The role of sugar-backbone heterogeneity and chimeras in the simultaneous emergence of RNA and DNA

Abstract

Hypotheses of the origins of RNA and DNA are generally centred on the prebiotic synthesis of a pristine system (pre-RNA or RNA), which gives rise to its descendent. However, a lack of specificity in the synthesis of genetic polymers would probably result in chimeric sequences; the roles and fate of such sequences are unknown. Here, we show that chimeras, exemplified by mixed threose nucleic acid (TNA)–RNA and RNA–DNA oligonucleotides, preferentially bind to, and act as templates for, homogeneous TNA, RNA and DNA ligands. The chimeric templates can act as a catalyst that mediates the ligation of oligomers to give homogeneous backbone sequences, and the regeneration of the chimeric templates potentiates a scenario for a possible cross-catalytic cycle with amplification. This process provides a proof-of-principle demonstration of a heterogeneity-to-homogeneity scenario and also gives credence to the idea that DNA could appear concurrently with RNA, instead of being its later descendent.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The prebiotic clutter generated heterogeneity-to-homogeneity scenario versus the biology-inspired model of replacing one homogeneous genetic system with its homogeneous genetic successor.
Fig. 2: The preferential association with, and ligation of homogeneous ligands by, a chimeric TRNA template over chimeric ligands.
Fig. 3: Chimeric RDNA templates preferentially associate and ligate homogeneous RNA and DNA ligands over chimeric ligands.
Fig. 4: The beneficial role of the chimeric RDNA template in overcoming the template–product inhibition based on the thermodynamic stability of the duplexes.
Fig. 5: Comparison of the efficiency between chimeric RDNA (CT2) and RNA (RT2) templates in producing the final ligation product RP3 under stepwise dilution conditions demonstrates the superior ability of CT2 to act as a template for ligation with turnover.
Fig. 6: Experiment to test the possibility of cross-catalytic amplification in oligonucleotide replication via regeneration of the chimeric RDNA (CT2) template.

Data availability

Full experimental details and data are provided in the Supplementary Information. The raw data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Gilbert, W. Origin of life—the RNA world. Nature 319, 618–618 (1986).

    Article  Google Scholar 

  2. 2.

    Joyce, G. F. & Orgel, L. E. in The RNA World 3rd edn, Vol. 43 (eds Gesteland, R. F., Cech, T. R. & Atkins, J. F.) 23–56 (Cold Spring Harbor Laboratory Press, 2006).

  3. 3.

    Gesteland, R. F, Cech, T. R. & Atkins, J. F. The RNA World 2nd edn (Cold Spring Harbor Laboratory Press, 1999).

  4. 4.

    Schwartz, A. in The Molecular Origins of Life: Assembling Pieces of the Puzzle (ed. Brack, A.) 237–254 (Cambridge Univ. Press, 1998).

  5. 5.

    Orgel, L. E. Prebiotic chemistry and the origin of the RNA world. Crit. Rev. Biochem. Mol. Biol. 39, 99–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Anastasi, C. et al. RNA: prebiotic product, or biotic invention? Chem. Biodivers. 4, 721–739 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Robertson, M. P. & Joyce, G. F. The origins of the RNA world. Cold Spring Harb. Perspect. Biol. 4, a003608 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Szostak, J. The eightfold path to non-enzymatic RNA replication. J. Sys. Chem. 3, 2 (2012).

    Article  CAS  Google Scholar 

  9. 9.

    Higgs, P. G. & Lehman, N. The RNA world: molecular cooperation at the origin of life. Nat. Rev. Genet. 16, 7–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Hud, N. V., Cafferty, B. J., Krishnamurthy, R. & Williams, L. D. The origin of RNA and ‘my grandfather’s axe’. Chem. Biol. 20, 466–474 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Joyce, G. F. The antiquity of RNA-based evolution. Nature 418, 214–221 (2002).

    Article  CAS  Google Scholar 

  12. 12.

    Islam, S. & Powner, M. W. Prebiotic systems chemistry: complexity overcoming clutter. Chem 2, 470–501 (2017).

    Article  CAS  Google Scholar 

  13. 13.

    Krishnamurthy, R. On the emergence of RNA. Isr. J. Chem. 55, 837–850 (2015).

    Article  CAS  Google Scholar 

  14. 14.

