scholarly journals The frequency of the known mitochondrial variants associated with drug-induced toxicity in a Korean population

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Vinh Hoa Pham ◽  
Van Lam Nguyen ◽  
Hye-Eun Jung ◽  
Yong-Soon Cho ◽  
Jae-Gook Shin
Keyword(s):  
Mitochondrial Genome ◽  
Variant Calling ◽  
Genome Project ◽  
Korean Population ◽  
Clinical Implementation ◽  
Mtdna Copy Number ◽  
Drug Induced ◽  
Mitochondrial Mutation ◽  
Mitochondrial Ribosomes ◽  
Genetic Biomarkers

Abstract Background Few studies have annotated the whole mitochondrial DNA (mtDNA) genome associated with drug responses in Asian populations. This study aimed to characterize mtDNA genetic profiles, especially the distribution and frequency of well-known genetic biomarkers associated with diseases and drug-induced toxicity in a Korean population. Method Whole mitochondrial genome was sequenced for 118 Korean subjects by using a next-generation sequencing approach. The bioinformatic pipeline was constructed for variant calling, haplogroup classification and annotation of mitochondrial mutation. Results A total of 681 variants was identified among all subjects. The MT-TRNP gene and displacement loop showed the highest numbers of variants (113 and 74 variants, respectively). The m.16189T > C allele, which is known to reduce the mtDNA copy number in human cells was detected in 25.4% of subjects. The variants (m.2706A > G, m.3010A > G, and m.1095T > C), which are associated with drug-induced toxicity, were observed with the frequency of 99.15%, 30.51%, and 0.08%, respectively. The m.2150T > A, a genotype associated with highly disruptive effects on mitochondrial ribosomes, was identified in five subjects. The D and M groups were the most dominant groups with the frequency of 34.74% and 16.1%, respectively. Conclusions Our finding was consistent with Korean Genome Project and well reflected the unique profile of mitochondrial haplogroup distribution. It was the first study to annotate the whole mitochondrial genome with drug-induced toxicity to predict the ADRs event in clinical implementation for Korean subjects. This approach could be extended for further study for validation of the potential ethnic-specific mitochondrial genetic biomarkers in the Korean population.

scholarly journals Next Generation Sequencing-Based Mitochondrial Genome Analysis In Relation To The Drug- Induced Toxicity In Korean Subjects

2021 ◽  
Author(s):  
Pham Vinh Hoa ◽  
Nguyen Van Lam ◽  
Hye-Eun Jung ◽  
Yong-Soon Cho ◽  
Jae-Gook Shin
Keyword(s):  
Next Generation Sequencing ◽  
Mitochondrial Genome ◽  
Korean Population ◽  
Next Generation ◽  
Clinical Implementation ◽  
Mtdna Copy Number ◽  
Drug Induced ◽  
Genetic Biomarkers ◽  
D Loop ◽  
Generation Sequencing

Abstract Background: Mitochondrial variants have been investigated to be associated with many diseases, which was reported largely from European populations. Few studies, however, have annotated the whole mitochondrial DNA (mtDNA) genome associated with drug responses including adverse drug reactions (ADRs), especially in Asian populations. This study was performed to characterize mtDNA genetic profiles, especially the distribution and frequency of well-known genetic biomarkers associated with diseases and drug-induced toxicity, in the Korean population by using high throughput next-generation sequencing.Results: A total of 681 variants was identified among all 118 Korean subjects. The MT-TRNP and displacement loop (D-loop) showed the highest numbers of variants (113 and 74 variants, respectively). In the D-loop, 25.4% of the subjects were identified to have m.16189T>C allele, which was known to reduce the mtDNA copy number variation in human cells. The variant m.1095T>C, annotated to aminoglycoside-induced ototoxicity, was found from only one subject in this study, while the frequency of m.2706A>G and m.3010A>G, which are associated with antibiotic-induced toxicity, were 99.15% and 30.51%, respectively. The 5 subjects were identified to have the variant m.2150T>TA, a genotype associated with highly disruptive effects on mitochondrial ribosomes. In addition, the mitochondrial haplogroups of 118 Korean subjects were found that D and M groups were the most dominant groups with the frequency of 34.74% and 16.1%, respectively. Conclusions: Our finding was constant with Korean 1K project and well reflected the unique profile of mitochondrial haplogroup distribution. It was the first study to annotate the whole mitochondrial genome with drug-induced toxicity to predict the ADRs event in clinical implementation for Korean population. This approach could be extended for further study for validation the potential ethnic specific mitochondrial genetic biomarkers in Korea population.

