1. Departments of Chemistry and Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Correspondence to: Gerald F. Joyce Correspondence and requests for materials should be addressed to G.F.J. (e-mail: Email: gjoyce@scripps.edu).

Abstract

RNA molecules are thought to have been prominent in the early history of life on Earth because of their ability both to encode genetic information and to exhibit catalytic function¹. The modern genetic alphabet relies on two sets of complementary base pairs to store genetic information. However, owing to the chemical instability of cytosine, which readily deaminates to uracil², a primitive genetic system composed of the bases A, U, G and C may have been difficult to establish. It has been suggested that the first genetic material instead contained only a single base-pairing unit^{3, 4, 5, 6, 7}. Here we show that binary informational macromolecules, containing only two different nucleotide subunits, can act as catalysts. In vitro evolution was used to obtain ligase ribozymes composed of only 2,6-diaminopurine and uracil nucleotides, which catalyse the template-directed joining of two RNA molecules, one bearing a 5'-triphosphate and the other a 3'-hydroxyl. The active conformation of the fastest isolated ribozyme had a catalytic rate that was about 36,000-fold faster than the uncatalysed rate of reaction. This ribozyme is specific for the formation of biologically relevant 3',5'-phosphodiester linkages.