    Gavette, J. V., Stoop, M., Hud, N. V. & Krishnamurthy, R. RNA–DNA chimeras in the context of an RNA world transition to an RNA/DNA world. Angew. Chem. Int. Ed. 55, 13204–13209 (2016).

    Article  CAS  Google Scholar 

  15. 15.

    Joyce, G. F., Schwartz, A. W., Miller, S. L. & Orgel, L. E. The case for an ancestral genetic system involving simple analogs of the nucleotides. Proc. Natl Acad. Sci. USA 84, 4398–4402 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Lazcano, A. & Miller, S. L. The origin and early evolution of life: prebiotic chemistry, the pre-RNA world, and time. Cell 85, 793–798 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Trevino, S. G., Zhang, N., Elenko, M. P., Luptak, A. & Szostak, J. W. Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity. Proc. Natl Acad. Sci. USA 108, 13492–13497 (2011).

    Article  PubMed  Google Scholar 

  18. 18.

    Sheng, J. et al. Structural insights into the effects of 2′-5′ linkages on the RNA duplex. Proc. Natl Acad. Sci. USA 111, 3050–3055 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Engelhart, A. E., Powner, M. W. & Szostak, J. W. Functional RNAs exhibit tolerance for non-heritable 2′–5′ versus 3′–5′ backbone heterogeneity. Nat. Chem. 5, 390–394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Eschenmoser, A. The TNA-family of nucleic acid systems: properties and prospects. Orig. Life Evol. Biosph. 34, 277–306 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Powner, M. W., Zheng, S.-L. & Szostak, J. W. Multicomponent assembly of proposed DNA precursors in water. J. Am. Chem. Soc. 134, 13889–13895 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Szostak, J. W. An optimal degree of physical and chemical heterogeneity for the origin of life? Phil. Trans. R. Soc. B 366, 2894–2901 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Orgel, L. E. & Lohrmann, R. Prebiotic chemistry and nucleic acid replication. Acc. Chem. Res. 7, 368–377 (1974).

    Article  CAS  Google Scholar 

  24. 24.

    Woese, C. R. The Genetic Code: The Molecular Basis for Genetic Expression. (Harper and Row, 1967).

  25. 25.

    Oró, J. & Stephen-Sherwood, E. in Cosmochemical Evolution and the Origins of Life (eds Oró, J., Miller, S. L., Ponnamperuma, C. & Young, R. S.) 159–172 (Springer, Dordrecht, 1974).

  26. 26.

    Becker, S. et al. Wet–dry cycles enable the parallel origin of canonical and non-canonical nucleosides by continuous synthesis. Nat. Commun. 9, 163 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Islam, S. et al. Detection of potential TNA and RNA nucleoside precursors in a prebiotic mixture by pure shift diffusion-ordered NMR spectroscopy. Chem. Eur. J. 19, 4586–4595 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Sutherland, J. D. & Whitfield, J. N. Prebiotic chemistry: a bioorganic perspective. Tetrahedron 53, 11493–11527 (1997).

    Article  CAS  Google Scholar 

  29. 29.

    Usher, D. Early chemical evolution of nucleic acids: a theoretical model. Science 196, 311–313 (1977).

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Mehta, A. P. et al. Bacterial genome containing chimeric DNA–RNA sequences. J. Am. Chem. Soc. 140, 11464–11473 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Song, X.-P., Maiti, M. & Herdewijn, P. Enzymatic synthesis of DNA employing pyrophosphate-linked dinucleotide substrates. J. Sys. Chem. 2, 3 (2011).

    Article  CAS  Google Scholar 

  32. 32.

    Schoning, K.-U. et al. The α-l-threofuranosyl-(3′→2′)-oligonucleotide system (‘TNA’): synthesis and pairing properties. Helv. Chim. Acta 85, 4111–4153 (2002).

    Article  CAS  Google Scholar 

  33. 33.

    Orgel, L. E. Origin of life: a simpler nucleic acid. Science 290, 1306–1307 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Krishnamurthy, R. Giving rise to life: transition from prebiotic chemistry to protobiology. Acc. Chem. Res. 50, 455–459 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Pallan, P. S. et al. Why does TNA cross-pair more strongly with RNA than with DNA? An answer from X-ray analysis. Angew. Chem. Int. Ed. 42, 5893–5895 (2003).

