{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:24:39Z","timestamp":1793363079164,"version":"4.5.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18H05214"],"award-info":[{"award-number":["JP18H05214"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K06095"],"award-info":[{"award-number":["18K06095"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K15125"],"award-info":[{"award-number":["JP22K15125"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. <jats:italic>De novo<\/jats:italic> DNA methylation in oocytes is mediated by the DNA methyltransferase DNMT3A, which has an ATRX-DNMT3-DNMT3L (ADD) domain that interacts with histone H3 tail unmethylated at lysine-4 (H3K4me0). The domain normally blocks the methyltransferase domain via intramolecular interaction and binding to histone H3K4me0 releases the autoinhibition. However, H3K4me0 is widespread in chromatin and the role of the ADD-histone interaction has not been studied <jats:italic>in vivo<\/jats:italic>. We herein show that amino-acid substitutions in the ADD domain of mouse DNMT3A cause dwarfism. Oocytes derived from homozygous females show mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from such oocytes die in mid-to-late gestation, with stochastic and often all-or-none-type CG-methylation loss at imprinting control regions and misexpression of the linked genes. The stochastic loss is a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. These results highlight an important role for the ADD domain in efficient, and likely processive, <jats:italic>de novo<\/jats:italic> CG methylation and pose a model for stochastic inheritance of epigenetic perturbations in germ cells to the next generation.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010855","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T17:24:22Z","timestamp":1690910662000},"page":"e1010855","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["The DNMT3A ADD domain is required for efficient de novo DNA methylation and maternal imprinting in mouse oocytes"],"prefix":"10.1371","volume":"19","author":[{"given":"Ryuji","family":"Uehara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Kin","family":"Au Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Toriyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-4093","authenticated-orcid":true,"given":"Hiroaki","family":"Ohishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehiro","family":"Toh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Suetake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-7404","authenticated-orcid":true,"given":"Kenjiro","family":"Shirane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8239-8275","authenticated-orcid":true,"given":"Hiroyuki","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,1]]},"reference":[{"issue":"5551","key":"pgen.1010855.ref001","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1126\/science.1065848","article-title":"Dnmt3L and the establishment of maternal genomic imprints","volume":"294","author":"D Bourc\u2019his","year":"2001","journal-title":"Science"},{"issue":"8","key":"pgen.1010855.ref002","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1242\/dev.129.8.1983","article-title":"Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice","volume":"129","author":"K Hata","year":"2002","journal-title":"Development"},{"issue":"6994","key":"pgen.1010855.ref003","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/nature02633","article-title":"Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting","volume":"429","author":"M Kaneda","year":"2004","journal-title":"Nature"},{"issue":"6","key":"pgen.1010855.ref004","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1042\/EBC20190043","article-title":"The role and mechanisms of DNA methylation in the oocyte","volume":"63","author":"G Sendzikaite","year":"2019","journal-title":"Essays Biochem"},{"issue":"34","key":"pgen.1010855.ref005","doi-asserted-by":"crossref","first-page":"26114","DOI":"10.1074\/jbc.M109.089433","article-title":"The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation","volume":"285","author":"A Dhayalan","year":"2010","journal-title":"J Biol Chem"},{"issue":"48","key":"pgen.1010855.ref006","article-title":"Application of Celluspots peptide arrays for the analysis of the binding specificity of epigenetic reading domains to modified histone tails","volume":"12","author":"I Bock","year":"2011","journal-title":"BMC Biochem"},{"issue":"24","key":"pgen.1010855.ref007","doi-asserted-by":"crossref","first-page":"5063","DOI":"10.1016\/j.jmb.2019.09.006","article-title":"H3K36me2\/3 Binding and DNA Binding of the DNA Methyltransferase DNMT3A PWWP Domain Both Contribute to its Chromatin Interaction","volume":"431","author":"M Dukatz","year":"2019","journal-title":"J Mol Biol"},{"issue":"1","key":"pgen.1010855.ref008","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41588-018-0274-x","article-title":"Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions","volume":"51","author":"P Heyn","year":"2019","journal-title":"Nat Genet"},{"issue":"1","key":"pgen.1010855.ref009","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1038\/s41467-019-09713-w","article-title":"A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice.","volume":"10","author":"G Sendzikaite","year":"2019","journal-title":"Nat Commun."