Mitochondrial genomes compete for transmission from mother to progeny. We explored this competition by introducing a second genome into Drosophila melanogaster to follow transmission. Competitions between closely related genomes favored those functional in electron transport, resulting in a host-beneficial purifying selection1. In contrast, matchups between distantly related genomes often favored those with negligible, negative or lethal consequences, indicating selfish selection. Exhibiting powerful selfish selection, a genome carrying a detrimental mutation displaced a complementing genome, leading to population death after several generations. In a different pairing, opposing selfish and purifying selection counterbalanced to give stable transmission of two genomes. Sequencing of recombinant mitochondrial genomes showed that the noncoding region, containing origins of replication, governs selfish transmission. Uniparental inheritance prevents encounters between distantly related genomes. Nonetheless, in each maternal lineage, constant competition among sibling genomes selects for super-replicators. We suggest that this relentless competition drives positive selection, promoting change in the sequences influencing transmission.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro
Communications Biology Open Access 14 May 2021
Nature Communications Open Access 16 June 2020
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ma, H., Xu, H. & O'Farrell, P.H. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat. Genet. 46, 393–397 (2014).
Hill, J.H., Chen, Z. & Xu, H. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat. Genet. 46, 389–392 (2014).
Hurst, G.D. & Werren, J.H. The role of selfish genetic elements in eukaryotic evolution. Nat. Rev. Genet. 2, 597–606 (2001).
Crow, J.F. Genes that violate Mendel's rules. Sci. Am. 240, 134–143, 146 (1979).
Hickey, D.A. Selfish DNA: a sexually-transmitted nuclear parasite. Genetics 101, 519–531 (1982).
MacAlpine, D.M., Kolesar, J., Okamoto, K., Butow, R.A. & Perlman, P.S. Replication and preferential inheritance of hypersuppressive petite mitochondrial DNA. EMBO J. 20, 1807–1817 (2001).
Taylor, D.R., Zeyl, C. & Cooke, E. Conflicting levels of selection in the accumulation of mitochondrial defects in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 99, 3690–3694 (2002).
Jasmin, J.N. & Zeyl, C. Rapid evolution of cheating mitochondrial genomes in small yeast populations. Evolution 68, 269–275 (2014).
Samuels, D.C. et al. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet. 9, e1003929 (2013).
Clark, K.A. et al. Selfish little circles: transmission bias and evolution of large deletion-bearing mitochondrial DNA in Caenorhabditis briggsae nematodes. PLoS One 7, e41433 (2012).
Phillips, W.S. et al. Selfish mitochondrial DNA proliferates and diversifies in small, but not large, experimental populations of Caenorhabditis briggsae. Genome Biol. Evol. 7, 2023–2037 (2015).
Moraes, C.T., Kenyon, L. & Hao, H. Mechanisms of human mitochondrial DNA maintenance: the determining role of primary sequence and length over function. Mol. Biol. Cell 10, 3345–3356 (1999).
Volz-Lingenhöhl, A., Solignac, M. & Sperlich, D. Stable heteroplasmy for a large-scale deletion in the coding region of Drosophila subobscura mitochondrial DNA. Proc. Natl. Acad. Sci. USA 89, 11528–11532 (1992).
Tsang, W.Y. & Lemire, B.D. Stable heteroplasmy but differential inheritance of a large mitochondrial DNA deletion in nematodes. Biochem. Cell Biol. 80, 645–654 (2002).
Celotto, A.M. et al. Mitochondrial encephalomyopathy in Drosophila. J. Neurosci. 26, 810–820 (2006).
Celotto, A.M., Chiu, W.K., Van Voorhies, W. & Palladino, M.J. Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction. PLoS One 6, e25823 (2011).
Ma, H. & O'Farrell, P.H. Selections that isolate recombinant mitochondrial genomes in animals. eLife 4, e07247 (2015).
Stoneking, M. Hypervariable sites in the mtDNA control region are mutational hotspots. Am. J. Hum. Genet. 67, 1029–1032 (2000).