    Article  CAS  Google Scholar 

  36. 36.

    Butlerov, A. Formation synthetique d’une substance sucree. Acad. Sci. 53, 145–147 (1861).

    Google Scholar 

  37. 37.

    Kim, H.-J. et al. Synthesis of carbohydrates in mineral-guided prebiotic cycles. J. Am. Chem. Soc. 133, 9457–9468 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Kim, H.-J. & Benner, S. A. Prebiotic stereoselective synthesis of purine and noncanonical pyrimidine nucleotide from nucleobases and phosphorylated carbohydrates. Proc. Natl Acad. Sci. USA 114, 11315–11320 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Weber, A. L. & Pizzarello, S. The peptide-catalyzed stereospecific synthesis of tetroses: a possible model for prebiotic molecular evolution. Proc. Natl Acad. Sci. USA 103, 12713–12717 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    von Kiedrowski, G. A self-replicating hexadeoxynucleotide. Angew. Chem. Int. Ed. 25, 932–935 (1986).

    Article  Google Scholar 

  41. 41.

    Wu, X., Delgado, G., Krishnamurthy, R. & Eschenmoser, A. 2,6-Diaminopurine in TNA: effect on duplex stabilities and on the efficiency of template-controlled ligations. Org. Lett. 4, 1283–1286 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Derr, J. et al. Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences. Nucleic Acids Res. 40, 4711–4722 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yu, H. Y., Zhang, S. & Chaput, J. C. Darwinian evolution of an alternative genetic system provides support for TNA as an RNA progenitor. Nat. Chem. 4, 183–187 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Xu, J., Green, N., Gibard, C., Krishnamurthy, R. & Sutherland, J. Prebiotic phosphorylation of 2- thiouridine provides either nucleotides or DNA building blocks via photoreduction. Nat. Chem. 11, 457–462 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Fernando, C., Von Kiedrowski, G. & Szathmáry, E. A stochastic model of nonenzymatic nucleic acid replication: ‘elongators’ sequester replicators. J. Mol. Evol. 64, 572–585 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Grossmann, T. N., Strohbach, A. & Seitz, O. Achieving turnover in DNA-templated reactions. ChemBioChem 9, 2185–2192 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    He, C., Gállego, I., Laughlin, B., Grover, M. A. & Hud, N. V. A viscous solvent enables information transfer from gene-length nucleic acids in a model prebiotic replication cycle. Nat. Chem. 9, 318–324 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Duim, H. & Otto, S. Towards open-ended evolution in self-replicating molecular systems. Beil. J. Org. Chem. 13, 1189–1203 (2017).

    Article  CAS  Google Scholar 

  49. 49.

    Ertem, G. & Ferris, J. P. Synthesis of RNA oligomers on heterogeneous templates. Nature 379, 238–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Prakash, T. P., Roberts, C. & Switzer, C. Activity of 2′,5′‐linked RNA in the template‐directed oligomerization of mononucleotides. Angew. Chem. Int. Ed. 36, 1522–1523 (1997).

    Article  CAS  Google Scholar 

  51. 51.

    Mutschler, H. et al. Random-sequence genetic oligomer pools display an innate potential for ligation and recombination. eLife 7, e43022 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Lutay, A. V., Chernolovskaya, E. L., Zenkova, M. A. & Vlassov, V. V. The nonenzymatic template- directed ligation of oligonucleotides. Biogeosciences 3, 243–249 (2006).

    Article  CAS  Google Scholar 

  53. 53.

    Gibard, C., Bhowmik, S., Karki, M., Kim, E.-K. & Krishnamurthy, R. Phosphorylation, oligomerization and self-assembly in water under potential prebiotic conditions. Nat. Chem. 10, 212–217 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Vaidya, N. et al. Spontaneous network formation among cooperative RNA replicators. Nature 491, 72–77 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Taran, O., Thoennessen, O., Achilles, K. & von Kiedrowski, G. Synthesis of information-carrying polymers of mixed sequences from double stranded short deoxynucleotides. J. Sys. Chem. 1, 9 (2010).

    Article  CAS  Google Scholar 

  56. 56.