},{"issue":"7773","key":"pgen.1010855.ref010","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41586-019-1534-3","article-title":"The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape","volume":"573","author":"DN Weinberg","year":"2019","journal-title":"Nature"},{"issue":"5","key":"pgen.1010855.ref011","doi-asserted-by":"crossref","first-page":"e1009570","DOI":"10.1371\/journal.pgen.1009570","article-title":"The DNMT3A PWWP domain is essential for the normal DNA methylation landscape in mouse somatic cells and oocytes","volume":"17","author":"K Kibe","year":"2021","journal-title":"PLoS Genet"},{"issue":"7154","key":"pgen.1010855.ref012","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nature05987","article-title":"DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA","volume":"448","author":"SK Ooi","year":"2007","journal-title":"Nature"},{"issue":"11","key":"pgen.1010855.ref013","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/embor.2009.218","article-title":"Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain","volume":"10","author":"J Otani","year":"2009","journal-title":"EMBO Rep"},{"issue":"13","key":"pgen.1010855.ref014","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1093\/nar\/gkq147","article-title":"Chromatin methylation activity of Dnmt3a and Dnmt3a\/3L is guided by interaction of the ADD domain with the histone H3 tail","volume":"38","author":"Y Zhang","year":"2010","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"pgen.1010855.ref015","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1038\/cr.2011.92","article-title":"Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase","volume":"21","author":"BZ Li","year":"2011","journal-title":"Cell Res"},{"issue":"7536","key":"pgen.1010855.ref016","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/nature13899","article-title":"Structural insight into autoinhibition and histone H3-induced activation of DNMT3A","volume":"517","author":"X Guo","year":"2015","journal-title":"Nature"},{"issue":"7262","key":"pgen.1010855.ref017","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature08315","article-title":"KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints","volume":"461","author":"DN Ciccone","year":"2009","journal-title":"Nature"},{"issue":"23","key":"pgen.1010855.ref018","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1101\/gad.271353.115","article-title":"Dynamic changes in histone modifications precede de novo DNA methylation in oocytes","volume":"29","author":"KR Stewart","year":"2015","journal-title":"Genes Dev"},{"issue":"25","key":"pgen.1010855.ref019","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1056\/NEJMoa1005143","article-title":"DNMT3A mutations in acute myeloid leukemia","volume":"363","author":"TJ Ley","year":"2010","journal-title":"N Engl J Med"},{"issue":"25","key":"pgen.1010855.ref020","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1038\/onc.2010.117","article-title":"Array-based genomic resequencing of human leukemia","volume":"29","author":"Y Yamashita","year":"2010","journal-title":"Oncogene"},{"issue":"4","key":"pgen.1010855.ref021","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/ng.788","article-title":"Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia","volume":"43","author":"XJ Yan","year":"2011","journal-title":"Nat Genet"},{"issue":"4","key":"pgen.1010855.ref022","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ng.2917","article-title":"Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability","volume":"46","author":"K Tatton-Brown","year":"2014","journal-title":"Nat Genet"},{"issue":"8","key":"pgen.1010855.ref023","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1101\/gr.156497.113","article-title":"The ancestor of extant Japanese fancy mice contributed to the mosaic genomes of classical inbred strains","volume":"23","author":"T Takada","year":"2013","journal-title":"Genome Res"},{"issue":"2","key":"pgen.1010855.ref024","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/gene.10168","article-title":"Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse","volume":"35","author":"N