Is the occurrence of some spontaneous mutations directed by environmental challenges?

Cairnsian mutations have been defined as nonrandom mutations that occur as specific and direct responses to environmental challenges. This article reviews the evidence for the occurrence of such mutations in Escherichia coli, and concludes that under conditions of prolonged, intense selection Cairnsian mutations occur at several loci, and include base substitution mutations, frameshift mutations, and mutations mediated by excision of mobile genetic elements. Cairnsian mutations occur in nondividing cells. They are thus time-dependent, rather than replication-dependent. The process that produces Cairnsian mutations is so powerful that it can generate double mutations at rates (mutations per cell per day) that approach the rates of the component single mutations under identical conditions. Several mechanisms, including slow repair of mis-matched bases, mutagenic transcription, and a hypothetical "hypermutable" physiological state, have been proposed to explain the occurrence of Cairnsian mutations by an underlying random process, rather than by the instructional, or "directed" process originally proposed by Cairns. Recent evidence, however, argues strongly against all of those proposed mechanisms and leaves us without a viable model to explain this powerful, and potentially very important, process.