Jamandre, B.W., Durand, J.D. & Tzeng, W.N. High sequence variations in mitochondrial DNA control region among worldwide populations of flathead mullet (Mugil cephalus). Int. J. Zool. 2014, 1–9 (2014).
Wilkinson, G.S., Mayer, F., Kerth, G. & Petri, B. Evolution of repeated sequence arrays in the D-loop region of bat mitochondrial DNA. Genetics 146, 1035–1048 (1997).
Lunt, D.H., Whipple, L.E. & Hyman, B.C. Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology. Mol. Ecol. 7, 1441–1455 (1998).
Lewis, D.L., Farr, C.L., Farquhar, A.L. & Kaguni, L.S. Sequence, organization, and evolution of the A+T region of Drosophila melanogaster mitochondrial DNA. Mol. Biol. Evol. 11, 523–538 (1994).
Chen, S. et al. A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila. Genetics 192, 483–493 (2012).
Rand, D.M. Population genetics of the cytoplasm and the units of selection on mitochondrial DNA in Drosophila melanogaster. Genetica 139, 685–697 (2011).
Wolff, J.N., Camus, M.F., Clancy, D.J. & Dowling, D.K. Complete mitochondrial genome sequences of thirteen globally sourced strains of fruit fly (Drosophila melanogaster) form a powerful model for mitochondrial research. Mitochondrial DNA http://dx.doi.org/10.3109/19401736.2015.1106496 (2015).
Solignac, M., Monnerot, M. & Mounolou, J.C. Concerted evolution of sequence repeats in Drosophila mitochondrial-DNA. J. Mol. Evol. 24, 53–60 (1986).
Tsujino, F. et al. Evolution of the A+T-rich region of mitochondrial DNA in the melanogaster species subgroup of Drosophila. J. Mol. Evol. 55, 573–583 (2002).
Schmitz-Linneweber, C. et al. Pigment deficiency in nightshade/tobacco cybrids is caused by the failure to edit the plastid ATPase α-subunit mRNA. Plant Cell 17, 1815–1828 (2005).
Meiklejohn, C.D. et al. An incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila. PLoS Genet. 9, e1003238 (2013).
Lee, H.Y. et al. Incompatibility of nuclear and mitochondrial genomes causes hybrid sterility between two yeast species. Cell 135, 1065–1073 (2008).
Špírek, M., Poláková, S., Jatzová, K. & Sulo, P. Post-zygotic sterility and cytonuclear compatibility limits in S. cerevisiae xenomitochondrial cybrids. Front. Genet. 5, 454 (2014).
Chen, Z. et al. Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. Mol. Biol. Cell 26, 674–684 (2015).
Petit, N. et al. Developmental changes in heteroplasmy level and mitochondrial gene expression in a Drosophila subobscura mitochondrial deletion mutant. Curr. Genet. 33, 330–339 (1998).
Burman, J.L. et al. A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer. Dis. Model. Mech. 7, 1165–1174 (2014).
Matsuura, E.T., Tanaka, Y.T. & Yamamoto, N. Effects of the nuclear genome on selective transmission of mitochondrial DNA in Drosophila. Genes Genet. Syst. 72, 119–123 (1997).
Doi, A., Suzuki, H. & Matsuura, E.T. Genetic analysis of temperature-dependent transmission of mitochondrial DNA in Drosophila. Heredity 82, 555–560 (1999).
Dunbar, D.R., Moonie, P.A., Jacobs, H.T. & Holt, I.J. Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc. Natl. Acad. Sci. USA 92, 6562–6566 (1995).
Niki, Y., Chigusa, S.I. & Matsuura, E.T. Complete replacement of mitochondrial DNA in Drosophila. Nature 341, 551–552 (1989).
De Stordeur, E. Nonrandom partition of mitochondria in heteroplasmic Drosophila. Heredity 79, 615–623 (1997).
