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Selfish drive can trump function when animal mitochondrial genomes compete

Abstract

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.

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Figure 1: Selection based on selfish drive in a heteroplasmic line containing the ATP6[1] mitochondrial genome and the temperature-sensitive double mutant mt:ND2del1 + mt:CoIT300I.
Figure 2: Stable transmission of D. yakuba mitochondrial DNA in the D. melanogaster nuclear background.
Figure 3: Cross-species analysis of functional conservation and the competitive strength of mitochondrial genomes.

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Acknowledgements

We thank M.J. Palladino (University of Pittsburgh) for kindly providing us flies with the ATP6[1] 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).

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H.M. and P.H.O'F. designed research, H.M. performed research, and H.M. and P.H.O'F. wrote the manuscript.

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Correspondence to Patrick H O'Farrell.

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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[1] 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[1] 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[1] 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[1] 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[1] 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.

Supplementary Figure 2 A summary of variations in noncoding sequences.

(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[1] 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[1] 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.

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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

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