MOLECULAR EVOLUTION OF INTERLEUKIN-3

Chimpanzee, tamarin, and marmoset interleukin-3 (IL-3) genes were clon ed, sequenced, and expressed. Western blot analysis demonstrated that functional genes were isolated. IL-3 sequences were compared with thos e of mouse, rat, rhesus monkey, gibbon, and man. Multiple alignment of the IL-3 coding regions showed that only a few regions had been conse rved during mammalian evolution, which are likely associated with func tional domains of the IL-3 protein. Substitution rates for the various lineages were calculated and the numbers of synonymous and nonsynonym ous substitutions were estimated separately. Distance matrices of the IL-3 coding regions were used to construct phylogenetic trees which re vealed large differences in IL-3 evolution rate as well as a more rapi d substitution rate for rodents and a rate slowdown during hominoid ev olution. Extremes were rhesus monkey IL-3, which accumulated few synon ymous substitutions, and gibbon IL-3, which had almost exclusively syn onymous substitutions. In rhesus monkey IL-3, nonsynonymous substituti ons outnumbered synonymous substitutions, which could not be readily e xplained by a random process of substitutions. We assume that during e volution of IL-3, the majority of the amino acid replacements and the impaired interspecies functional cross-reactivity originate from selec tion mechanisms with the most likely selective force being the structu re of the heterodimeric IL-3 cell-surface receptor. Insight into IL-3 architecture and structural analysis of the IL-3 receptor are needed t o analyze the unusually fast evolution of IL-3 in more detail.