A sex chromosome inversion is associated with copy number variation of mitochondrial DNA in zebra finch sperm

The propulsion of sperm cells via movement of the flagellum is of vital importance for successful fertilization. While the exact mechanism of energy production for this movement varies between species, in avian species energy is thought to come predominantly from the mitochondria located in the sperm midpiece. Larger midpieces may contain more mitochondria, which should enhance the energetic capacity and possibly promote mobility. Due to an inversion polymorphism on their sex chromosome TguZ , zebra finches ( Taeniopygia guttata castanotis ) exhibit large within-species variation in sperm midpiece length, and those sperm with the longest midpieces swim the fastest. Here, we test through quantitative real-time PCR in zebra finch ejaculates whether the inversion genotype has an effect on the copy number of mitochondrial DNA (mtDNA). We find that zebra finches carrying the derived allele (correlated with longer sperm midpieces) have more copies of the mtDNA in their ejaculates than those homozygous for the ancestral allele (shorter midpieces). We suggest downstream effects of mtDNA copy number variation on the rate of adenosine triphosphate production, which in turn may influence sperm swimming speed and fertilization success. Central components of gamete energy metabolism may thus be the proximate cause for a fitness-relevant genetic polymorphism, stabilizing a megabase-scale inversion at an intermediate allele frequency in the wild.

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A sex chromosome inversion is associated with copy number variation of mitochondrial DNA in zebra finch sperm

10.1101/776054 ◽

2019 ◽

Author(s):

Ulrich Knief ◽

Wolfgang Forstmeier ◽

Bart Kempenaers ◽

Jochen B. W. Wolf

Keyword(s):

Mitochondrial Dna ◽

Zebra Finch ◽

Copy Number ◽

Sex Chromosome ◽

Data Availability ◽

Species Variation ◽

Zebra Finches ◽

Chromosome Inversion ◽

Atp Production ◽

Sperm Midpiece

AbstractPropulsion of sperm cells via movement of the flagellum is of vital importance for successful fertilization. Presumably, the energy for this movement comes from the mitochondria in the sperm midpiece. Larger midpieces may contain more mitochondria, which should enhance the energetic capacity and hence promote mobility. Due to an inversion polymorphism on their sex chromosome TguZ, zebra finches (Taeniopygia guttata castanotis) exhibit large within-species variation in sperm midpiece length, and those sperm with the longest midpieces swim the fastest. Here, we test through quantitative real-time PCR in zebra finch ejaculates whether the inversion genotype has an effect on the copy number of mitochondrial DNA. Taking the inversion genotype as a proxy for midpiece length, we find that zebra finches with longer midpieces indeed have more copies of the mitochondrial DNA in their ejaculates than those with shorter midpieces, with potential downstream effects on the rate of ATP production and sperm swimming speed. This study sheds light on the proximate cause of a fitness-relevant genetic polymorphism, suggesting the involvement of central components of gamete energy metabolism.Data availabilitySupplementary data file

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Mitochondrial DNA Copy Number Variation Across Human Cancers

10.1101/021535 ◽

2015 ◽

Author(s):

Ed Reznik ◽

Martin Miller ◽

Yasin Senbabaoglu ◽

Nadeem Riaz ◽

William Lee ◽

...

Keyword(s):

Mitochondrial Dna ◽

Copy Number Variation ◽

Copy Number ◽

Large Scale ◽

Tumor Type ◽

Mtdna Copy Number ◽

Tissue Samples ◽

Mitochondrial Dna Copy Number ◽

Number Variation ◽

Tumor Types

In cancer, mitochondrial dysfunction, through mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), contributes to the malignant transformation and progression of tumors. Here, we report the first large-scale survey of mtDNA copy number variation across 21 distinct solid tumor types, examining over 13,000 tissue samples profiled with next-generation sequencing methods. We find a tendency for cancers, especially of the bladder and kidney, to be significantly depleted of mtDNA, relative to matched normal tissue. We show that mtDNA copy number is correlated to the expression of mitochondrially-localized metabolic pathways, suggesting that mtDNA copy number variation reflect gross changes in mitochondrial metabolic activity. Finally, we identify a subset of tumor-type-specific somatic alterations, including IDH1 and NF1 mutations in gliomas, whose incidence is strongly correlated to mtDNA copy number. Our findings suggest that modulation of mtDNA copy number may play a role in the pathology of cancer.

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Mitochondrial DNA copy number variation across human cancers

eLife ◽

10.7554/elife.10769 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 177

Author(s):

Ed Reznik ◽

Martin L Miller ◽

Yasin Şenbabaoğlu ◽

Nadeem Riaz ◽

Judy Sarungbam ◽

...

Keyword(s):

Mitochondrial Dna ◽

Copy Number Variation ◽

Copy Number ◽

The Cancer Genome Atlas ◽

Mtdna Copy Number ◽

Mitochondrial Dna Copy Number ◽

Number Variation ◽

Somatic Alterations ◽

Immunohistochemical Evidence ◽

Tumor Types

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.