    Edeleva, E. et al. Continuous nonenzymatic cross-replication of DNA strands with in situ activated DNA oligonucleotides. Chem. Sci. 10, 5807–5814 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Mutschler, H., Wochner, A. & Holliger, P. Freeze–thaw cycles as drivers of complex ribozyme assembly. Nat. Chem. 7, 502–508 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Forsythe, J. G. et al. Ester-mediated amide bond formation driven by wet–dry cycles: a possible path to polypeptides on the prebiotic Earth. Angew. Chem. Int. Ed. 127, 10009–10013 (2015).

    Article  Google Scholar 

  59. 59.

    Joyce, G. F. & Szostak, J. W. Protocells and RNA self-replication. Cold Spring Harb. Perspect. Biol. 10, a034801 (2018).

    Article  PubMed  Google Scholar 

  60. 60.

    Ruiz-Mirazo, K., Briones, C. & de la Escosura, A. Prebiotic systems chemistry: new perspectives for the origins of life. Chem. Rev. 114, 285–366 (2014).

    Article  CAS  Google Scholar 

  61. 61.

    Kamat, N. P., Tobe, S., Hill, I. T. & Szostak, J. W. Electrostatic localization of RNA to protocell membranes by cationic hydrophobic peptides. Angew. Chem. Int. Ed. 54, 11735–11739 (2015).

    Article  CAS  Google Scholar 

  62. 62.

    Chen, I. A. & Walde, P. From self-assembled vesicles to protocells. Cold Spring Harb. Perspect. Biol. 2, a002170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Joyce, G. F., Inoue, T. & Orgel, L. E. Non-enzymic template-directed synthesis on RNA random copolymers. poly(C, U) templates. J. Mol. Biol. 176, 279–306 (1984).

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    Prywes, N., Blain, J. C., Del Frate, F. & Szostak, J. W. Nonenzymatic copying of RNA templates containing all four letters is catalyzed by activated oligonucleotides. eLife 5, e17756 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Pfeffer, D., Sosson, M. & Richert, C. Enzyme-free ligation of dimers and trimers to RNA primers. Nucl. Acids Res. 47, 3836–3845 (2019).

    Article  PubMed  Google Scholar 

  66. 66.

    Leu, K., Obermayer, B., Rajamani, S., Gerland, U. & Chen, I. A. The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA. Nucl. Acids Res. 39, 8135–8147 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Tupper, A., Shi, K. & Higgs, P. The role of templating in the emergence of RNA from the prebiotic chemical mixture. Life 7, 41 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  68. 68.

    Dworkin, J. P., Lazcano, A. & Miller, S. L. The roads to and from the RNA world. J. Theor. Biol. 222, 127–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Brewin, N. Catalytic role for RNA in DNA replication. Nat. New Biol. 236, 101 (1972).

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Krishnamurthy, R. RNA as an emergent entity: an understanding gained through studying its nonfunctional alternatives. Synlett 25, 1511–1517 (2014).

    Article  CAS  Google Scholar 

  71. 71.

    Ribó, J. M., Hochberg, D., Crusats, J., El-Hachemi, Z. & Moyano, A. Spontaneous mirror symmetry breaking and origin of biological homochirality. J. R. Soc. Interface 14, 20170699 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Krishnamurthy, R. Life’s biological chemistry: a destiny or destination starting from prebiotic chemistry? Chem. Eur. J. 24, 16708–16715 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work was supported by a grant from NASA (NNX14AP59G) and the Simons Foundation to R.K. (327124). S.B. thanks the NASA Astrobiology Postdoctoral Program for a fellowship. We thank the S. F. Dowdy laboratory for the use of their instrument for MALDI–TOF analysis. We thank J. Szostak, I. Chen, D. Braun, U. Muller, L. Leman, A. Lazcano and our lab members for helpful discussions.

Author information

Affiliations

Authors

Contributions

R.K. conceived the project. R.K. and S.B. designed the experiments. S.B. performed all the experiments. R.K. wrote the paper with inputs from S.B. Both authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Ramanarayanan Krishnamurthy.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary information provides details of the synthesis and ligation of TNA–RNA and DNA–RNA chimeric oligonucleotide sequences, and of the stepwise dilution and cross-catalytic self-replication studies.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bhowmik, S., Krishnamurthy, R. The role of sugar-backbone heterogeneity and chimeras in the simultaneous emergence of RNA and DNA. Nat. Chem. 11, 1009–1018 (2019). https://doi.org/10.1038/s41557-019-0322-x

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing