ArticleProceedings of the National Academy of Sciences of the United States of America2019
Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Parental Age and Childhood Lymphoma and Solid Tumor Risk: A Literature Review and Meta-Analysis.JNCI cancer spectrum · 2022Pooled it
- Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.Archives of toxicology · 2026Review
- Inheritance and selection of the mitochondrial genome.Nature reviews. Genetics · 2026Review
- Pedigree-Based comparison of short-read and long-read sequencing for forensic mitochondrial genome analysis.International journal of legal medicine · 2026Article
- Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.bioRxiv : the preprint server for biology · 2026Article
- Intrahost mutational dynamics parallel long-term genome evolution in endosymbionts.Molecular biology and evolution · 2026Article
- Mitochondrial genetic variation across tissues of the human body.Nucleic acids research · 2026Article
- Ongoing structural changes highlight the dynamic nature of chloroplast genomes.Nucleic acids research · 2026Article
- Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.PLoS genetics · 2025Article
- Tom70-mediated mitochondria-nuclear envelope contacts regulate nuclear pore complex inheritance during gametogenesis.bioRxiv : the preprint server for biology · 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
- Understanding the impact of mitochondrial DNA mutations on aging and carcinogenesis (Review).International journal of molecular medicine · 2025Review
- Genome-wide analysis in human populations reveals mitonuclear disequilibrium in genes related to neurological function.Scientific reports · 2025Article
- Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm.Science China. Life sciences · 2025Review
- Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.Aging and disease · 2025Review
- The interplay between mitochondrial DNA genotypes, female infertility, ovarian response, and mutagenesis in oocytes.Human reproduction open · 2025Article
- Article
- Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.Biogerontology · 2024Review
- Article
11 more citing papers are in PubMed but not listed here.
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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
Abstract
Heteroplasmy-the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual-can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. Here, we study patterns of heteroplasmy in 2 tissues from each of 345 humans in 96 multigenerational families, each with, at least, 2 siblings (a total of 249 mother-child transmissions). This experimental design has allowed us to estimate the timing of mtDNA mutations, drift, and selection with unprecedented precision. Our results are remarkably concordant between 2 complementary population-genetic approaches. We find evidence for a severe germline bottleneck (7-10 mtDNA segregating units) that occurs independently in different oocyte lineages from the same mother, while somatic bottlenecks are less severe. We demonstrate that divergence between mother and offspring increases with the mother's age at childbirth, likely due to continued drift of heteroplasmy frequencies in oocytes under meiotic arrest. We show that this period is also accompanied by mutation accumulation leading to more de novo mutations in children born to older mothers. We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.
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