Mechanism of directional mutations?

It is of fundamental biological importance to know 1) whether there are classes of environmentally sensitive mutations that are neither “spontaneous” nor “random” and 2) if so, what the genetic mechanisms are likely to be. Our laboratory has been investigating the origin of nonrandom mutations in eukaryotes for some 10 years (Steele, 1979; Steele et al., 1984; Steele and Pollard, 1987). Recently, Cairns et al. (1988) presented interesting data suggesting “directional” mutation phenomena in bacteria. Mutants of Escherichia coli requiring lactose for growth (lac-) can be “encouraged under certain conditions to produce lac + (wild-type) revertants if they are cultured in the presence of lactose. The general interpretation of this phenomenon is that it is consistent with a Lamarckian process of adaptive evolutionary genetic change (the phenomenon is real; the basic process has been confirmed in another system; Hall, 1988). Indeed Cairns et al. do not hesitate in drawing this conclusion; after discussion a possible genetic process, they suggest it “ . provide(s) a mechanism for the inheritance of acquired characteristics. ” The purpose of this letter is to point out that, although the data of Cairns et al. are new, the explanation they use and the implications they describe for evolution are not new. The same mechanisms were proposed at least 1 year earlier by Steele and Pollard (1987); we outlined a mechanism to explain the process of somatic hypermutation in immunoglobulin variable (V-) region genes, which occurs in antigen stimulated B lymphocytes (Moller, 1987). In addition, the same basic concepts as applied to the origin of mutations in the germline genes of higher animals were outlined in a book I wrote 10 years ago (Steele, 1979). These “reverse transcriptase-based directional mutator” ideas were used to explain controversial acquired paternal inheritance data in the immune system published by Gorczynski and Steele (1980, 1981). The contents of the book and both these papers caused substantial commentary in the pages of Nature, Science, New Scientist, and elsewhere during 1980 and 1981 (e.g., Steele, 1981). The controversy surrounding the Gorczynski-Steele experiments centered on the ambiguous report by Brent et al. (19811, who were apparently unable to replicate the phenomenon. Careful analysis of their data revealed that they had in fact published positive transmission results (Steele, 1981); viz., significant paternal transmission of delayed skin graft rejection responses appeared in the progeny of male mice made neonatally tolerant to the same foreign skin tissue used to test their progeny. Subsequent to this report, positive acquired paternal transmission reports have appeared from other independent groups (Mullbacher et al., 1983; Cooper-Willis et al., 1985) as well as later studies from my own and Dr. Gorczynski’s laboratories (Steele, 1984a,b; Gorczynski et al., 1983; Steele et al., 1984). It should be noted that most of the Mullbacher et al. study was conducted in the same laboratory as that of Brent et al. Although it is clear that Cairns et al. are working in an experimental area entirely different from that of myself and colleagues, the same conceptual tools and explanatory models have been employed by both groups. However, Steele et al. have priority for the development of a substantial portion of the mechanisms of these basic Lamarckian processes, viz., “reverse transcriptase-based directional mutator mechanisms. ” These allow feedback of ‘‘environmentally’’ selected mutations to the genes in the genome of individual cells or the germ line of higher organisms. For individual B lymphocytes, this process allows the cell, under antigenic (“natural”) selection pressure, to test the utility of V-region variants. Because the DNA-to-RNAto-DNA copying loop is intrinsically error-prone, this enables the rapid generation of variants upon which the forces of natural (antigenic) selection can act. It is postulated that “nonrandom” mutations localized to the DNA within and surrounding rearranged Vregions arise quite rapidly within the B-cell compartment of the immune system after antigenic stimulation. These antigen-driven responses thus involve “directional” genetic change as B cells bearing superior variant receptors on their surface are selected for their utility or antigen-binding strength (this is manifest during the course of an immune response by the increase in the overall antigen-binding affinity of the serum antibody population). One of the starting points for our work was the seminal “protovirus” ideas of Temin (1971), who, together with Baltimore, established the facts of reverse transcription in eukaryotic viruses (Temin and Mitzutani, 1970; Baltimore, 1970). Temin in fact began describing retroviral variation in 1960 and has been publishing work on this ever since (see, e.g., Mizutani and Temin,