Saito, S., Tamura, K. & Aotsuka, T. Replication origin of mitochondrial DNA in insects. Genetics 171, 1695–1705 (2005).
van Valen, L. A new evolutionary law. Evol. Theory 1, 1–30 (1973).
van Oven, M. & Kayser, M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum. Mutat. 30, E386–E394 (2009).
McMillan, W.O. & Palumbi, S.R. Rapid rate of control-region evolution in Pacific butterflyfishes (Chaetodontidae). J. Mol. Evol. 45, 473–484 (1997).
Stoneking, M., Hedgecock, D., Higuchi, R.G., Vigilant, L. & Erlich, H.A. Population variation of human mtDNA control region sequences detected by enzymatic amplification and sequence-specific oligonucleotide probes. Am. J. Hum. Genet. 48, 370–382 (1991).
Townsend, J.P. & Rand, D.M. Mitochondrial genome size variation in New World and Old World populations of Drosophila melanogaster. Heredity 93, 98–103 (2004).
Casane, D. & Guéride, M. Evolution of heteroplasmy at a mitochondrial tandem repeat locus in cultured rabbit cells. Curr. Genet. 42, 66–72 (2002).
Hoelzel, A.R., Lopez, J.V., Dover, G.A. & O'Brien, S.J. Rapid evolution of a heteroplasmic repetitive sequence in the mitochondrial DNA control region of carnivores. J. Mol. Evol. 39, 191–199 (1994).
Faber, J.E. & Stepien, C.A. Tandemly repeated sequences in the mitochondrial DNA control region and phylogeography of the Pike–Perches Stizostedion. Mol. Phylogenet. Evol. 10, 310–322 (1998).
Lee, W.J., Conroy, J., Howell, W.H. & Kocher, T.D. Structure and evolution of teleost mitochondrial control regions. J. Mol. Evol. 41, 54–66 (1995).
Fumagalli, L., Taberlet, P., Favre, L. & Hausser, J. Origin and evolution of homologous repeated sequences in the mitochondrial DNA control region of shrews. Mol. Biol. Evol. 13, 31–46 (1996).
We thank M.J. Palladino (University of Pittsburgh) for kindly providing us flies with the ATP6 mitochondrial genome. This research was supported by US NIH funding (ES020725 and GM120005) to P.H.O'F. H.M. was supported by a long-term postdoctoral fellowship from the Human Frontiers Science Program (LT000138/2010-l).
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Exchange of the noncoding region is sufficient to confer robust drive to the ATP6 genome.
(a) PacBio sequencing of a second recombinant genome (GenBank KU764535) showed that its coding sequence (amber) is the same as that of the ATP6 genome, whereas the entire noncoding region matches that of the mt:ND2del1 + mt:CoIT300I genome. Black arrows indicate approximate points of exchange, with the given range defined by the nearest neighboring polymorphisms. (b) A restriction fragment length polymorphism distinguishes the noncoding regions of the ATP6 and mt:ND2del1 + mt:CoIT300I genomes, while sensitivity to XhoI cleavage tracks the allele state of mt:CoI. As shown in the Southern blot using the indicated probe (purple; mt1579–2369), the fragments present at generation 3 (G3) are consistent with predominance of the mt:ND2del1 + mt:CoIT300I genome (XhoI-resistant 11.5-kb band), a minority of the ATP6 genome (XhoI-sensitive 9.9-kb band), which has declined from its starting level (~80%), and no detectable recombinant. At generation 10 (G10) at 29 °C, a recombinant (XhoI-sensitive 11.5-kb band) has become dominant and the ATP6 genome has been lost. DNA isolated from 40 adults for each generation was cut with EcoRI in the presence or absence of XhoI. (c) The predominance of the recombinant genome in the population was further confirmed by qPCR in individual flies at generation 20 (G20) at 29 °C. qPCR was performed as described in Figure 1 and the Online Methods.
