ArticleProceedings of the National Academy of Sciences of the United States of America2014
Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers, 2 of them syntheses that pooled it.
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Who cites it
134 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Parental Age and Childhood Lymphoma and Solid Tumor Risk: A Literature Review and Meta-Analysis.JNCI cancer spectrum · 2022Pooled it
- Age-associated changes in cumulus cells and follicular fluid: the local oocyte microenvironment as a determinant of gamete quality.Biology of reproduction · 2022Pooled it
- Inheritance and selection of the mitochondrial genome.Nature reviews. Genetics · 2026Review
- Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.bioRxiv : the preprint server for biology · 2026Article
- Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.Archives of toxicology · 2026Review
- Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.medRxiv : the preprint server for health sciences · 2026Article
- Evaluating open LLMs for agentic analysis orchestration in a typical biomedical lab.bioRxiv : the preprint server for biology · 2026Article
- Mammalian mitochondrial DNA accumulates insertions and deletions with age in energetically demanding tissues.Molecular biology and evolution · 2026Article
- The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?NAR molecular medicine · 2026Article
- Pervasive non-random mitochondrial DNA heteroplasmy in the hybrid water frog Pelophylax esculentus.BMC ecology and evolution · 2025Article
- SimHumanity: Using SLiM 5.0 to run whole-genome simulations of human evolution.bioRxiv : the preprint server for biology · 2025Article
- Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.Science advances · 2025Article
- Causes of and Solutions to Mitochondrial Disorders: A Literature Review.International journal of molecular sciences · 2025Review
- Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm.Science China. Life sciences · 2025Review
- Exploring the Impact of Mitonuclear Discordance on Disease in Latin American Admixed Populations.Genes · 2025Article
- The interplay between mitochondrial DNA genotypes, female infertility, ovarian response, and mutagenesis in oocytes.Human reproduction open · 2025Article
- Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.Biogerontology · 2024Review
- Mitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes.International journal of molecular sciences · 2024Review
- Article
- Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA.Nature aging · 2024Article
74 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors.
Funding
Abstract
The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10(-8) (interquartile range from 4.2 × 10(-9) to 4.1 × 10(-8)) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.
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