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BRoyRao, AnupamaAnupamaRaoAncliff, PhilipPhilipAncliffBabbs, ChristianChristianBabbsLayton, D MarkD MarkLaytonMead, Adam JAdam JMeadO'Sullivan, JenniferJenniferO'SullivanOkoli, StevenStevenOkoliRoberts, IreneIreneRobertsSaleem, MoinMoinSaleemBierzynska, AgnieszkaAgnieszkaBierzynskaDiz, Carmen BugarinCarmen BugarinDizColby, ElizabethElizabethColbyEkani, Melanie NMelanie NEkaniSatchell, SimonSimonSatchellKoziell, AniaAniaKoziellFowler, TomTomFowlerRendon, AugustoAugustoRendonScott, RichardRichardScottSmedley, DamianDamianSmedleySmith, Katherine RKatherine RSmithThomas, EllenEllenThomasCaulfield, MarkMarkCaulfieldAbbs, StephenStephenAbbsBurrows, NigelNigelBurrowsChitre, ManaliManaliChitreDewhurst, Eleanor FEleanor FDewhurstFloto, R AndresR AndresFlotoGattens, MichaelMichaelGattensGurnell, MarkMarkGurnellHolden, SimonSimonHoldenKelsall, WilfWilfKelsallMehta, SarjuSarjuMehtaPoole, Ken ESKen ESPooleRoss-Russell, RobertRobertRoss-RussellSpasic-Boskovic, OliveraOliveraSpasic-BoskovicTwiss, PhilipPhilipTwissWagner, AnnetteAnnetteWagnerBanka, SiddharthSiddharthBankaBlack, Graeme CGraeme CBlackClayton-Smith, JillJillClayton-SmithDouzgou, SofiaSofiaDouzgouNewman, William GWilliam GNewmanAbulhoul, LaraLaraAbulhoulAurora, PaulPaulAuroraBockenhauer, DetlefDetlefBockenhauerCleary, MaureenMaureenClearyDattani, MehulMehulDattaniGanesan, VijeyaVijeyaGanesanPilkington, ClarissaClarissaPilkingtonRahman, ShamimaShamimaRahmanShah, NeilNeilShahWedderburn, LucyLucyWedderburnBitner-Glindzicz, Maria AKMaria AKBitner-GlindziczBueser, TeofilaTeofilaBueserCompton, Cecilia JCecilia JComptonDeshpande, CharuCharuDeshpandeFassihi, HivaHivaFassihiHaque, EshikaEshikaHaqueIzatt, LouiseLouiseIzattJosifova, DraganaDraganaJosifovaMohammed, Shehla NShehla NMohammedRobert, LeemaLeemaRobertRose, Sarah JSarah JRoseRuddy, Deborah MDeborah MRuddySarkany, Robert NRobert NSarkanySayer, GenevieveGenevieveSayerShaw, Adam CAdam CShawIrving, MelitaMelitaIrvingFlinter, Frances AFrances AFlinterCampbell, CarolynCarolynCampbellGibson, KateKateGibsonKoelling, NilsNilsKoellingLester, TracyTracyLesterNemeth, Andrea HAndrea HNemethPalles, ClaireClairePallesPatel, SmitaSmitaPatelRoy, Noemi BNoemi BRoySen, ArjuneArjuneSenTaylor, JohnJohnTaylorTomlinson, Ian PIan PTomlinsonTaylor, Jenny CJenny CTaylorWilkie, Andrew OMAndrew OMWilkieArno, GavinGavinArnoMalka, SamanthaSamanthaMalkaMichaelides, MichelMichelMichaelidesMoore, Anthony TAnthony TMooreWebster, Andrew RAndrew RWebsterBrennan, PaulPaulBrennanBrowning, Andrew CAndrew CBrowningBurn, JohnJohnBurnChinnery, Patrick FPatrick FChinneryDe Soyza, AnthonyAnthonyDe SoyzaGraham, JodieJodieGrahamHorvath, RitaRitaHorvathPearce, SimonSimonPearceQuinton, RichardRichardQuintonSchaefer, Andrew MAndrew MSchaeferWilson, Brian TBrian TWilsonWright, MichaelMichaelWrightYu-Wai-Man, PatrickPatrickYu-Wai-ManSayer, John AJohn ASayerSimpson, MichaelMichaelSimpsonSyrris, PetrosPetrosSyrrisElliott, PerryPerryElliottHoulden, HenryHenryHouldenBeales, Phil LPhil LBealesAshford, SofieSofieAshfordPenkett, Christopher JChristopher JPenkettStirrups, Kathleen EKathleen EStirrupsRendon, AugustoAugustoRendonOuwehand, Willem HWillem HOuwehandBradley, John RJohn RBradleyRaymond, F LucyF LucyRaymondCaulfield, MarkMarkCaulfieldTurro, ErnestErnestTurroChinnery, Patrick FPatrick FChinnery2019-06-212019-06-212019-05-24Science, 2019, 364 (6442)0036-8075http://hdl.handle.net/10044/1/70789INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Vol 364 on 24 May 2019, DOI: 10.1126/science.aau6520Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsLEIGH-DISEASEHETEROPLASMYMTDNAMUTATIONSGENOMETRANSCRIPTIONREPLICATIONASSOCIATIONREPLACEMENTSEQUENCEJournal Articlehttps://www.dx.doi.org/10.1126/science.aau6520MR/J011711/1107469/Z/15/Z1095-9203