(a) The origin regions and repeat structure of the Drosophila noncoding region. The central panel shows type I (brown) and type II (gray) repeats of a typical D. melanogaster mitochondrial genome (for example, mt:ND2del1 + mt:CoIT300I). Individual repeats for each type are highly conserved1. The ATP6 genome lacks two entire type I repeats (B1 and A/C) and two entire type II repeats (B2 and C)2, whereas the D. yakuba genome lacks the majority (>75%) of the repeated sequences3. Nucleotide sequences near the origins of replication for the heavy (OH) and light (OL) chains for the mt:ND2del1 + mt:CoIT300I, ATP6 and D. yakuba genomes show conservation with potentially significant polymorphisms. The direction of replication is indicated by an arrow. The 5′ ends of mtDNA were mapped to define the sites at which mtDNA synthesis began in the D. yakuba genome: the nucleotides in the green boxes are the sites where the ends were mapped for OH and OL (ref. 4). (b) Rapid divergence of the noncoding region suggests positive selection. The divergence of the noncoding region is so fast and includes so many deletions and insertions that it is difficult to make a meaningful determination of the number of changes separating the genomes of different species. Recently reported complete genome sequences for 13 mitochondrial haplotypes from diverse wild strains of D. melanogaster5 allowed us to compare more recently diverged genomes. Even among these, the number of changes makes some comparisons difficult. We selected four pairs of strains where each pair represents two especially closely related genomes and each pair represents a different branch of the tree of relatedness for the 13 sequenced genomes5. The tree shown here (left) gives the relatedness of the four pairs of sequences we analyzed. For comparison, the relatedness to D. yakuba, the reference sequence for D. melanogaster (NC 024511), and the sequence we obtained for the temperature-sensitive genome used in this study (derived from a laboratory stock of w1118) are also indicated. Because the target size for synonymous mutation in protein-coding sequence is about one-third of the total, the ~12 kb of protein-coding sequence for the mitochondrial genome provides about 4,000 potential sites for synonymous changes, an amount roughly equal to the total number of sites in the non-coding region. As synonymous changes are in general considered neutral, the number of synonymous changes in the protein-coding regions should reflect the neutral mutation rate, and if the number of changes in the noncoding region is substantially higher positive selection could be invoked. The distribution of sequence differences distinguishing the members of each pair is shown on the right. (c) Southern blot analysis showing length polymorphism of the noncoding region of mtDNA from several Drosophila species. Total DNA was isolated from flies homoplasmic for various mitochondrial genotypes and then digested with XbaI and HindIII. The Southern blot was probed with a DIG-labeled DNA fragment recognizing mt21–400 (pink).
Supplementary Figure 3 D. mauritiana mtDNA rapidly outcompeted three D. melanogaster mitochondrial genotypes at 25 °C in the D. melanogaster nuclear background.
(a) The starting abundance for endogenous wild-type D. melanogaster mtDNA was high, but the abundance decreased to a low percent after four generations in two heteroplasmic lineages. PCR using primers to common sequences amplified a region of mtDNA (mt11517–12529) from both genomes. XhoI cutting was used to selectively cleave the product derived from D. mauritiana. Separation on agarose gels showed one large band representing the D. melanogaster genome and two smaller bands representing the D. mauritiana genome. The changing ratio of the top two bands illustrates the declining relative abundance of the D. melanogaster genome and the increase in the D. mauritiana genome. (b) qPCR performed as described in the Online Methods showed that the level of D. mauritiana mtDNA increased quickly when the recipients were flies homoplasmic for mt:ND2del1 + mt:CoIT300I or mt:ND2del1. After a few generations, D. melanogaster flies were left with only D. mauritiana mtDNA.
About this article
Cite this article
Ma, H., O'Farrell, P. Selfish drive can trump function when animal mitochondrial genomes compete. Nat Genet 48, 798–802 (2016). https://doi.org/10.1038/ng.3587
This article is cited by
Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro
Communications Biology (2021)
Nature Reviews Genetics (2021)
Nature Communications (2020)
Cell Research (2019)