RECIPROCAL RELATIONSHIP BETWEEN STEM-LOOP POTENTIAL AND SUBSTITUTION DENSITY IN RETROVIRAL QUASI-SPECIES UNDER POSITIVE DARWINIAN SELECTION

Nucleic acids have the potential to form intrastrand stem-loops if com plementary bases are suitably located. Computer analyses of poliovirus and retroviral RNAs have revealed a reciprocal relationship between ' 'statistically significant'' stem-loop potential and ''sequence variab ility.'' The statistically significant stem-loop potential of a nuclei c acid segment has been defined as a function of the difference betwee n the folding energy of the natural segment (FONS) and the mean foldin g energy of a set of randomized (shuffled) versions of the natural seg ment (FORS-M). Since FONS is dependent on both base composition and ba se order, whereas FORS-M is solely dependent on base composition (a ge nomic characteristic), it follows that statistically significant stem- loop potential (FORS-D) is a function of base order (a local character istic). In retroviral genomes, as in all DNA genomes studied, positive FORS-D values are widely distributed. Thus there have been pressures on base order both to encode specific functions and to encode stem-loo ps. As in the case of DNA genomes under positive Darwinian selection p ressure, in HIV-1 specific function appears to dominate in rapidly evo lving regions. Here high sequence variability, expressed as substituti on density (not indel density), is associated with negative FORS-D val ues (impaired base-order-dependent stem-loop potential). This suggests that in these regions HIV-I genomes are under positive selection pres sure by host defenses. The general function of stem-loops is recombina tion. This is a vital process if, from among members of viral ''quasis pecies,'' functional genomes are to be salvaged. Thus, for rapidly evo lving RNA genomes, it is as important to conserve base-order-dependent stemloop potential as to conserve other functions.