Random Genetic Drift Determines the Level of Mutant mtDNA in Human Primary Oocytes

A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Goto, Y.-I., Nonaka, I., & Horai, S. (1990) · Nature · doi:10.1038/348651a0 · Cited by 2,070

A quantitative and cytological study of germ cells in human ovaries

Baker, T. G. (1963) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1963.0055 · Cited by 1,094

The theory of gene frequencies

Wright, S. (1969) · University of Chicago Press eBooks · Cited by 755

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA

Jenuth, J. P., Peterson, A. C., Fu, K., & Shoubridge, E. A. (1996) · Nature Genetics · doi:10.1038/ng1096-146 · Cited by 591

MELAS: Clinical features, biochemistry, and molecular genetics

Ciafaloni, E., Ricci, E., Shanske, S., Moraes, C. T., Silvestri, G., Hirano, M., Simonetti, S., Angelini, C. I., Donati, M. A., Garcia, C., et al. (1992) · Annals of Neurology · doi:10.1002/ana.410310408 · Cited by 500

MOLECULAR GENETIC ASPECTS OF HUMAN MITOCHONDRIAL DISORDERS

Larsson, N.-G., & Clayton, D. A. (1995) · Annual Review of Genetics · doi:10.1146/annurev.ge.29.120195.001055 · Cited by 493

Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes

Chinnery, P. F. (1997) · Brain · doi:10.1093/brain/120.10.1713 · Cited by 382

Mitochondrial respiratory chain disorders I: mitochondrial DNA defects

Leonard, J., & Schapira, A. H. V. (2000) · The Lancet · doi:10.1016/s0140-6736(99)05225-3 · Cited by 365

Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes

Inoue, K., Nakada, K., Ogura, A., Isobe, K., Goto, Y.-I., Nonaka, I., & Hayashi, J.-I. (2000) · Nature Genetics · doi:10.1038/82826 · Cited by 333

In Vitro Genetic Transfer of Protein Synthesis and Respiration Defects to Mitochondrial DNA-Less Cells with Myopathy-Patient Mitochondria

Chomyn, A., Meola, G., Bresolin, N., Lai, S. T., Scarlato, G., & Attardi, G. M. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.4.2236 · Cited by 301

Evolutionary toxicology: contaminant-induced genetic mutations in mosquitofish from Sumgayit, Azerbaijan

Rinner, B. P., Matson, C. W., Islamzadeh, A., McDonald, T. J., Donnelly, K. C., & Bickham, J. W. (2011) · Ecotoxicology · doi:10.1007/s10646-010-0587-8 · Cited by 20

Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations

Arbeithuber, B., Anthony, K., Higgins, B., Oppelt, P., Shebl, O. J., Tiemann‐Boege, I., Chiaromonte, F., Ebner, T., & Makova, K. D. (2025) · Science Advances · doi:10.1126/sciadv.adw4954 · Cited by 20

Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations

Zhang, J., Koolmeister, C., Han, J., Filograna, R., Hanke, L., Ádori, M., Sheward, D. J., Teifel, S., Gopalakrishna, S., Shao, Q., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.167656 · Cited by 18

Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA

Ru, Y., Deng, X., Chen, J., Zhang, L., Xu, Z., Lv, Q., Long, S., Huang, Z., Kong, M., Guo, J., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00672-6 · Cited by 17

A maternal line study investigating the 4977-bp mitochondrial DNA deletion

Thayer, R. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(03)00033-0 · Cited by 18

Clinical application of sequencing-based methods for parallel preimplantation genetic testing for mitochondrial DNA disease and aneuploidy

Späth, K., Babariya, D., Konstantinidis, M., Lowndes, J., Child, T. J., GRIFO, J. A., Poulton, J., & Wells, D. (2021) · Fertility and Sterility · doi:10.1016/j.fertnstert.2021.01.026 · Cited by 17

