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Compensatory evolution in mitochondrial tRNAs navigates valleys of low fitness

Abstract

A long-standing controversy in evolutionary biology is whether or not evolving lineages can cross valleys on the fitness landscape that correspond to low-fitness genotypes, which can eventually enable them to reach isolated fitness peaks1,2,3,4,5,6,7,8,9. Here we study the fitness landscapes traversed by switches between different AU and GC Watson–Crick nucleotide pairs at complementary sites of mitochondrial transfer RNA stem regions in 83 mammalian species. We find that such Watson–Crick switches occur 30–40 times more slowly than pairs of neutral substitutions, and that alleles corresponding to GU and AC non-Watson–Crick intermediate states segregate within human populations at low frequencies, similar to those of non-synonymous alleles. Substitutions leading to a Watson–Crick switch are strongly correlated, especially in mitochondrial tRNAs encoded on the GT-nucleotide-rich strand of the mitochondrial genome. Using these data we estimate that a typical Watson–Crick switch involves crossing a fitness valley of a depth of about 10-3 or even about 10-2, with AC intermediates being slightly more deleterious than GU intermediates. This compensatory evolution must proceed through rare intermediate variants that never reach fixation2. The ubiquitous nature of compensatory evolution in mammalian mitochondrial tRNAs and other molecules10,11 implies that simultaneous fixation of two alleles that are individually deleterious may be a common phenomenon at the molecular level.

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Figure 1: Fitness landscapes resulting from an interaction between two complementary sites in an RNA stem structure.
Figure 2: Watson–Crick switches in mammalian mt-tRNAs.
Figure 3: Mutation strand bias in mammalian mitochondria.
Figure 4: Polymorphism frequency distribution of minor alleles in the human population.

References

  1. Wright, S. in Proceedings of the Sixth International Congress of Genetics, Ithaca, New York Vol. 1 (ed. Jones, D. F.) 356–366 (Brooklyn Botanic Garden, 1932)

    Google Scholar 

  2. Kimura, M. The role of compensatory neutral mutations in molecular evolution. J. Genet. 64, 7–19 (1985)

    Article  CAS  Google Scholar 

  3. Innan, H. & Stephan, W. Selection intensity against deleterious mutations in RNA secondary structures and rate of compensatory nucleotide substitutions. Genetics 159, 389–399 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Crow, J. F. Mid-century controversies in population genetics. Annu. Rev. Genet. 42, 1–16 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. Wade, M. J. & Goodnight, C. J. Wright’s shifting balance theory: an experimental study. Science 253, 1015–1018 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Coyne, J. A., Barton, N. H. & Turelli, M. Is Wright’s shifting balance process important in evolution? Evolution 54, 306–317 (2000)

    Article  CAS  PubMed  Google Scholar 

  7. Weinreich, D. M. & Chao, L. Rapid evolutionary escape by large populations from local fitness peaks is likely in nature. Evolution 59, 1175–1182 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. Chen, Y. & Stephan, W. Compensatory evolution of a precursor messenger RNA secondary structure in the Drosophila melanogaster Adh gene. Proc. Natl Acad. Sci. USA 100, 11499–11504 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Piskol, R. & Stephan, W. Analyzing the evolution of RNA secondary structures in vertebrate introns using Kimura’s model of compensatory fitness interactions. Mol. Biol. Evol. 25, 2483–2492 (2008)

    Article  CAS  PubMed  Google Scholar 

  10. Kondrashov, A. S., Sunyaev, S. & Kondrashov, F. A. Dobzhansky–Muller incompatibilities in protein evolution. Proc. Natl Acad. Sci. USA 99, 14878–14883 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kern, A. D. & Kondrashov, F. A. Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs. Nature Genet. 36, 1207–1212 (2004)

    Article  CAS  PubMed  Google Scholar 

  12. Maynard Smith, J. Natural selection and the concept of protein space. Nature 225, 563–564 (1970)

    Article  ADS  Google Scholar 

  13. Poelwijk, F. J., Kiviet, D. J., Weinreich, D. M. & Tans, S. J. Empirical fitness landscapes reveal accessible evolutionary paths. Nature 445, 383–386 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Dobzhansky, T. Studies on hybrid sterility. II. Localization of sterility factors in Drosophila pseudoobscura hybrids. Genetics 21, 113–135 (1936)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Muller, H. J. Reversibility in evolution considered from the standpoint of genetics. Biol. Rev. Camb. Philos. Soc. 14, 261–280 (1939)

    Article  Google Scholar 

  16. Orr, H. A. The population genetics of speciation: the evolution of hybrid incompatibilities. Genetics 139, 1805–1813 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Popadin, K. Y., Mamirova, L. A. & Kondrashov, F. A. A manually curated database of tetrapod mitochondrially encoded tRNA sequences and secondary structures. BMC Bioinformatics 8, 441 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bazykin, G. A., Kondrashov, F. A., Ogurtsov, A. Y., Sunyaev, S. & Kondrashov, A. S. Positive selection at sites of multiple amino acid replacements since rat-mouse divergence. Nature 429, 558–562 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Donmez, N., Bazykin, G. A., Brudno, M. & Kondrashov, A. S. Polymorphism due to multiple amino acid substitutions at a codon site within Ciona savignyi . Genetics 181, 685–690 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  20. Davis, A. R. & Znosko, B. M. Thermodynamic characterization of single mismatches found in naturally occurring RNA. Biochemistry 46, 13425–13436 (2007)

    Article  CAS  PubMed  Google Scholar 

  21. Kelley, S. O., Steinberg, S. V. & Schimmel, P. Functional defects of pathogenic human mitochondrial tRNAs related to structural fragility. Nature Struct. Biol. 7, 862–865 (2000)

    Article  CAS  PubMed  Google Scholar 

  22. Wittenhagen, L. M. & Kelley, S. O. Impact of disease-related mitochondrial mutations on tRNA structure and function. Trends Biochem. Sci. 28, 605–611 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. McFarland, R., Elson, J. L., Taylor, R. W., Howell, N. & Turnbull, D. M. Assigning pathogenicity to mitochondrial tRNA mutations: when ‘definitely maybe’ is not good enough. Trends Genet. 20, 591–596 (2004)

    Article  CAS  PubMed  Google Scholar 

  24. Tanaka, M. & Ozawa, T. Strand asymmetry in human mitochondrial DNA mutations. Genomics 22, 327–335 (1994)

    Article  CAS  PubMed  Google Scholar 

  25. Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sunyaev, S. et al. Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591–597 (2001)

    Article  CAS  PubMed  Google Scholar 

  27. Howell, N. et al. The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates. Am. J. Hum. Genet. 72, 659–670 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Malyarchuk, B. A., Rogozin, I. B., Berikov, V. B. & Derenko, M. V. Analysis of phylogenetically reconstructed mutational spectra in human mitochondrial DNA control region. Hum. Genet. 111, 46–53 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. McDonald, J. H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila . Nature 351, 652–654 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Popadin, K. Y., Mamirova, L. A. & Kondrashov, F. A. A manually curated database of tetrapod mitochondrially encoded tRNA sequences and secondary structures. BMC Bioinformatics 8, 441 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yang, Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl. Biosci. 13, 555–556 (1997)

    CAS  PubMed  Google Scholar 

  32. Kivisild, T. et al. The role of selection in the evolution of human mitochondrial genomes. Genetics 172, 373–387 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Benson, D. A., Karsch-Mizrachi, I., Lipman, D. J., Ostell, J. & Wheeler, D. L. GenBank. Nucleic Acids Res. 34, D16–D20 (2006)

    Article  CAS  PubMed  Google Scholar 

  34. Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ronquist, F. & Huelsenbeck, J. P. MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19, 1572–1574 (2003)

    Article  CAS  PubMed  Google Scholar 

  36. Flynn, J. J., Finarelli, J. A., Zehr, S., Hsu, J. & Nedbal, M. A. Molecular phylogeny of the carnivora (mammalia): assessing the impact of increased sampling on resolving enigmatic relationships. Syst. Biol. 54, 317–337 (2005)

    Article  PubMed  Google Scholar 

  37. Fulton, T. L. & Strobeck, C. Molecular phylogeny of the Arctoidea (Carnivora): effect of missing data on supertree and supermatrix analyses of multiple gene data sets. Mol. Phylogenet. Evol. 41, 165–181 (2006)

    Article  CAS  PubMed  Google Scholar 

  38. Springer, M. S., Teeling, E. C., Madsen, O., Stanhope, M. J. & de Jong, W. W. Integrated fossil and molecular data reconstruct bat echolocation. Proc. Natl Acad. Sci. USA 98, 6241–6246 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Teeling, E. C. et al. A molecular phylogeny for bats illuminates biogeography and the fossil record. Science 307, 580–584 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Price, S. A., Bininda-Emonds, O. R. & Gittleman, J. L. A complete phylogeny of the whales, dolphins and even-toed hoofed mammals (Cetartiodactyla). Biol. Rev. Camb. Philos. Soc. 80, 445–473 (2005)

    Article  PubMed  Google Scholar 

  41. Agnarsson, I. & May-Collado, L. J. The phylogeny of Cetartiodactyla: the importance of dense taxon sampling, missing data, and the remarkable promise of cytochrome b to provide reliable species-level phylogenies. Mol. Phylogenet. Evol. 48, 964–985 (2008)

    Article  CAS  PubMed  Google Scholar 

  42. Murphy, W. J. et al. Molecular phylogenetics and the origins of placental mammals. Nature 409, 614–618 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Schmitz, J., Roos, C. & Zischler, H. Primate phylogeny: molecular evidence from retroposons. Cytogenet. Genome Res. 108, 26–37 (2005)

    Article  CAS  PubMed  Google Scholar 

  44. Matsui, A., Rakotondraparany, F., Munechika, I., Hasegawa, M. & Horai, S. Molecular phylogeny and evolution of prosimians based on complete sequences of mitochondrial DNAs. Gene 441, 53–66 (2009)

    Article  CAS  PubMed  Google Scholar 

  45. Horner, D. S. et al. Phylogenetic analyses of complete mitochondrial genome sequences suggest a basal divergence of the enigmatic rodent Anomalurus . BMC Evol. Biol. 7, 16 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  46. Quérouil, S. et al. Phylogeny and evolution of African shrews (Mammalia: Soricidae) inferred from 16s rRNA sequences. Mol. Phylogenet. Evol. 20, 185–195 (2001)

    Article  PubMed  Google Scholar 

  47. Douady, C. J. et al. Molecular phylogenetic evidence confirming the Eulipotyphla concept and in support of hedgehogs as the sister group to shrews. Mol. Phylogenet. Evol. 25, 200–209 (2002)

    Article  CAS  PubMed  Google Scholar 

  48. Hatch, L. T., Dopman, E. B. & Harrison, R. G. Phylogenetic relationships among the baleen whales based on maternally and paternally inherited characters. Mol. Phylogenet. Evol. 41, 12–27 (2006)

    Article  CAS  PubMed  Google Scholar 

  49. Xiong, Y., Brandley, M. C., Xu, S., Zhou, K. & Yang, G. Seven new dolphin mitochondrial genomes and a time-calibrated phylogeny of whales. BMC Evol. Biol. 9, 20 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank H. Innan, M. Laessig, R. Guigo, I. Povolotskaya, D. Ivankov and M. Breen for thoughtful discussions and critical reading of the manuscript.

Author Contributions M.V.M., Y.A.R. and F.A.K. obtained the initial evolutionary and polymorphism data. A.S.K. and F.A.K. supplied the theoretical treatment of the primary data. F.A.K. designed the study. All authors participated in writing the paper.

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Correspondence to Fyodor A. Kondrashov.

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Meer, M., Kondrashov, A., Artzy-Randrup, Y. et al. Compensatory evolution in mitochondrial tRNAs navigates valleys of low fitness. Nature 464, 279–282 (2010). https://doi.org/10.1038/nature08691

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