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Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster

Nature Genetics volume 46, pages 393–397 (2014)Cite this article

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Abstract

It is not known how selection affects mutations in the multiple copies of the mitochondrial genome1,2,3,4,5,6,7,8,9,10,11. We transferred cytoplasm between D. melanogaster embryos carrying mitochondrial mutations to create heteroplasmic lines transmitting two mitochondrial genotypes. Increased temperature imposed selection against a temperature-sensitive mutation affecting cytochrome oxidase, driving decreases in the abundance of the mutant genome over successive generations. Selection did not influence the health or fertility of the flies but acted during midoogenesis to influence competition between the genomes. Mitochondria might incur an advantage through selective localization, survival or proliferation, yet timing and insensitivity to park mutation suggest that preferential proliferation underlies selection. Selection drove complete replacement of the temperature-sensitive mitochondrial genome by a wild-type genome but also stabilized the multigenerational transmission of two genomes carrying complementing detrimental mutations. While they are so balanced, these stably transmitted mutations have no detrimental phenotype, but their segregation could contribute to disease phenotypes and somatic aging.

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Figure 1: Stable transmission of genetically marked mitochondrial genomes in the background of mt:ND2del1.
Figure 2: Segregation of mitochondrial genotypes in progeny.
Figure 3: Purifying selection against the temperature-sensitive genome.
Figure 4: Temperature shift of mothers followed by analysis of mitochondrial genome abundance in eggs shows the timing of selection in the germ line.

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Acknowledgements

We thank D. Martinez for helping perform the park RNAi experiment and G. Mardon (Baylor College of Medicine) for kindly providing the dpkΔ21 strain. This research was supported by the US National Institutes of Health (GM086854 and ES020725) and by United Mitochondrial Disease Foundation funding to P.H.O. H.M. was supported by the Human Frontiers Science Program (LT000138/2010-l).

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  1. Hong Xu

    Present address: Present address: Laboratory of Molecular Genetics, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.,

Authors and Affiliations

  1. Department of Biochemistry, University of California, San Francisco, San Francisco, California, USA

    Hansong Ma, Hong Xu & Patrick H O'Farrell

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Contributions

H.M., H.X. and P.H.O. designed the research, H.M. performed the research, H.X. contributed reagents, and H.M. and P.H.O. 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 Abundance distribution of donor mtDNA in the progeny (n = 316) of a single mother (mother 1 in Table 1) changed over successive days.

Transmission at 22 °C from a mother carrying 1.29% of her mtDNA as mt:CoIT300I in the background of mt:ND2del1. (A) Histograms showing the number of progeny within different abundance intervals for the mt:CoIT300I genome, where each histogram shows the progeny arising from the eggs collected over the indicated time period. The black bar indicates the number of progeny lacking PCR-detectable mt:CoIT300I genomes. (B) Means, percentages of homoplasmic individuals (P0), variances and estimated effective inherited units (N) for serial cohorts of progeny. See Supplementary Table 3 for predictions of the number of segregating units using different formulas.

Supplementary Figure 2 Elimination of the temperature-sensitive genome after multiple generations of selection at 29 °C.

The abundance of the temperature-sensitive mutant was measured by PCR amplifying a mtDNA region (mt1579–2799) using mtDNA from 30 adults as template followed by restriction digestion using XhoI in 4 heteroplasmic lines. (A) The upper panel shows that the mt:ND2del1 + mt:CoIT300I genome, when coexisting with wild type, declined to a few percent after ten generations of selection. The lower panel is Southern blot analysis of the digested PCR products, which showed disappearance of the temperature-sensitive allele in the tested heteroplasmic lines at generation 18. (B) mt:ND2del1 + mt:CoIT300I double-mutant genome was eliminated when coexisting with mt:ND2del1 in 2 of the 4 lines after 18 generations of selection.

Supplementary Figure 3 Biased transmission mt:ND2del1 when coresident with the wild-type or mt:CoIR301Q genome at 25 °C.

(A) The abundance of the wild-type genome was followed in five heteroplasmic lines for six generations. (B) The abundance of mt:CoIR301Q was followed in four heteroplasmic lines for ten generations (note that the amount of mt:CoIR301Q was not measured at generation 6– 9).

Supplementary Figure 4 Probing the level of selection.

(A) Abundance of the temperature-sensitive genome affected neither mtDNA copy number nor fecundity. Individual mothers were born and raised at 29 °C. (B) Selection does not increase as the number of germline stem cell divisions increases in the mother. The abundance of mt:CoIT300I is shown for three heteroplasmic mothers (mt:CoIT300I/mt:ND2del1 females raised at 29 °C) and the eggs she laid over successive days. A reduction in abundance is seen between the mother and eggs, and there is no significant change in the degree of this reduction over time.

Supplementary Figure 5 Temperature-dependent changes in the proportions of the mt:CoIT300I genome over generations in additional lines.

(A) Eight mt:CoIT300I/mt:ND2del1 sublines at 29 °C (restrictive) and (B) ten mt:CoIT300I/mt:ND2del1 sublines at 22 °C (permissive). All 18 sublines had more than 40% defective genome to start with.

Supplementary Figure 6 Schematic of the establishment of heteroplasmic lines.

Original heteroplasmic mothers were generated through pole plasm transplantation, and their individual F1 female progeny (known as G0 or founding mothers) were crossed to mt:ND2del1 males to establish isofemale lines. Sometimes, single females from further generations were used to establish sublines.

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Ma, H., Xu, H. & O'Farrell, P. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat Genet 46, 393–397 (2014). https://doi.org/10.1038/ng.2919

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