A Wide Range of 3243A>G/tRNALeu(UUR) (MELAS) Mutation Loads May Segregate in Offspring through the Female Germline Bottleneck

Pallotti, F., Binelli, G., Fabbri, R., Valentino, M. L., Vicenti, R., Macciocca, M., Cevoli, S., Baruzzi, A., DiMauro, S., & Carelli, V. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096663 · Cited by 16

Genetic and reproductive strategies to prevent mitochondrial diseases

Castelluccio, N., Späth, K., Li, D., de Coo, I. F. M., Butterworth, L., Wells, D., Mertes, H., Poulton, J., & Heindryckx, B. (2025) · Human Reproduction Update · doi:10.1093/humupd/dmaf004 · Cited by 15

Mitochondrial Gene Therapy: An Evaluation of Strategies for the Treatment of Mitochondrial DNA Disorders

Doyle, S. R., & Chan, C. K. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.090 · Cited by 15

Mitochondrial DNA Mutations in Tumors

Czarnecka, A. M., & Bartnik, E. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-435-3_9 · Cited by 14

Polar body mutation load analysis in a patient with A3243G tRNALeu(UUR) point mutation

Vandewoestyne, M., Heindryckx, B., Lepez, T., Coster, R. V., Gerris, J., Sutter, P. D., & Deforce, D. L. D. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.03.123 · Cited by 12

Mitochondrial Disease

Thornton, B., Cohen, B. H., Copeland, W. C., & Maria, B. L. (2014) · Journal of Child Neurology · doi:10.1177/0883073814537379 · Cited by 12

Organelle bottlenecks facilitate evolvability by traversing heteroplasmic fitness valleys

Radzvilavicius, A. L., & Johnston, I. G. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.974472 · Cited by 11

Mitochondrial DNA competition: starving out the mutant genome

Spinazzola, A., Pérez‐Rodríguez, D., Ježek, J., & Holt, I. J. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.01.011 · Cited by 11

Avoiding misleading estimates using mtDNA heteroplasmy statistics to study bottleneck size and selection

Giannakis, K., Broz, A. K., Sloan, D. B., & Johnston, I. G. (2023) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkad068 · Cited by 10

Gene therapy for the treatment of mitochondrial DNA disorders

Taylor, R. W. (2005) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.5.2.183 · Cited by 9

Mitochondrial DNA, nuclear context, and the risk for carcinogenesis

Kaufman, B. A., Picard, M. A., & Sondheimer, N. (2018) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22169 · Cited by 8

Heredity and segregation of mtDNA

Burr, S. P., & Chinnery, P. F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819656-4.00004-8 · Cited by 6

Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations

Preston, G. J., Jacob, N., Elsharkawi, I., Morava, É., & Kozicz, T. (2025) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2025.109197 · Cited by 5

Study of mitochondrial DNA A1555G and C1494T mutations in a large cohort of women individuals

Wang, L., Wang, X., Cai, X., & Qiang, R. (2018) · Mitochondrial DNA Part A · doi:10.1080/24701394.2018.1475477 · Cited by 5

The Mitochondrial Genome and Human Mitochondrial Diseases

Sukernik, R. I., Derbeneva, O. A., Starikovskaya, E. B., Volodko, N. V., Mikhailovskaya, I. E., Bychkov, I. Y., Lott, M. T., Brown, M., & Wallace, D. C. (2002) · Russian Journal of Genetics · doi:10.1023/a:1014369624346 · Cited by 5

Variations in mitochondrial DNA coding and d-loop region are associated with early embryonic development defects in infertile women

Liu, Y., Zhao, S., Chen, X., Bian, Y., Cao, Y., Xu, P., Zhang, C., Zhang, J., Zhao, S., & Zhao, H. (2022) · Human Genetics · doi:10.1007/s00439-022-02505-1 · Cited by 4

Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success

Ji, D., Zhang, N., Zou, W., Zhang, Z., Marley, J. L., Liu, Z., Liang, C., Shen, L., Liu, Y., Liang, D., et al. (2023) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-023-02880-2 · Cited by 4

The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I

Ahmadi, Z. A., & Brandt, U. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167996 · Cited by 6

The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?

John, J. C. S. (2025) · NAR Molecular Medicine · doi:10.1093/narmme/ugaf042 · Cited by 3

Mitochondrial DNA: Structure, Genetics, Replication and Defects

Taanman, J., & Kroon, A. M. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-811752-1.00005-5 · Cited by 5

Selecting the Right Embryo in Mitochondrial Disorders

Sallevelt, S. C. E. H., Dreesen, J. C. F. M., de Coo, I. F. M., de Die-Smulders, C. E. M., & Smeets, H. J. M. (2015) · Springer eBooks · doi:10.1007/978-3-319-16892-0_17 · Cited by 3

The Human Mitochondrial Genome: Mechanisms of Expression and Maintenance

Berdanier, C. D. (2005) · CRC Press eBooks · doi:10.1201/9781420028843-8 · Cited by 3

The Human Mitochondrial Genome

Taanman, J., & Williams, S. L. (2005) · Oxidative stress and disease · doi:10.1201/9781420028843.ch3 · Cited by 3

Mitochondrial DNA Mutation Load

DiMauro, S. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.4401 · Cited by 3

Mitochondrial DNA and its mutations: novel fields in a new era

Sáfrány, E., Csöngei, V., Járomi, L., Maász, A., Magyari, L., Sipeky, C., & Melegh, B. (2007) · Orvosi Hetilap · doi:10.1556/oh.2007.28014 · Cited by 2

Fluorescent Duplex Allele-Specific PCR and Amplicon Melting for Rapid Homogeneous mtDNA Haplogroup H Screening and Sensitive Mixture Detection

Niederstätter, H., & Parson, W. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008374 · Cited by 2

Diseases of adenosine triphosphate synthesis in children

Sims, K. B., & Holtzman, D. H. (2002) · Current Opinion in Neurology · doi:10.1097/00019052-200204000-00004 · Cited by 2

Difficulties and Possible Solutions in the Genetic Management of mtDNA Disease in the Preimplantation Embryo

Poulton, J., Oakeshott, P., & Kennedy, S. (2007) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)77008-9 · Cited by 2

Holocene human peopling of Libyan Sahara: molecular analysis of maternal lineages in ancient and extant populations of Fezzan

Ottoni, C. (2008) · Cineca Institutional Research Information System (Tor Vergata University) · doi:10.58015/ottoni-claudio_phd2008-09-30 · Cited by 2

Mitochondrial DNA

Gojobori, J. (2021) · Evolutionary studies · doi:10.1007/978-4-431-56904-6_4 · Cited by 1

Mitochondrial DNA variation in extremely selected traits: longevity and elite athletic performance

Niemi, A. (2005) · Cited by 1

Current Perspectives of Mitochondrial Dysfunction and Associated Diseases

Gupta, N. (2016) · MOJ Cell Science & Report · doi:10.15406/mojcsr.2016.03.00043

The Transmission and Segregation of Mitochondrial DNA in Homo Sapiens

Chinnery, P. F. (2006) · Springer eBooks · doi:10.1007/3-540-31789-9_2 · Cited by 1

Mitochondrial disorders

McFarland, R., Taylor, R. W., Schaefer, A. M., & Turnbull, D. M. (2012) · Cambridge University Press eBooks · doi:10.1017/cbo9781139087711.013 · Cited by 1

Evolutionary and biological theories of senescence

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.003 · Cited by 1

Ethics at the interface of reproductive medicine and genetic technology : the case of mitochondrial disorders

Bredenoord, A. L. (2010) · doi:10.26481/dis.20100618ab · Cited by 1

Mitochondrial Heteroplasmy and Disease

Elson, J. L., & Lightowlers, R. N. (2006) · Encyclopedia of Life Sciences · doi:10.1038/npg.els.0006079 · Cited by 1

Membranous core domain of Complex I and mitochondrial disease modeling

Kervinen, M. (2006) · Cited by 1

Transferência de citoplasma submetido ao estresse oxidativo como modelo para o estudo da herança de doenças mitocondriais

Machado, T. S. (2014) · doi:10.11606/d.10.2014.tde-12012015-085943 · Cited by 1

Mitochondriale DNA des Menschen

Wissinger, B. (2008) · Springer eBooks · doi:10.1007/978-3-540-69414-4_5

Preface

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.001

Mitochondrial dysfunction in ageing and degenerative disease

Wredenberg, A. (2007) · Figshare

Human variation: chronic diseases, risk factors, and senescence

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.005

The roles of mutation rate and selective pressure on observed levels of the human mitochondrial DNA deletion $\rm mtDNA\sp 4977$

Navidi, W. C., Tavaré, S., & Arnheim, N. (2003) · Lecture notes-monograph series · doi:10.1214/lnms/1215091146

References

(2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.008

Clinical Heterogeneity, Tissue Distribution, and Intergenerational Segregation of mtDNA Mutation A3243G

Tesařová, M., Hansíková, H., Kytnarová, J., Houšt'ková, H., Böhm, M., Cerna, L., Zeman, J., & Houštěk, J. (2004) · Toxicology Mechanisms and Methods · doi:10.1080/15376520490257527

Mitochondrial DNA mutations. Brain developmental and ageing consequences, and possible treatments

Ross, J. M. (2012) · Figshare

Theoretical and Statistical Approaches to Understand Human Mitochondrial DNA Heteroplasmy Inheritance

Wonnapinij, P., Samuels, D. C., Smith, E. J., Hoeschele, I., Lewis, R. M., & Dickerman, A. W. (2010) · VTechWorks (Virginia Tech)

A mitokondriális DNS és mutációi: újabb ismeretek egy új területen

Magyari, L. (2007) · Orvosi Hetilap

Introduction and background

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.002

Mitochondrial DNA sequence variation in patients with sensorineural hearing impairment and in the Finnish population

Lehtonen, M. S. (2002)

Human variation: growth, development, life history, and senescence

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.004

On Glucose Metabolism in Patients with the m.3243A>G Mutation

Lindroos, M. M. (2013) · UTUPub (University of Turku)

Discussion and perspectives

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.007

Human life span and life extension

Crews, D. E. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511542350.006

Preventing the transmission of mitochondrial diseases

Sallevelt (2017) · doi:10.26481/dis.20170203ss

The impact of the mitochondrial bottleneck on mtDNA disease risk and embryogenesis

Otten, A. B. C. (2016) · Research Publications (Maastricht University) · doi:10.26481/dis.20161115ao

Genetic variation and disease in the Roma (Gypsies)

Gresham, D. (2001) · Australasian Journal of Paramedicine

Statistical Methods in Population Genetics for Next-Generation Sequencing Data

Rothwell, R. (2016) · Deep Blue (University of Michigan)

Mitofusinas em oócitos murinos: seus papéis na fertilidade e na herança mitocondrial

Machado, T. S. (2020) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.10.2020.tde-19062019-105614

Resolving the role of genetic defects and mtDNA copy number in mitochondrial disease and development

Kamps, R. (2020) · doi:10.26481/dis.20201120rk

Structural and diffusion magnetic resonance imaging in mitochondrial disease : validation, optimisation, and implementation

Hossain, C. L. (2019)

[The salary of a German pharmacist around 1900].

Helmstädter, A. (1994) · PubMed

Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responsesPreprint

Zhang, J., Koolmeister, C., Han, J., Filograna, R., Hanke, L., Ádori, M., Sheward, D. J., Teifel, S., Liu, Y., Harris, R. A., et al. (2021) · medRxiv · doi:10.1101/2021.10.05.21264464

Mitochondriale DNA des Menschen

Wissinger, B. (2003) · Springer eBooks · doi:10.1007/978-3-662-07588-3_4

Estudo do efeito da quantidade de cópias de DNA mitocondrial sobre o desenvolvimento embrionário

Chiaratti, M. R. (2010) · doi:10.47749/t/unicamp.2010.773702 · Cited by 1

Heteroplasmy

(2004) · Encyclopedic Dictionary of Genetics, Genomics and Proteomics · doi:10.1002/0471684228.egp05639

Genetic variation of maternal and paternal lineages within the Havasupai Indians of northern Arizona

Coon, K. D. (2002) · UA Campus Repository (The University of Arizona)

Comprehensive Phenotype and Treatment Description of Mitochondrial Diabetes: Insights From a Large Cohort Study

Enriquez, L. P., Ibrahim, R., Ayari, L., Gavrilova, R. H., & Kudva, Y. M. (2026) · Endocrine Practice · doi:10.1016/j.eprac.2026.01.010

Darwin’s Symptoms and the Mitochondrial Defect Idea

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0008

Darwin’s Illness: Its Significance Today

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0010

Mitochondria and Their Genetic Discontents

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0007

Preface

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.002.0007

List of Illustrations

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0014

Notes

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0019

Note on the Text

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.002.0006

Epigraph

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.002.0005

Armchair Diagnoses II. Psychogenic hypotheses

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0005

The Enigma of Darwin’s Illness

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0001

Dedication

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.002.0004

The Darwin Family Tree and What it Reveals

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0006

Acronyms/Abbreviations

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0016

His Doctors’ Dilemma

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0003

Armchair diagnoses I. “Organic” causes

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0004

Darwin’s Chronic Illness

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.001.0001

Darwin’s Illness, the Visible History

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0002

Testing the Mitochondrial Hypothesis

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0009

Glossary

Hayman, J., & Wilkins, A. S. (2026) · doi:10.1093/9780197834190.003.0012

Inheritance and selection of the mitochondrial genome

Xie, Q., Walker, H. E., Minczuk, M. A., Chiaratti, M. R., & Chinnery, P. F. (2026) · Nature Reviews Genetics · doi:10.1038/s41576-026-01019-0

Etude de la ségrégation de l'ADN mitochondrial au cours du développement embryofoetal humain

Steffann, J. (2006) · OpenGrey (Institut de l'Information Scientifique et Technique)

Skewed Segregation of the mtDNA nt 8993 (TrG) Mutation in Human Oocytes

Blok, R. B., Gook, D. A., Thorburn, D. R., & Dahl, H. M. (1997) · The American Journal of Human Genetics · doi:10.1086/515453 · Cited by 174

Mutation-specific effects in germline transmission of pathogenic mtDNA variants

Otten, A. B. C., Sallevelt, S. C. E. H., Carling, P. J., Dreesen, J. C. F. M., Drüsedau, M., Spierts, S., Paulussen, A. D. C., de Die-Smulders, C. E. M., Herbert, M., Chinnery, P. F., et al. (2018) · Human Reproduction · doi:10.1093/humrep/dey114 · Cited by 50

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA

Jenuth, J. P., Peterson, A. C., Fu, K., & Shoubridge, E. A. (1996) · Nature Genetics · doi:10.1038/ng1096-146 · Cited by 591

Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age

Elson, J. L., Samuels, D. C., Turnbull, D. M., & Chinnery, P. F. (2001) · The American Journal of Human Genetics · doi:10.1086/318801 · Cited by 340

mtDNA point mutations are present at various levels of heteroplasmy in human oocytes

Jacobs, L. J. A. M., Gerards, M., Chinnery, P. F., Dumoulin, J. C. M., de Coo, I. F. M., Geraedts, J. P. M., & Smeets, H. J. M. (2007) · Molecular Human Reproduction · doi:10.1093/molehr/gal112 · Cited by 45