Investigation of Heteroplasmy in the Human Mitochondrial DNA Control Region: A Synthesis of Observations from More Than 5000 Global Population Samples

Irwin, Jodi A.; Saunier, Jessica L.; Niederstätter, Harald; Strouss, Katharine; Sturk, Kimberly A.; Diegoli, Toni M.; Brandstätter, Anita; Parson, Walther; Parsons, Thomas J.

doi:10.1007/s00239-009-9227-4

Cited by 151 publications

(131 citation statements)

References 47 publications

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“…In addition, length heteroplasmy found in this region of the HVS-I reproduced a complex DGGE pattern. In our study, individuals with HVS-I motif 126-163-186-189-294 (haplogroup T1) resulting in a string of seven cytosines did not exhibit length heteroplasmy, thereby supporting the hypothesis that eight cytosines is likely the critical number (Melton 2004;Chen et al, 2009;Irwin et al, 2009;Forster et al, 2010).…”

Section: Accepted Manuscriptsupporting

confidence: 82%

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Pliss

Brakmanis

Ranka

et al. 2011

Experimental Gerontology

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To cite this version:This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractVarious studies have demonstrated that mitochondrial DNA (mtDNA) heteroplasmy tends to increase with age and that the observed frequency of heteroplasmy among populations mostly depends on the way it is measured. Therefore, we investigated age-related association on the presence of mtDNA heteroplasmy within the hypervariable segment 1 (HVS-I) in a selected study group. The study group consisted of 300 maternally unrelated Latvians ranging in age from 18 to over 90 years. To determine the optimal method for mtDNA heteroplasmy detection, three The results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. The above is supported by evidence to eventual increase of the probability of heteroplasmy with age due to specific mitochondrial haplogroup background. Research HighlightsThe results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. Consequently, a strong association is found to exist between the mtDNA heteroplasmy and ageing in the studied population.We found that the Denaturing Gradient Gel Electrophoresis (DGGE) and the SURVEYOR TM Mutation Detection Kit assay exhibited a lower limit of detection (LOD) of mtDNA heteroplasmy and revealed the presence of heteroplasmy at the already existing 1% and 5% occurrence in the sample.

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Section: Accepted Manuscriptsupporting

confidence: 82%

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Pliss

Brakmanis

Ranka

et al. 2011

Experimental Gerontology

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“…We found seven point heteroplasmic transitions in a total of six samples (499R, 16284R twice, 204Y three times) concurring with heteroplasmic sites observed in more than 5,000 global population samples [23] whereas one instance of heteroplasmy (16327Y) has not been reported there.…”

Section: Point Heteroplasmysupporting

confidence: 79%

Mitochondrial DNA control region data from indigenous Angolan Khoe-San lineages

Fendt

Huber

Röck

et al. 2012

Forensic Science International: Genetics

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Here we provide 129 complete mitochondrial control region sequences of indigenous KhoeSan individuals from Angola to contribute to the still underrepresented pool of data from Africa. The dataset consists of exclusively African lineages with a majority of Sub-Saharan haplogroups. The probability of a random match was calculated as 0.09. The data set comprises 21 haplotypes occurring more than once and 17 unique haplotypes. Upon publication, haplotypes were incorporated in the EMPOP database (www.empop.org; Only few Angolan mtDNA sequences were available in the literature, which were typed for the first and second hypervariable segment of the control region [11][12][13]. The blood samples for this study came from 129 healthy randomly drawn volunteer donors of to our knowledge unrelated individuals collected in the Schmidtsdrift community. Individuals identified themselves as !Xu (113) and Khwe (13). Ethnicities of three individuals remained unknown.Informed written/oral consent was obtained from all human subjects. Ethic approval was obtained by the Hans Snykers Institute for the collection of samples for both biochemical and genetic studies on the Bushmen from the Faculty of Medicine, University of Pretoria Ethics Committee. DNA extraction, amplification and sequencingGenomic DNA was extracted from peripheral blood as described in [14]. Full mitochondrial control region (CR) was amplified, sequenced and interpreted as reported in [15]. 3 Data analysisAccording to our in-house data quality management process, the resulting consensus sequences were inspected independently by two different analysts using the sequence analysis software Sequencher (Version 4.8) and reviewed by a third scientist. Consensus sequences covered a common reading frame from position 16024 to 576 and were reported as differences to the rCRS [16] following updated nomenclature guidelines for mtDNA [17].Haplogroups were assigned according to Phylotree, build 12 [18]. Within our Khoe-San sample set the random match probability was calculated as the sum of squared CR frequencies, disregarding length variants at positions 16193, 309 and 573. The haplotypes from this study will be available on the EMPOP database (www.empop.org) upon publication (EMPOP accession number EMP00069). Results Observed CR haplotypes and diversity indicesThe entire control region analysis revealed exclusively typical Africa-specific L lineages with a majority of Sub-Saharan origin (Table S1). Within our dataset, we found 90.7% L0 haplotypes, hence it is remarkable that 97.4% of all L0 haplotypes (or 88.4% of the observed Khoe-San dataset) belonged to the Khoe-San specific L0d/L0k cluster which is reported to account for ~ 60% in observed Khoe-San populations [19]. Among these, the most frequent haplogroups within the Angolan Khoe-San samples were L0d1c1 (33.3%) as well as L0k1 (27.1%). However, we identified a minor contribution of 9.3% of haplogroups L2 and L3 within the Khoe-San. The absence of lineages L1, L5, L6, and L4 in our dataset corresponds to their docu...

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“…Before the application of next-generation sequencing (NGS) technologies, most studies focused on the mtDNA control region and revealed that 6∼11.6% of the population carry heteroplasmy in this region (9)(10)(11). The advent of NGS technologies enables the inquiry of mitochondrial heteroplasmy at the genome-wide scale.…”

mentioning

confidence: 99%

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Lü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

213

222

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A majority of mitochondrial DNA (mtDNA) mutations reported to be implicated in diseases are heteroplasmic, a status with coexisting mtDNA variants in a single cell. Quantifying the prevalence of mitochondrial heteroplasmy and its pathogenic effect in healthy individuals could further our understanding of its possible roles in various diseases. A total of 1,085 human individuals from 14 global populations have been sequenced by the 1000 Genomes Project to a mean coverage of ∼2,000× on mtDNA. Using a combination of stringent thresholds and a maximum-likelihood method to define heteroplasmy, we demonstrated that ∼90% of the individuals carry at least one heteroplasmy. At least 20% of individuals harbor heteroplasmies reported to be implicated in disease. Mitochondrial heteroplasmy tend to show high pathogenicity, and is significantly overrepresented in disease-associated loci. Consistent with their deleterious effect, heteroplasmies with derived allele frequency larger than 60% within an individual show a significant reduction in pathogenicity, indicating the action of purifying selection. Purifying selection on heteroplasmies can also be inferred from nonsynonymous and synonymous heteroplasmy comparison and the unfolded site frequency spectra for different functional sites in mtDNA. Nevertheless, in comparison with population polymorphic mtDNA mutations, the purifying selection is much less efficient in removing heteroplasmic mutations. The prevalence of mitochondrial heteroplasmy with high pathogenic potential in healthy individuals, along with the possibility of these mutations drifting to high frequency inside a subpopulation of cells across lifespan, emphasizes the importance of managing mitochondrial heteroplasmy to prevent disease progression.

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Investigation of Heteroplasmy in the Human Mitochondrial DNA Control Region: A Synthesis of Observations from More Than 5000 Global Population Samples

Cited by 151 publications

References 47 publications

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Mitochondrial DNA control region data from indigenous Angolan Khoe-San lineages

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

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