The Frequency of Heteroplasmy in the HVII Region of mtDNA Differs across Tissue Types and Increases with Age

Calloway, Cassandra; Reynolds, Rebecca; Herrin, George; Anderson, Wyatt W.

doi:10.1086/302844

Cited by 145 publications

(88 citation statements)

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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.…”

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confidence: 99%

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Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Lü

et al. 2014

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

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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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confidence: 99%

“…It has been recognized that mitochondrial heteroplasmy across the genome increases with age (9,(18)(19)(20) and acquires unique patterns in tumors (21,22). A recent epidemiological study indicates that pathogenic mtDNA mutations might be more common in the general population than previously appreciated (23).…”

mentioning

confidence: 99%

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Lü

et al. 2014

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

224

222

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“…The point mutations, A189G and T408A, were identified in skeletal muscle. The fibroblastspecific T414G was absent in muscle and heart in several studies (Calloway et al ., 2000;Wang et al ., 2001;Nekhaeva et al ., 2002) yet another study found T414G in muscle but not in brain (Murdock et al ., 2000). A more recent study has linked reduced COX activity to an increasing burden of multiple mtDNA point mutations, rather than a single specific point mutation, present in the genes coding for COX (Lin et al ., 2002).…”

Section: High Levels Of Mtdna Mutations Cause Diseasementioning

confidence: 88%

Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging

et al. 2003

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SummaryThe hypothesis that mitochondrial DNA damage accumulates and contributes to aging was proposed decades ago. Only recently have technological advancements, which facilitate microanalysis of single cells or portions of cells, revealed that mtDNA deletion mutations and, perhaps, single nucleotide mutations accumulate to physiologically relevant levels in the tissues of various species with age. Although a link between single nucleotide mutations and physiological consequences in aging tissue has not been established, the accumulation of deletion mutations in skeletal muscle fibres has been associated with sarcopenia. Different, and apparently random, deletion mutations are specific to individual fibres. However, the mtDNA deletion mutation within a phenotypically abnormal region of a fibre is the same, suggesting a selection, amplification and clonal expansion of the initial deletion mutation. mtDNA deletion mutations within a muscle fibre are associated with specific electron transport system abnormalities, muscle fibre atrophy and fibre breakage. These data point to a causal relationship between mitochondrial DNA mutations and the age-related loss of muscle mass.

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“…(20). This commercial kit contains more probes than previously published immobilized SSO typing assays (7,8,(23)(24)(25).…”

Section: Dna Sequencingmentioning

confidence: 99%

Mitochondrial DNA Typing Screens with Control Region and Coding Region SNPs

Kline

Vallone

Redman

et al. 2005

Journal of Forensic Sciences

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Mitochondrial DNA (mtDNA) analysis has found an important niche in forensic DNA typing. It is used with highly degraded samples or low-copy number materials such as might be found from shed hair or bones exposed to severe environmental conditions. The primary advantage of mtDNA is that it is present in high copy number within cells and therefore more likely to be recovered from highly degraded specimens. A major disadvantage to traditional forensic mtDNA analysis is that it is time-consuming and labor-intensive to generate and review the 610 nucleotides of sequence information commonly targeted in hypervariable regions I and II (HVI and HVII) of the control region. In addition, common haplotypes exist in HVI/HVII mtDNA sequences that can reduce the ability to differentiate two unrelated samples. In this report we describe the utility of two newly available screening assays for rapid exclusion of non-matching samples. The LINEAR ARRAY mtDNA HVI/HVII Region-Sequencing Typing Kit (Roche Applied Science, Indianapolis, IN) was used to type 666 individuals from U.S. Caucasian, African American, and Hispanic groups. Processing of the LINEAR ARRAY probe panels "mito strips" was automated on a ProfiBlot workstation. Observable variation in 666 individuals is reported and frequencies of the mitotypes within and between populations are presented. Samples exhibiting the most common Caucasian mitotype were subdivided with a multiplexed amplification and detection assay using eleven single nucleotide polymorphisms in the mitochondrial genome. These types of screening assays should enable more rapid evaluation of forensic casework samples such that only samples not excluded would be subjected to further characterization through full HVI/HVII mtDNA sequence analysis.KEYWORDS: forensic science, DNA typing, mtDNA, SSO probes, mitochondrial DNA coding region, primer extension For the past decade, DNA sequencing of hypervariable regions I (HVI) and II (HVII) in the control region of mitochondrial DNA (mtDNA) has been useful in forensic casework for the analysis of human remains when nuclear DNA systems fail due to low amounts of DNA or highly degraded specimens (1-3). However, considerable effort and expense are required to develop a full HVI and HVII mtDNA sequence (typically positions 16024-16365 and 1 Biotechnology Division, National Institute of Standards and Technology, Gaithersburg, MD 20899.2 Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899.3 Department of Human Genetics, Roche Molecular Systems, Alameda, CA 94501. 4 Comparative Biochemistry Group, University of California, Berkeley, CA. * Contribution of the U.S. National Institute of Standards and Technology. Not subject to copyright. Certain commercial equipment, instruments and materials are identified in order to specify experimental procedures as completely as possible. In no case does such identification imply a recommendation or endorsement by the National Institute of Standards and Technology nor does it...

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The Frequency of Heteroplasmy in the HVII Region of mtDNA Differs across Tissue Types and Increases with Age

Cited by 145 publications

References 43 publications

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging

Mitochondrial DNA Typing Screens with Control Region and Coding Region SNPs

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