{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:13:40Z","timestamp":1789229620223,"version":"build-2803163510"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020","award":["805046"],"award-info":[{"award-number":["805046"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 GM118046"],"award-info":[{"award-number":["R01 GM118046"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mitochondrial DNA heteroplasmy samples can shed light on vital developmental and genetic processes shaping mitochondrial DNA populations. The sample means and sample variance of a set of heteroplasmy observations are typically used both to estimate bottleneck sizes and to perform fits to the theoretical \u201cKimura\u201d distribution in seeking evidence for mitochondrial DNA selection. However, each of these applications raises problems. Sample statistics do not generally provide optimal fits to the Kimura distribution and so can give misleading results in hypothesis testing, including false positive signals of selection. Using sample variance can give misleading results for bottleneck size estimates, particularly for small samples. These issues can and do lead to false positive results for mitochondrial DNA mechanisms\u2014all published experimental datasets we re-analyzed, reported as displaying departures from the Kimura model, do not in fact give evidence for such departures. Here we outline a maximum likelihood approach that is simple to implement computationally and addresses all of these issues. We advocate the use of maximum likelihood fits and explicit hypothesis tests, not fits and Kolmogorov\u2013Smirnov tests via summary statistics, for ongoing work with mitochondrial DNA heteroplasmy.<\/jats:p>","DOI":"10.1093\/g3journal\/jkad068","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T11:34:46Z","timestamp":1679571286000},"source":"Crossref","is-referenced-by-count":10,"title":["Avoiding misleading estimates using mtDNA heteroplasmy statistics to study bottleneck size and selection"],"prefix":"10.1093","volume":"13","author":[{"given":"Konstantinos","family":"Giannakis","sequence":"first","affiliation":[{"name":"Department of Mathematics, University of Bergen , 5007 Bergen , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda K","family":"Broz","sequence":"additional","affiliation":[{"name":"Department of Biology, Colorado State University , Fort Collins, CO 80523 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B","family":"Sloan","sequence":"additional","affiliation":[{"name":"Department of Biology, Colorado State University , Fort Collins, CO 80523 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8559-3519","authenticated-orcid":false,"given":"Iain G","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University of Bergen , 5007 Bergen , Norway"},{"name":"Computational Biology Unit, University of Bergen , 5008 Bergen , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"issue":"4","key":"2024022108013821000_jkad068-B1","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1534\/genetics.119.302423","article-title":"Mitochondrial network state scales mtDNA genetic dynamics","volume":"212","author":"Aryaman","year":"2019","journal-title":"Genetics"},{"issue":"5","key":"2024022108013821000_jkad068-B2","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1177\/0013164407301534","article-title":"Unbiased estimates of variance components with bootstrap procedures","volume":"67","author":"Brennan","year":"2007","journal-title":"Educ Psychol Meas."},{"issue":"2","key":"2024022108013821000_jkad068-B3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1086\/318190","article-title":"Random genetic drift determines the level of mutant mtDNA in human primary oocytes","volume":"68","author":"Brown","year":"2001","journal-title":"Am J Hum Genet"},{"issue":"34","key":"2024022108013821000_jkad068-B4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206973119","article-title":"Sorting of mitochondrial and plastid heteroplasmy in Arabidopsis is extremely rapid and depends on MSH1 activity","volume":"119","author":"Broz","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"2024022108013821000_jkad068-B5","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.1016\/j.celrep.2014.05.020","article-title":"MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage","volume":"7","author":"Burgstaller","year":"2014","journal-title":"Cell Rep."},{"issue":"1","key":"2024022108013821000_jkad068-B6","doi-asserted-by":"publisher","first-page":"2488","DOI":"10.1038\/s41467-018-04797-2","article-title":"Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations","volume":"9","author":"Burgstaller","year":"2018","journal-title":"Nat Commun."