eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data

Goudenège, David; Bris, Céline; Hoffmann, Virginie; Desquiret-Dumas, Valérie; Jardel, Claude; Rucheton, Benoît; Bannwarth, Sylvie; Paquis‐Flucklinger, Véronique; Lèbre, Anne Sophie; Colin, Estelle; Amati‐Bonneau, Patrizia; Bonneau, Dominique; Reynier, Pascal; Lenaers, Guy; Procaccio, Vincent

doi:10.1038/s41436-018-0350-8

Cited by 39 publications

(28 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The functional effect of the variants were predicted using open-source algorithms including PolyPhen-2 131 , PANTHER 132 , Envision 133 , MutationAssessor 134 , MutPred2 135 and SNPs&GO 136 . The mtDNA deletion was also determined via MitoDel 137 and eKLIPse 138 . MitoDel is a tool for detecting and quantifying mtDNA deletions even at low heteroplasmy levels via the BLAT split read mapping method.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin

Leong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC). However, the intrinsic or acquired resistance against cisplatin remains a major obstacle to treatment efficacy in OSCC. Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers. However, the role of mtDNA alterations in OSCC has not been comprehensively studied. In this study, we evaluated the correlation between mtDNA alterations (mtDNA content, point mutations, large-scale deletions, and methylation status) and cisplatin sensitivity using two OSCC cell lines, namely SAS and H103, and stem cell-like tumour spheres derived from SAS. By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin. By qPCR analysis, we found that the cells with less mtDNA were less responsive to cisplatin (H103 and the tumour spheres). Based on the findings, we theorised that the metabolic changes in the tumour spheres probably resulted in mtDNA depletion, as the cells suppressed mitochondrial respiration and switched to an alternative mode of energy production, i.e. glycolysis. Then, to ascertain the origin of the variation in mtDNA content, we used MinION, a nanopore sequencer, to sequence the mitochondrial genomes of H103, SAS, and the tumour spheres. We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome. Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response. Cis-diamminedichloroplatinum (II), or cisplatin, is one of the most commonly used chemotherapy agents in the treatment of various solid tumours such as ovarian, colorectal, prostate, lung, and head and neck tumours 1-5. To date, the intrinsic or acquired resistance of cancer cells to cisplatin remains a challenge in the chemotherapy of several cancers including oral squamous cell carcinoma (OSCC) 3,6. OSCC, which affects the epithelial layer of the oral cavity, is a common malignant tumour of the head and neck with low survival rates and high risks of recurrence 7. The well-characterized mode of action of cisplatin is via causing the formation of DNA adducts upon its binding to the nucleophilic N7 sites of purines, which further leads to DNA damage responses and apoptosis 2,6,8. Cisplatin resistance in general involves reduced DNA damage due to an increase in DNA adduct repair, reduced drug uptake, or increased drug inactivation 1,3,4,6. Activation of these mechanisms depends on multiple factors including genetic changes, epigenetic alterations at both molecular and cellular levels, and heterogeneity among cancer cells 4,9,10. The recently proposed cancer stem cells (CSCs) model highlighted tumour heterogeneity as an important basis of treatment resistance and relapse in cancer. According to the model, CSCs comprise a tumourigenic subpopulation where they exhibit stem cell-like features ...

show abstract

Section: Methodsmentioning

confidence: 99%

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin

Leong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Although, statistical analyzes never reached a significant P value, a trend toward a difference was found for each heteroplasmy level category in blood samples between controls and patients, while not in urine (Supplemental Figures 4 and 5). We then searched for differences between the frequency of mtDNA deletions in blood and urine samplings using eKLIPSE software (18), but without evidence of significant differences. Long-range PCR revealed the absence of mtDNA deletion in the skin biopsies (Supplemental Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

Piro-Mégy¹,

Sarzi²,

Tarrés-Solé³

et al. 2019

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders.

show abstract

“…Another manual curation, including coverage, being away from indels, and MNPs, as well as the Ts/Tv ratio, was used in the filtering process. Long-range structural variation was run using eKLIPse [ 59 ].…”

Section: Methodsmentioning

confidence: 99%

Genomic Landscape of the Mitochondrial Genome in the United Arab Emirates Native Population

Al‐Jasmi

Vijayan

Sudalaimuthuasari

et al. 2020

Genes

View full text Add to dashboard Cite

In order to assess the genomic landscape of the United Arab Emirates (UAE) mitogenome, we sequenced and analyzed the complete genomes of 232 Emirate females mitochondrial DNA (mtDNA) within and compared those to Africa. We investigated the prevalence of haplogroups, genetic variation, heteroplasmy, and demography among the UAE native population with diverse ethnicity and relatively high degree of consanguinity. We identified 968 mtDNA variants and high-resolution 15 haplogroups. Our results show that the UAE population received enough gene flow from Africa represented by the haplogroups L, U6, and M1, and that 16.8% of the population has an eastern provenance, depicted by the U haplogroup and the M Indian haplogroup (12%), whereas western Eurasian and Asian haplogroups (R, J, and K) represent 11 to 15%. Interestingly, we found an ancient migration present through the descendant of L (N1 and X) and other sub-haplogroups (L2a1d and L4) and (L3x1b), which is one of the oldest evolutionary histories outside of Africa. Our demographic analysis shows no population structure among populations, with low diversity and no population differentiation. In addition, we show that the transmission of mtDNA in the UAE population is under purifying selection with hints of diversifying selection on ATP8 gene. Last, our results show a population bottleneck, which coincides with the Western European contact (1400 ybp). Our study of the UAE mitogenomes suggest that several maternal lineage migratory episodes liking African–Asian corridors occurred since the first modern human emerges out of Africa.

show abstract

eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data

Cited by 39 publications

References 38 publications

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

Genomic Landscape of the Mitochondrial Genome in the United Arab Emirates Native Population

Contact Info

Product

Resources

About