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Mitochondrial DNA Copy Number Variation as a Potential Predictor of Renal Cell Carcinoma

The International Journal of Biological Markers ◽

10.5301/ijbm.5000268 ◽

2017 ◽

Vol 32 (3) ◽

pp. 313-318 ◽

Cited By ~ 2

Author(s):

Eman T. Elsayed ◽

Mohamed M. Hashad ◽

Iman E. Elgohary

Keyword(s):

Renal Cell Carcinoma ◽

Mitochondrial Dna ◽

Copy Number Variation ◽

Peripheral Blood ◽

Predictive Value ◽

Renal Cell ◽

Copy Number ◽

Mtdna Copy Number ◽

Increased Risk ◽

Number Variation

Background Peripheral blood mitochondrial DNA (mtDNA) copy number alteration has been suggested as a risk factor for several types of cancer. The aim of the present study was to assess the role of peripheral blood mtDNA copy number variation as a noninvasive biomarker in the prediction and early detection of renal cell carcinoma (RCC) in a cohort of Egyptian patients. Methods Quantitative real-time polymerase chain reaction (qPCR) was used to measure peripheral blood mtDNA copy numbers in 57 patients with newly diagnosed, early-stage localized RCC and 60 age- and sex-matched healthy individuals as a control group. Results Median mtDNA copy number was significantly higher in RCC cases than in controls (166 vs. 91, p<0.001). Increased mtDNA copy number was associated with an 18-fold increased risk of RCC (95% confidence interval: 5.065-63.9). On receiver operating characteristic curve analysis, it was found that mtDNA could distinguish between RCC patients and healthy controls, with 86% sensitivity, 80% specificity, 80.3% positive predictive value and 85.7% negative predictive value at a cutoff value of 108.5. Conclusions Our results showed that increased peripheral blood mtDNA copy number was associated with increased risk of RCC. Therefore, RCC might be considered as part of a range of potential tumors in cases with elevated blood mtDNA copy number.

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Relative telomere length and mitochondrial DNA copy number variation with age: Association with plasma folate and vitamin B12

Mitochondrion ◽

10.1016/j.mito.2020.01.007 ◽

2020 ◽

Vol 51 ◽

pp. 79-87 ◽

Cited By ~ 3

Author(s):

Guruvaiah Praveen ◽

Tattari Shalini ◽

Mudili Sivaprasad ◽

G. Bhanuprakash Reddy

Keyword(s):

Mitochondrial Dna ◽

Copy Number Variation ◽

Vitamin B12 ◽

Telomere Length ◽

Copy Number ◽

Dna Copy Number Variation ◽

Relative Telomere Length ◽

Mitochondrial Dna Copy Number ◽

Number Variation ◽

Folate And Vitamin B12

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Abstract 4729: Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer

10.1158/1538-7445.am2017-4729 ◽

2017 ◽

Author(s):

Abhijit Chandra ◽

Hasan R. Kazmi ◽

Leena K. Satyam ◽

Saket Kumar

Keyword(s):

Mitochondrial Dna ◽

Copy Number Variation ◽

Gallbladder Cancer ◽

Peripheral Blood ◽

Copy Number ◽

Dna Copy Number ◽

Dna Copy Number Variation ◽

Mitochondrial Dna Copy Number ◽

Number Variation ◽

Peripheral Blood Leucocytes

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Copy Number Assessment by Competitive PCR with Limiting Deoxynucleotide Triphosphates and High-Resolution Melting

Clinical Chemistry ◽

10.1373/clinchem.2014.236208 ◽

2015 ◽

Vol 61 (5) ◽

pp. 724-733 ◽

Cited By ~ 18

Author(s):

Luming Zhou ◽

Robert A Palais ◽

Christian N Paxton ◽

Katherine B Geiersbach ◽

Carl T Wittwer

Keyword(s):

Copy Number Variation ◽

Motor Neuron ◽

Copy Number ◽

Sex Chromosome ◽

Melting Curve ◽

Growth Factor Receptor ◽

Relative Quantification ◽

Pcr Products ◽

Number Variation ◽

Survival Of Motor Neuron

Abstract BACKGROUND DNA copy number variation is associated with genetic disorders and cancer. Available methods to discern variation in copy number are typically costly, slow, require specialized equipment, and/or lack precision. METHODS Multiplex PCR with different primer pairs and limiting deoxynucleotide triphosphates (dNTPs) (3–12 μmol/L) were used for relative quantification and copy number assessment. Small PCR products (50–121 bp) were designed with 1 melting domain, well-separated Tms, minimal internal sequence variation, and no common homologs. PCR products were displayed as melting curves on derivative plots and normalized to the reference peak. Different copy numbers of each target clustered together and were grouped by unbiased hierarchical clustering. RESULTS Duplex PCR of a reference gene and a target gene was used to detect copy number variation in chromosomes X, Y, 13, 18, 21, epidermal growth factor receptor (EGFR), survival of motor neuron 1, telomeric (SMN1), and survival of motor neuron 2, centromeric (SMN2). Triplex PCR was used for X and Y and CFTR exons 2 and 3. Blinded studies of 50 potential trisomic samples (13, 18, 21, or normal) and 50 samples with potential sex chromosome abnormalities were concordant to karyotyping, except for 2 samples that were originally mosaics that displayed a single karyotype after growth. Large cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7) (CFTR) deletions, EGFR amplifications, and SMN1 and SMN2 copy number assessments were also demonstrated. Under ideal conditions, copy number changes of 1.11-fold or lower could be discerned with CVs of about 1%. CONCLUSIONS Relative quantification by restricting the dNTP concentration with melting curve display is a simple and precise way to assess targeted copy number variation.

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