Age-Related and Heteroplasmy-Related Variation in Human mtDNA Copy Number

Autor: Burkhard Madea, Mingkun Li, Mark Stoneking, Manja Wachsmuth, Alexander Hübner
Rok vydání: 2015
Předmět:
Male
Molecular biology
DNA cloning
Mitochondria
Liver
Genome
Biochemistry
Mathematical and Statistical Techniques
Gene Frequency
Digital polymerase chain reaction
Energy-Producing Organelles
Genetics
Shotgun sequencing
Age Factors
Chromosome Mapping
Genomics
Heteroplasmy
Uncorrelated
Mitochondrial DNA
Mitochondria
Nucleic acids
Organ Specificity
Physical Sciences
Regression Analysis
Cellular Structures and Organelles
Statistics (Mathematics)
Research Article
DNA Replication
lcsh:QH426-470
DNA Copy Number Variations
Forms of DNA
Biology
Bioenergetics
Linear Regression Analysis
DNA
Mitochondrial
Age related
Humans
Statistical Methods
Muscle
Skeletal
Sequencing Techniques
Aged
Shotgun Sequencing
Evolutionary Biology
Biology and life sciences
Population Biology
Gene Mapping
Computational Biology
DNA
Cell Biology
Genome Analysis
Genomic Libraries
Minor allele frequency
Research and analysis methods
lcsh:Genetics
Molecular biology techniques
Genome
Mitochondrial
Haplogroups
Population Genetics
Mathematics
Cloning
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 3, p e1005939 (2016)
ISSN: 1553-7404
Popis: The mitochondrial (mt) genome is present in many copies in human cells, and intra-individual variation in mtDNA sequences is known as heteroplasmy. Recent studies found that heteroplasmies are highly tissue-specific, site-specific, and allele-specific, however the functional implications have not been explored. This study investigates variation in mtDNA copy numbers (mtCN) in 12 different tissues obtained at autopsy from 152 individuals (ranging in age from 3 days to 96 years). Three different methods to estimate mtCN were compared: shotgun sequencing (in 4 tissues), capture-enriched sequencing (in 12 tissues) and droplet digital PCR (ddPCR, in 2 tissues). The highest precision in mtCN estimation was achieved using shotgun sequencing data. However, capture-enrichment data provide reliable estimates of relative (albeit not absolute) mtCNs. Comparisons of mtCN from different tissues of the same individual revealed that mtCNs in different tissues are, with few exceptions, uncorrelated. Hence, each tissue of an individual seems to regulate mtCN in a tissue-related rather than an individual-dependent manner. Skeletal muscle (SM) samples showed an age-related decrease in mtCN that was especially pronounced in males, while there was an age-related increase in mtCN for liver (LIV) samples. MtCN in SM samples was significantly negatively correlated with both the total number of heteroplasmic sites and with minor allele frequency (MAF) at two heteroplasmic sites, 408 and 16327. Heteroplasmies at both sites are highly specific for SM, accumulate with aging and are part of functional elements that regulate mtDNA replication. These data support the hypothesis that selection acting on these heteroplasmic sites is reducing mtCN in SM of older individuals.
Author Summary The total number of mitochondrial genomes in a human cell differs between individuals and between the tissues of a single individual; however the factors that influence this variation remain unknown. We estimated mtDNA copy number (mtCN) in 12 different tissues of 152 individuals applying three different methods, and found age-related variation for two tissues: mtCN in skeletal muscle is negatively correlated with age (especially in males) while mtCN in liver is positively correlated with age. Overall, mtCNs of different tissues within an individual are mainly independent of each other, indicating that tissue-specific rather than individual-specific processes largely influence mtCN. Heteroplasmy refers to intra-individual differences in the sequence of the mtDNA genome and heteroplasmic mutations accumulate during aging. Linear and partial regression analyses of mtCN with heteroplasmy (determined in a previous study of these same samples) revealed that the decrease of mtCN in skeletal muscle is mainly correlated with an increasing total number of heteroplasmic sites, and with increasing minor allele frequency at two sites (408 and 16327), that are heteroplasmic almost exclusively in skeletal muscle. As both sites are part of functional elements required for regulation of mtDNA replication, we suggest that selection may be acting via increasing heteroplasmy to reduce mtCN during aging.
Databáze: OpenAIRE
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