},{"issue":"8","key":"2024022108013821000_jkad068-B7","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1175\/1520-0450(1975)014&lt;1600:ANOTPM&gt;2.0.CO;2","article-title":"A note on the possible misuse of the Kolmogorov-Smirnov test","volume":"14","author":"Crutcher","year":"1975","journal-title":"J Appl Meteorol (1962\u20131982)"},{"issue":"1","key":"2024022108013821000_jkad068-B8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/BF00260866","article-title":"The generation of transplasmic Drosophila simulans by cytoplasmic injection effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy","volume":"220","author":"de Stordeur","year":"1989","journal-title":"Mol General Genet MGG"},{"issue":"3","key":"2024022108013821000_jkad068-B9","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1080\/00031305.1999.10474471","article-title":"The complications of the fourth central moment","volume":"53","author":"Dodge","year":"1999","journal-title":"Am Stat."},{"issue":"1","key":"2024022108013821000_jkad068-B10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1214\/aoms\/1177732451","article-title":"Moments of any rational integral isobaric sample moment function","volume":"8","author":"Dwyer","year":"1937","journal-title":"Ann Math Stat"},{"issue":"4","key":"2024022108013821000_jkad068-B11","doi-asserted-by":"publisher","first-page":"e3001153","DOI":"10.1371\/journal.pbio.3001153","article-title":"Avoiding organelle mutational meltdown across eukaryotes with or without a germline bottleneck","volume":"19","author":"Edwards","year":"2021","journal-title":"PLoS Biol."},{"key":"2024022108013821000_jkad068-B12","doi-asserted-by":"crossref","DOI":"10.1201\/9780429246593","volume-title":"An introduction to the Bootstrap","author":"Efron","year":"1994"},{"issue":"11","key":"2024022108013821000_jkad068-B13","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1038\/ng.2427","article-title":"Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission","volume":"44","author":"Freyer","year":"2012","journal-title":"Nat Genet."},{"issue":"3","key":"2024022108013821000_jkad068-B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010953","article-title":"Mitochondrial network structure controls cell-to-cell mtDNA variability generated by cell divisions","volume":"19","author":"Glastad","year":"2023","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"2024022108013821000_jkad068-B15","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1214\/aoms\/1177731020","article-title":"The theory of unbiased estimation","volume":"17","author":"Halmos","year":"1946","journal-title":"Ann Math Stat"},{"issue":"6","key":"2024022108013821000_jkad068-B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007023","article-title":"Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations","volume":"15","author":"Hoitzing","year":"2019","journal-title":"PLoS Comput Biol."},{"issue":"49","key":"2024022108013821000_jkad068-B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2122073119","article-title":"Stochastic survival of the densest and mitochondrial DNA clonal expansion in ageing","volume":"119","author":"Insalata","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2024022108013821000_jkad068-B18","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/ng1096-146","article-title":"Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA","volume":"14","author":"Jenuth","year":"1996","journal-title":"Nat Genet."},{"key":"2024022108013821000_jkad068-B19","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3389\/fcell.2019.00294","article-title":"Varied mechanisms and models for the varying mitochondrial bottleneck","volume":"7","author":"Johnston","year":"2019","journal-title":"Front Cell Dev Biol."},{"key":"2024022108013821000_jkad068-B20","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07464","article-title":"Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism","volume":"4","author":"Johnston","year":"2015","journal-title":"Elife"},{"issue":"4","key":"2024022108013821000_jkad068-B21","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1093\/hmg\/ddv508","article-title":"Tissue-specific modulation of mitochondrial DNA segregation by a defect in mitochondrial division","volume":"25","author":"Jokinen","year":"2016","journal-title":"Hum Mol Genet."},{"key":"2024022108013821000_jkad068-B22","first-page":"33","volume-title":"Cold Spring Harbor Symposia on Quantitative Biology (Vol. 20)","author":"Kimura","year":"1954"},{"issue":"3","key":"2024022108013821000_jkad068-B23","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1073\/pnas.41.3.144","article-title":"Solution of a process of random genetic drift with a continuous model","volume":"41","author":"Kimura","year":"1955","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2024022108013821000_jkad068-B24","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1002\/humu.21417","article-title":"Segregation of mtDNA throughout human embryofetal development: m. 3243A &gt; G as a model system","volume":"32","author":"Monnot","year":"2011","journal-title":"Hum Mutat."