scholarly journals Variability in mitochondrial import, mitochondrial health and mtDNA copy number using Type II and Type V CRISPR effectors

2020 ◽  
Author(s):  
Zuriñe Antón ◽  
Grace Mullally ◽  
Holly Ford ◽  
Marc W. van der Kamp ◽  
Mark D. Szczelkun ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Copy Number ◽  
Protein Targeting ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Basic Research ◽  
Strategy Development ◽  
Mtdna Copy Number ◽  
Mitochondrial Import

ABSTRACTCurrent methodologies for targeting the mitochondrial genome for basic research and/or therapeutic strategy development in mitochondrial diseases are restricted by practical limitations and technical inflexibility. The development of a functional molecular toolbox for CRISPR-mediated mitochondrial genome editing is therefore desirable, as this could enable precise targeting of mtDNA haplotypes using the precision and tuneability of CRISPR enzymes; however, published reports of “MitoCRISPR” systems have, to date, lacked reproducibility and independent corroboration. Here, we have explored the requirements for a functional MitoCRISPR system in human cells by engineering several versions of CRISPR nucleases, including the use of alternative mitochondrial protein targeting sequences and smaller paralogues, and the application of gRNA modifications that reportedly induce mitochondrial import. We demonstrate varied mitochondrial targeting efficiencies and influences on mitochondrial dynamics/function of different CRISPR nucleases, with Lachnospiraceae bacterium ND2006 (Lb) Cas12a being better targeted and tolerated than Cas9 variants. We also provide evidence of Cas9 gRNA association with mitochondria in HeLa cells and isolated yeast mitochondria, even in the absence of a targeting RNA aptamer. Finally, we present evidence linking mitochondrial-targeted LbCas12a/crRNA with increased mtDNA copy number dependent upon DNA binding and cleavage activity. We discuss reproducibility issues and the future steps necessary if MitoCRISPR is to be realised.

Numt identification and removal with RtN!

2020 ◽  
Vol 36 (20) ◽  
pp. 5115-5116 ◽  
Author(s):  
August E Woerner ◽  
Jennifer Churchill Cihlar ◽  
Utpal Smart ◽  
Bruce Budowle
Keyword(s):  
Mitochondrial Genome ◽  
Massively Parallel Sequencing ◽  
Sequence Similarity ◽  
Variant Calling ◽  
Supplementary Information ◽  
Mitochondrial Genomes ◽  
Sequencing Data ◽  
Read Mapping ◽  
Genome Data ◽  
Mitochondrial Sequences

Abstract Motivation Assays in mitochondrial genomics rely on accurate read mapping and variant calling. However, there are known and unknown nuclear paralogs that have fundamentally different genetic properties than that of the mitochondrial genome. Such paralogs complicate the interpretation of mitochondrial genome data and confound variant calling. Results Remove the Numts! (RtN!) was developed to categorize reads from massively parallel sequencing data not based on the expected properties and sequence identities of paralogous nuclear encoded mitochondrial sequences, but instead using sequence similarity to a large database of publicly available mitochondrial genomes. RtN! removes low-level sequencing noise and mitochondrial paralogs while not impacting variant calling, while competing methods were shown to remove true variants from mitochondrial mixtures. Availability and implementation https://github.com/Ahhgust/RtN Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Mitochondrial import, health and mtDNA copy number variability seen when using type II and type V CRISPR effectors

