNA ,Escherichia coli ,Animals ,Humans ,Non-coding RNA ,General Immunology and Microbiology ,Biology and life sciences ,Adenine ,TRNA Methyltransferase ,Organisms ,Correction ,DNA ,RNA extraction ,Gene regulation ,Research and analysis methods ,030104 developmental biology ,RNA ,Gene expression ,Ribosomes ,HeLa Cells - Abstract
The mitochondrial ribosome, which translates all mitochondrial DNA (mtDNA)-encoded proteins, should be tightly regulated pre- and post-transcriptionally. Recently, we found RNA-DNA differences (RDDs) at human mitochondrial 16S (large) rRNA position 947 that were indicative of post-transcriptional modification. Here, we show that these 16S rRNA RDDs result from a 1-methyladenosine (m1A) modification introduced by TRMT61B, thus being the first vertebrate methyltransferase that modifies both tRNA and rRNAs. m1A947 is conserved in humans and all vertebrates having adenine at the corresponding mtDNA position (90% of vertebrates). However, this mtDNA base is a thymine in 10% of the vertebrates and a guanine in the 23S rRNA of 95% of bacteria, suggesting alternative evolutionary solutions. m1A, uridine, or guanine may stabilize the local structure of mitochondrial and bacterial ribosomes. Experimental assessment of genome-edited Escherichia coli showed that unmodified adenine caused impaired protein synthesis and growth. Our findings revealed a conserved mechanism of rRNA modification that has been selected instead of DNA mutations to enable proper mitochondrial ribosome function., PLoS Biology, 14 (9), ISSN:1544-9173, ISSN:1545-7885
- Published
- 2016
47. Initiation of mtDNA transcription is followed by pausing, and diverges across human cell types and during evolution
- Author
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Dan Mishmar, Edward J. Rice, Charles G. Danko, Amit Blumberg, and Anshul Kundaje
- Subjects
0301 basic medicine ,Primates ,Mitochondrial DNA ,DNA footprinting ,Rodentia ,Biology ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Conserved sequence ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,Transcription (biology) ,Genetics ,Animals ,Humans ,Gene ,Genetics (clinical) ,Transcription Initiation, Genetic ,biology.organism_classification ,Invertebrates ,030104 developmental biology ,chemistry ,Organ Specificity ,Drosophila melanogaster ,Transcription Initiation Site ,Sequence motif ,Transcriptome ,Corrigendum ,DNA - Abstract
Mitochondrial DNA (mtDNA) genes are long known to be cotranscribed in polycistrones, yet it remains impossible to study nascent mtDNA transcripts quantitatively in vivo using existing tools. To this end, we used deep sequencing (GRO-seq and PRO-seq) and analyzed nascent mtDNA-encoded RNA transcripts in diverse human cell lines and metazoan organisms. Surprisingly, accurate detection of human mtDNA transcription initiation sites (TISs) in the heavy and light strands revealed a novel conserved transcription pausing site near the light-strand TIS. This pausing site correlated with the presence of a bacterial pausing sequence motif, with reduced SNP density, and with a DNase footprinting signal in all tested cells. Its location within conserved sequence block 3 (CSBIII), just upstream of the known transcription–replication transition point, suggests involvement in such transition. Analysis of nonhuman organisms enabled de novo mtDNA sequence assembly, as well as detection of previously unknown mtDNA TIS, pausing, and transcription termination sites with unprecedented accuracy. Whereas mammals (Pan troglodytes, Macaca mulatta, Rattus norvegicus, and Mus musculus) showed a human-like mtDNA transcription pattern, the invertebrate pattern (Drosophila melanogaster and Caenorhabditis elegans) profoundly diverged. Our approach paves the path toward in vivo, quantitative, reference sequence-free analysis of mtDNA transcription in all eukaryotes.
- Published
- 2016
48. Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns
- Author
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Liron Levin, Dan Mishmar, and Tal Cohen
- Subjects
0301 basic medicine ,Cancer Research ,Molecular biology ,Gene Expression ,RNA-binding proteins ,Biochemistry ,Haplogroup ,Sequencing techniques ,Human Genome Project ,Genetics (clinical) ,Energy-Producing Organelles ,Genetics ,Regulation of gene expression ,mtDNA control region ,education.field_of_study ,RNA sequencing ,Mitochondrial DNA ,Mitochondria ,Nucleic acids ,Transfer RNA ,Cellular Structures and Organelles ,Research Article ,Ribosomal Proteins ,lcsh:QH426-470 ,DNA Copy Number Variations ,Forms of DNA ,Population ,Black People ,Biology ,Bioenergetics ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Evolution, Molecular ,Mitochondrial Proteins ,03 medical and health sciences ,Humans ,Gene Regulation ,education ,Non-coding RNA ,Gene ,Ecology, Evolution, Behavior and Systematics ,Evolutionary Biology ,Base Sequence ,Biology and life sciences ,Population Biology ,Gene Expression Profiling ,Haplotype ,Proteins ,DNA ,Cell Biology ,Gene expression profiling ,Research and analysis methods ,lcsh:Genetics ,030104 developmental biology ,Molecular biology techniques ,Haplotypes ,RNA ,Haplogroups ,Population Genetics - Abstract
Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world., Author Summary The mitochondrion is an organelle found in all cells of our body and plays a significant role in the energy and heat production. This is the only organelle in animal cells harboring its own genome outside of the nucleus. Mitochondrial DNA (mtDNA) variants have been traditionally used as neutral markers to trace ancient population migrations. As a result, the functional impact of human mtDNA population variants on gene regulation is poorly understood. To address this question, we analyzed available data of mtDNA gene expression pattern in a large group of individuals (454) from diverse human populations. Here, we show for the first time that the ancient migration of humans out of Africa correlated with differences in mitochondrial gene expression patterns, and could be explained by the activity of certain RNA-binding proteins. These findings suggest a major mitochondrial regulatory transition, as humans left Africa to populate the rest of the world.
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- 2016
49. The genomic landscape of evolutionary convergence in mammals, birds and reptiles
- Author
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Liron Levin and Dan Mishmar
- Subjects
0301 basic medicine ,Mitochondrial DNA ,Ecology ,biology ,biology.organism_classification ,Nuclear DNA ,03 medical and health sciences ,030104 developmental biology ,Protein structure ,Phylogenetics ,Evolutionary biology ,Convergent evolution ,Amniote ,NODAL ,Gene ,Ecology, Evolution, Behavior and Systematics - Abstract
Many lineage-defining (nodal) mutations possess high functionality. However, differentiating adaptive nodal mutations from those that are functionally compensated remains challenging. To address this challenge, we identified functional nodal mutations (fNMs) in ~3,400 nuclear DNA (nDNA) and 4 mitochondrial DNA (mtDNA) protein structures from 91 and 1,003 species, respectively, representing the entire mammalian, bird and reptile phylogeny. A screen for candidate compensatory mutations among co-occurring amino acid changes in close structural proximity revealed that such compensated fNMs encompass 37% and 27% of the mtDNA and nDNA datasets, respectively. Analysis of the remaining (non-compensated) mutations, which are enriched for adaptive mutations, showed that birds and mammals share most such recurrent fNMs (N = 51). Among the latter, we discovered mutations in thermoregulation-related genes. These represent the best candidates to explain the molecular basis of convergent body thermoregulation in birds and mammals. Our analysis reveals the landscape of possible mutational compensation and convergence in amniote phylogeny. Certain mutations are characteristic of specific lineages across the phylogeny of birds, reptiles and mammals. Here, protein structural information is used to separate out such mutations that are adaptive from those that compensate changes at other sites.
- Published
- 2016
50. Mitochondrial and Nuclear Genome Coevolution
- Author
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Dan Mishmar, Gilad Barshad, and Amit Blumberg
- Subjects
Genetics ,Mitochondrial DNA ,Nuclear gene ,mitochondrial fusion ,Mitochondrial translation ,Biology ,Mitochondrion ,Human mitochondrial genetics ,Genome ,Nuclear DNA - Abstract
The mitochondrion is the only organelle in animal cells with its own genome (mtDNA). Nevertheless, most mitochondrial proteins are encoded by the nuclear genome and are then imported into the mitochondria. Because animal mtDNA has a higher order of mutation rate compared to the nuclear genome, tight mitochondrial–nuclear coevolution is required to maintain mitochondrial function. Here we discuss three levels of such coevolution: protein–protein interaction within the mitochondrial oxidative phosphorylation system; nuclear-encoded protein–mtDNA-encoded RNA interactions in the mitochondrial translation system; nuclear DNA-encoded protein–mtDNA binding sites interactions as part of the mitochondrial transcription and replication machineries.
- Published
- 2016
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