},{"key":"2024022108013821000_jkad068-B25","author":"Nguyen","year":"2018."},{"issue":"7","key":"2024022108013821000_jkad068-B26","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1093\/humrep\/dey114","article-title":"Mutation-specific effects in germline transmission of pathogenic mtDNA variants","volume":"33","author":"Otten","year":"2018","journal-title":"Hum Reprod."},{"key":"2024022108013821000_jkad068-B27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/978-3-642-57489-4_66","volume-title":"Compstat","author":"Rose","year":"2002"},{"issue":"3","key":"2024022108013821000_jkad068-B28","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1093\/humrep\/des439","article-title":"Preventing the transmission of pathogenic mitochondrial DNA mutations: can we achieve long-term benefits from germ-line gene transfer?","volume":"28","author":"Samuels","year":"2013","journal-title":"Hum Reprod."},{"key":"2024022108013821000_jkad068-B29","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1201\/9780203753064-4","volume-title":"Goodness-of-fit Techniques","author":"Stephens","year":"2017"},{"issue":"9","key":"2024022108013821000_jkad068-B30","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/nrg3966","article-title":"The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease","volume":"16","author":"Stewart","year":"2015","journal-title":"Nat Rev Genet"},{"issue":"11","key":"2024022108013821000_jkad068-B31","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021220","article-title":"Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease","volume":"5","author":"Wallace","year":"2013","journal-title":"Cold Spring Harb Perspect Biol."},{"issue":"6442","key":"2024022108013821000_jkad068-B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6520","article-title":"Germline selection shapes human mitochondrial DNA diversity","volume":"364","author":"Wei","year":"2019","journal-title":"Science"},{"key":"2024022108013821000_jkad068-B33","author":"Weston","year":"2020"},{"key":"2024022108013821000_jkad068-B34","author":"Weston","year":"2022"},{"key":"2024022108013821000_jkad068-B35","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"},{"key":"2024022108013821000_jkad068-B36","volume-title":"devtools: Tools to Make Developing R Packages Easier","author":"Wickham","year":"2020"},{"key":"2024022108013821000_jkad068-B37","author":"Wiley","year":"2001"},{"issue":"5","key":"2024022108013821000_jkad068-B38","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.ajhg.2008.10.007","article-title":"The distribution of mitochondrial DNA heteroplasmy due to random genetic drift","volume":"83","author":"Wonnapinij","year":"2008","journal-title":"Am J Hum Genet"},{"issue":"4","key":"2024022108013821000_jkad068-B39","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.ajhg.2010.02.023","article-title":"Previous estimates of mitochondrial DNA mutation level variance did not account for sampling error: comparing the mtDNA genetic bottleneck in mice and humans","volume":"86","author":"Wonnapinij","year":"2010","journal-title":"Am J Hum Genet"},{"issue":"2","key":"2024022108013821000_jkad068-B40","doi-asserted-by":"publisher","first-page":"775","DOI":"10.2307\/2405441","article-title":"Experimental studies of the distribution of gene frequencies in very small populations of Drosophila melanogaster. II. Bar","volume":"8","author":"Wright","year":"1954","journal-title":"Evolution"},{"issue":"50","key":"2024022108013821000_jkad068-B41","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abi5657","article-title":"Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission","volume":"7","author":"Zhang","year":"2021","journal-title":"Sci Adv."}],"container-title":["G3: Genes, Genomes, Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/g3journal\/advance-article-pdf\/doi\/10.1093\/g3journal\/jkad068\/49947291\/jkad068.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/6\/jkad068\/56716204\/jkad068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/6\/jkad068\/56716204\/jkad068.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T03:01:58Z","timestamp":1708484518000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/g3journal\/article\/doi\/10.1093\/g3journal\/jkad068\/7084750"}},"subtitle":[],"editor":[{"given":"J","family":"Comeron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3,23]]},"published-print":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/g3journal\/jkad068","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.09.06.506828","asserted-by":"object"}]},"ISSN":["2160-1836"],"issn-type":[{"value":"2160-1836","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2023,3,23]]},"article-number":"jkad068"}}