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


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.

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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.


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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.

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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.

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Correspondence to Ramanarayanan Krishnamurthy.

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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.

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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).

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