A theoretical scheme for self-replication in vitro of a minimal genome dependent only on small molecule substrates. A nicked double-stranded DNA circle (blue strands) encoding all of the macromolecular replication components undergoes rolling-circle DNA synthesis by a DNA polymerase (blue ball) to give an oligomeric single-stranded DNA. Lagging strand DNA synthesis is primed by RNA, then recombination duplicates the original circular template (not shown). RNA (red strand) is synthesized by an RNA polymerase (red ball), cleaved (not shown), and translated into protein (green strand) by encoded ribosomes (green) and other translation factors (not shown).