2020 ◽  
Vol 133 (18) ◽  
pp. jcs248468 ◽  
Author(s):  
Zuriñe Antón ◽  
Grace Mullally ◽  
Holly C. Ford ◽  
Marc W. van der Kamp ◽  
Mark D. Szczelkun ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Copy Number ◽  
Protein Targeting ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Mtdna Copy Number ◽  
Data Link ◽  
Mitochondrial Import ◽  
Type V

ABSTRACTCurrent methodologies for targeting the mitochondrial genome for research and/or therapy development in mitochondrial diseases are restricted by practical limitations and technical inflexibility. A molecular toolbox for CRISPR-mediated mitochondrial genome editing is desirable, as this could enable targeting of mtDNA haplotypes using the precision and tuneability of CRISPR enzymes. Such ‘MitoCRISPR’ systems described to date lack reproducibility and independent corroboration. We have explored the requirements for MitoCRISPR in human cells by CRISPR nuclease engineering, including the use of alternative mitochondrial protein targeting sequences and smaller paralogues, and the application of guide (g)RNA modifications for mitochondrial import. We demonstrate varied mitochondrial targeting efficiencies and effects on mitochondrial dynamics/function of different CRISPR nucleases, with Lachnospiraceae bacterium ND2006 (Lb) Cas12a being better targeted and tolerated than Cas9 variants. We also provide evidence of Cas9 gRNA association with mitochondria in HeLa cells and isolated yeast mitochondria, even in the absence of a targeting RNA aptamer. Our data link mitochondrial-targeted LbCas12a/crRNA with increased mtDNA copy number dependent upon DNA binding and cleavage activity. We discuss reproducibility issues and the future steps necessary for MitoCRISPR.

Drug-Induced Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Call for Optimum Patient Stratification and Theranostics via Pharmacogenomics

2018 ◽  
Vol 19 (1) ◽  
pp. 329-353 ◽  
Author(s):  
Chonlaphat Sukasem ◽  
Theodora Katsila ◽  
Therdpong Tempark ◽  
George P. Patrinos ◽  
Wasun Chantratita
Keyword(s):  
Toxic Epidermal Necrolysis ◽  
Clinical Care ◽  
Genomic Medicine ◽  
Stevens Johnson Syndrome ◽  
Future Research ◽  
Great Promise ◽  
Patient Stratification ◽  
Clinical Implementation ◽  
Drug Induced ◽  
Johnson Syndrome

The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions. This review focuses on the current understanding of the surveillance, pathogenesis, and treatment of SJS/TEN, including the role of genomics and pharmacogenomics in the etiology, treatment, and eradication of preventable causes of drug-induced SJS/TEN. Gaps, unmet needs, and priorities for future research have been identified for the optimal management of drug-induced SJS/TEN in various ethnic populations. Pharmacogenomics holds great promise for optimal patient stratification and theranostics, yet its clinical implementation needs to be cost-effective and sustainable.

scholarly journals Extensive sequencing of seven human genomes to characterize benchmark reference materials

2015 ◽  
Author(s):  
Justin M Zook ◽  
David Catoe ◽  
Jennifer McDaniel ◽  
Lindsay Vang ◽  
Noah Spies ◽  
...  
Keyword(s):  
Human Genome ◽  
Reference Materials ◽  
De Novo ◽  
Variant Calling ◽  
Genome Project ◽  
Genome Comparison ◽  
Personal Genome ◽  
Sequencing Data ◽  
Sequencing Technologies ◽  
Human Genomes

The Genome in a Bottle Consortium, hosted by the National Institute of Standards and Technology (NIST) is creating reference materials and data for human genome sequencing, as well as methods for genome comparison and benchmarking. Here, we describe a large, diverse set of sequencing data for seven human genomes; five are current or candidate NIST Reference Materials. The pilot genome, NA12878, has been released as NIST RM 8398. We also describe data from two Personal Genome Project trios, one of Ashkenazim Jewish ancestry and one of Chinese ancestry. The data come from 12 technologies: BioNano Genomics, Complete Genomics paired-end and LFR, Ion Proton exome, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCodeTM WGS, and Illumina exome and WGS paired-end, mate-pair, and synthetic long reads. Cell lines, DNA, and data from these individuals are publicly available. Therefore, we expect these data to be useful for revealing novel information about the human genome and improving sequencing technologies, SNP, indel, and structural variant calling, and de novo assembly.

scholarly journals The conflict within: origin, proliferation and persistence of a spontaneously arising selfish mitochondrial genome

2019 ◽  
Vol 375 (1790) ◽  
pp. 20190174 ◽  
Author(s):  
Joseph James Dubie ◽  
Avery Robert Caraway ◽  
McKenna Margaret Stout ◽  
Vaishali Katju ◽  
Ulfar Bergthorsson
Keyword(s):  
Population Dynamics ◽  
Mitochondrial Genome ◽  
Complex Iii ◽  
Population Bottlenecks ◽  
Mtdna Copy Number ◽  
Fitness Effects ◽  
Individual Fitness ◽  
Slow Decline ◽  
Large Populations ◽  
Mitochondrial Genotype

Mitochondrial genomes can sustain mutations that are simultaneously detrimental to individual fitness and yet, can proliferate within individuals owing to a replicative advantage. We analysed the fitness effects and population dynamics of a mitochondrial genome containing a novel 499 bp deletion in the cytochrome b(1) ( ctb-1 ) gene (Δ ctb-1 ) encoding the cytochrome b of complex III in Caenorhabditis elegans. Δ ctb-1 reached a high heteroplasmic frequency of 96% in one experimental line during a mutation accumulation experiment and was linked to additional spontaneous mutations in nd5 and tRNA-Asn . The Δ ctb-1 mutant mitotype imposed a significant fitness cost including a 65% and 52% reduction in productivity and competitive fitness, respectively, relative to individuals bearing wild-type (WT) mitochondria. Deletion-bearing worms were rapidly purged within a few generations when competed against WT mitochondrial DNA (mtDNA) bearing worms in experimental populations. By contrast, the Δ ctb-1 mitotype was able to persist in large populations comprising heteroplasmic individuals only, although the average intracellular frequency of Δ ctb-1 exhibited a slow decline owing to competition among individuals bearing different frequencies of the heteroplasmy. Within experimental lines subjected to severe population bottlenecks ( n = 1), the relative intracellular frequency of Δ ctb-1 increased, which is a hallmark of selfish drive. A positive correlation between Δ ctb-1 and WT mtDNA copy-number suggests a mechanism that increases total mtDNA per se , and does not discern the Δ ctb-1 mitotype from the WT mtDNA. This study demonstrates the selfish nature of the Δ ctb-1 mitotype, given its transmission advantage and substantial fitness load for the host, and highlights the importance of population size for the population dynamics of selfish mtDNA. This article is part of the theme issue ‘Linking the mitochondrial genotype to phenotype: a complex endeavour’.

Mitochondrial Genome Instability in AML Is Associated with Reduction in the Mitochondrial Replication.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2754-2754
Author(s):  
Myung-Geun Shin ◽  
Hyeoung-Joon Kim ◽  
Hye-Ran Kim ◽  
Il-Kwon Lee ◽  
Duck Cho ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Control Region ◽  
Buccal Mucosa ◽  
Copy Number ◽  
Genome Instability ◽  
Point Mutations ◽  
Mtdna Copy Number ◽  
Control Subjects ◽  
Length Changes ◽  
Mtdna Variants

Abstract Genetic changes in mitochondrial DNA (mtDNA) have been hypothesized more widely to play important roles in senescence, autoimmune disease and malignancy because of a paucity of introns and limited repair mechanisms. Malfunction of mismatch repair genes produces genome instability which plays an important role in the development of human cancers. The mtDNA markers for mitochondrial genome instability (mtGI) were point mutations, insertions, deletions and length changes in homopolymeric nucleotide tracts. We investigated the mtGI in AML cells and its effect to alteration in mtDNA copy number. Forty-eight matched AML bone marrow and buccal mucosa samples, and blood samples from 57 control subjects were collected after receiving Institutional Review Board approval and informed consent. We directly sequenced the control region, the tRNA leucine 1 gene plus a part of NADH dehydrogenase (ND)1 and cytochrome b (CYTB) of mtDNA. In an attempt to investigate mtGI, we carried out a qualitative and quantitative profiling mtDNA length heteroplasmies of six mtGIs (np 303–315 poly C, np 16184–16193 poly C, np 514–511 CA repeats, np 3566–3572 poly C, np 12385–12391 poly C and np 12418–12426 poly A) using a size-based PCR product separation by capillary electrophoresis (ABI Prism Genotyper version 3.1). Length heteroplasmy was further confirmed by cloning and sequencing. Quantitative analysis of mtDNA molecules was performed using the QuantiTect SYBR Green PCR kit (Qiagen). In the current study, we detected a large number of polymorphisms as well as new mtDNA variants. A total of 606 mtDNA sequence variants were identified. Among these, 15 mtDNA variants were identified as novel mutations that were absent from corresponding buccal mucosa, control subjects and established mtDNA polymorphism databases. In the control region, we found two types of mtDNA alterations - base substitutions and small deletions/insertions as well as the length heteroplasmies in the np 303 to 315 poly-C, np 16184 to 16193 poly-C and 514–515 CA repeats. Seven patients (15%) had leukemia cell-specific mtDNA substitution mutations in the ND1 and CYTB genes. Somatic mtDNA control region mutations found in this study preferentially altered known mtDNA regulatory elements. AML cells had about a two-fold decrease in mtDNA copy number compared with the results from control subjects (63 x 106 molecules/ul ± 23 x 106 vs 122 x 106 molecules/ul ± 73 x 106). Our results are consistent with a recent observation that carcinogenesis in the liver, kidney and lung involves a decrease of the cellular mitochondrial content and decreased mtDNA copy number (Mutat Res2004;547:71–78). In conclusion, mtGI including point mutations, length changes (insertions or deletions) in homopolymeric tracts commonly occurred in AML cells and reduction in mtDNA copy number may result from either mtDNA control region mutations or impairment of mitochondrial biogenesis. These findings suggest that biogenesis of mitochondria is repressed in the leukemogenesis process of the human hematopoietic tissue.

scholarly journals MMS19 localizes to mitochondria and protects the mitochondrial genome from oxidative damage

2018 ◽  
Vol 96 (1) ◽  
pp. 44-49 ◽  
Author(s):  
Rui Wu ◽  
Qunsong Tan ◽  
Kaifeng Niu ◽  
Yuqi Zhu ◽  
Di Wei ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Oxidative Damage ◽  
Genome Stability ◽  
Excision Repair ◽  
Mass Spectrometry Analysis ◽  
Mtdna Copy Number ◽  
Repair Capacity ◽  
Spectrometry Analysis ◽  
Mitochondrial Genome Stability ◽  
Mtdna Repair

MMS19 localizes to the cytoplasmic and nuclear compartments involved in transcription and nucleotide excision repair (NER). However, whether MMS19 localizes to mitochondria, where it plays a role in maintaining mitochondrial genome stability, remains unknown. In this study, we provide the first evidence that MMS19 is localized in the inner membrane of mitochondria and participates in mtDNA oxidative damage repair. MMS19 knockdown led to mitochondrial dysfunctions including decreased mtDNA copy number, diminished mtDNA repair capacity, and elevated levels of mtDNA common deletion after oxidative stress. Immunoprecipitation – mass spectrometry analysis identified that MMS19 interacts with ANT2, a protein associated with mitochondrial ATP metabolism. ANT2 knockdown also resulted in a decreased mtDNA repair capacity after oxidative damage. Our findings suggest that MMS19 plays an essential role in maintaining mitochondrial genome stability.

Sign in / Sign up

Export Citation Format

Share Document