Lane","year":"2003","journal-title":"Genesis"},{"issue":"7284","key":"pgen.1010855.ref025","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nature08829","article-title":"Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency","volume":"463","author":"C Popp","year":"2010","journal-title":"Nature"},{"issue":"6","key":"pgen.1010855.ref026","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.molcel.2012.11.001","article-title":"The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells","volume":"48","author":"S Seisenberger","year":"2012","journal-title":"Mol Cell"},{"issue":"6118","key":"pgen.1010855.ref027","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.1229277","article-title":"Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine","volume":"339","author":"JA Hackett","year":"2013","journal-title":"Science"},{"issue":"4","key":"pgen.1010855.ref028","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1101\/gr.148023.112","article-title":"High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice","volume":"23","author":"H Kobayashi","year":"2013","journal-title":"Genome Res"},{"issue":"4","key":"pgen.1010855.ref029","doi-asserted-by":"crossref","first-page":"e1003439","DOI":"10.1371\/journal.pgen.1003439","article-title":"Mouse oocyte methylomes at base resolution reveal genome-wide accumulation of non-CpG methylation and role of DNA methyltransferases","volume":"9","author":"K Shirane","year":"2013","journal-title":"PLoS Genet"},{"issue":"1","key":"pgen.1010855.ref030","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.celrep.2019.03.002","article-title":"Histone H3K9 methyltransferase G9a in oocytes is essential for preimplantation development but dispensable for CG methylation protection","volume":"27","author":"WK Au Yeung","year":"2019","journal-title":"Cell Rep"},{"issue":"1","key":"pgen.1010855.ref031","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13148-021-01116-3","article-title":"Oxygen concentration affects de novo DNA methylation and transcription in in vitro cultured oocytes","volume":"13","author":"F Naillat","year":"2021","journal-title":"Clin Epigenetics"},{"issue":"21","key":"pgen.1010855.ref032","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1016\/j.devcel.2021.10.010","article-title":"Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages","volume":"56","author":"D Andergassen","year":"2021","journal-title":"Dev Cell"},{"key":"pgen.1010855.ref033","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.placenta.2019.09.013","article-title":"Klf14 is an imprinted transcription factor that regulates placental growth","volume":"88","author":"E Koppes","year":"2019","journal-title":"Placenta"},{"issue":"6","key":"pgen.1010855.ref034","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.febslet.2012.01.059","article-title":"Imprinted DNA methylation reprogramming during early mouse embryogenesis at the Gpr1-Zdbf2 locus is linked to long cis-intergenic transcription","volume":"586","author":"H Kobayashi","year":"2012","journal-title":"FEBS Lett"},{"issue":"5","key":"pgen.1010855.ref035","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1101\/gad.232058.113","article-title":"The Gpr1\/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals","volume":"28","author":"R Duffie","year":"2014","journal-title":"Genes Dev"},{"issue":"5","key":"pgen.1010855.ref036","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.cell.2019.01.043","article-title":"Genomic imprinting and physiological processes in mammals","volume":"176","author":"V Tucci","year":"2019","journal-title":"Cell"},{"issue":"10","key":"pgen.1010855.ref037","doi-asserted-by":"crossref","first-page":"e1007042","DOI":"10.1371\/journal.pgen.1007042","article-title":"Role of UHRF1 in de novo DNA methylation in oocytes and maintenance methylation in preimplantation embryos","volume":"13","author":"S Maenohara","year":"2017","journal-title":"PLoS Genet"},{"key":"pgen.1010855.ref038","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-3-319-43624-1_5","article-title":"Enzymology of mammalian DNA methyltransferases","volume":"945","author":"RZ Jurkowska","year":"2016","journal-title":"Adv Exp Med Biol"},{"issue":"4","key":"pgen.1010855.ref039","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.devcel.2008.08.014","article-title":"A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints","volume":"15","author":"X Li","year":"2008","journal-title":"Dev Cell"},{"issue":"3","key":"pgen.1010855.ref040","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.molcel.2011.08.032","article-title":"In embryonic stem cells, ZFP57\/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions","volume":"44","author":"S Quenneville","year":"2011","journal-title":"Mol Cell"},{"issue":"9","key":"pgen.1010855.ref041","doi-asserted-by":"crossref","first-page":"5080","DOI":"10.1093\/nar\/gkac344","article-title":"Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain","volume":"50","author":"S Kojima","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"pgen.1010855.ref042","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrg3142","article-title":"Epigenetics and the environment: emerging patterns and implications","volume":"13","author":"R Feil","year":"2012","journal-title":"Nat Rev Genet"},{"key":"pgen.1010855.ref043","doi-asserted-by":"crossref","first-page":"123484","DOI":"10.1155\/2015\/123484","article-title":"Environmental Impact on DNA Methylation in the Germline: State of the Art and Gaps of Knowledge","volume":"2015","author":"F Pacchierotti","year":"2015","journal-title":"Biomed Res Int"},{"key":"pgen.1010855.ref044","doi-asserted-by":"crossref","first-page":"5396","DOI":"10.1038\/srep05396","article-title":"Rapid generation of mouse models with defined point mutations by the CRISPR\/Cas9 system.","volume":"4","author":"M Inui","year":"2014","journal-title":"Sci Rep"},{"issue":"6","key":"pgen.1010855.ref045","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1262\/jrd.19067","article-title":"Efficient strontium-induced activation of mouse oocytes in standard culture media by chelating calcium","volume":"53","author":"Dec","year":"2007","journal-title":"J Reprod Dev"},{"issue":"17","key":"pgen.1010855.ref046","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1093\/nar\/gks454","article-title":"Amplification-free whole-genome bisulfite sequencing by post-bisulfite adaptor tagging","volume":"40","author":"F Miura","year":"2012","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"pgen.1010855.ref047","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1093\/bioinformatics\/btr167","article-title":"Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications","volume":"27","author":"F Krueger","year":"2011","journal-title":"Bioinformatics"},{"key":"pgen.1010855.ref048","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.12688\/f1000research.9037.1","article-title":"SNPsplit: Allele-specific splitting of alignments between genomes with known SNP genotypes.","volume":"5","author":"F Krueger","year":"2016","journal-title":"F1000Res."},{"issue":"4","key":"pgen.1010855.ref049","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2.","volume":"9","author":"B Langmead","year":"2012","journal-title":"Nat Methods"},{"issue":"8","key":"pgen.1010855.ref050","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"D Kim","year":"2019","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pgen.1010855.ref051","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s13059-019-1910-1","article-title":"Transcriptome assembly from long-read RNA-seq alignments with StringTie2","volume":"20","author":"S Kovaka","year":"2019","journal-title":"Genome Biol"},{"issue":"12","key":"pgen.1010855.ref052","first-page":"2825","article-title":"Scikit-learn- Machine learning in python","author":"F Pedregosa","year":"2011","journal-title":"Journal of Machine Learning Research"},{"issue":"15","key":"pgen.1010855.ref053","doi-asserted-by":"crossref","first-page":"4929","DOI":"10.1093\/nar\/gkq200","article-title":"A tripartite paternally methylated region within the Gpr1-Zdbf2 imprinted domain on mouse chromosome 1 identified by meDIP-on-chip","volume":"38","author":"H Hiura","year":"2010","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pgen.1010855.ref054","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1242\/dev.061416","article-title":"Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes","volume":"138","author":"S Tomizawa","year":"2011","journal-title":"Development"},{"issue":"1","key":"pgen.1010855.ref055","doi-asserted-by":"crossref","first-page":"e1002440","DOI":"10.1371\/journal.pgen.1002440","article-title":"Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks","volume":"8","author":"H Kobayashi","year":"2012","journal-title":"PLoS Genet"},{"key":"pgen.1010855.ref056","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1038\/srep03658","article-title":"Active DNA demethylation is required for complete imprint erasure in primordial germ cells","volume":"4","author":"Y Kawasaki","year":"2014","journal-title":"Sci Rep"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010855","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T17:24:53Z","timestamp":1690910693000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010855"}},"subtitle":[],"editor":[{"given":"Duncan","family":"Sproul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,1]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1010855","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,1]]}}}