Immunoglobulin (Ig) genes are hypermutated in B lymphocytes that are the precursors to memory B cells. The mutations are linked to transcription initiation, but non-Ig promoters are permissible for the mutation process; thus, other genes expressed in mutating B cells may also be subject to somatic hypermutation. Significant mutations were not observed in c-MYC, S14, or alpha-fetoprotein (AFP) genes, but BCL-6 was highly mutated in a large proportion of memory B cells of normal individuals. The mutation pattern was similar to that of Ig genes.

To identify DNA sequences that target the somatic hypermutation process, the immunoglobulin gene promoter located upstream of the variable (V) region was duplicated upstream of the constant (C) region of a kappa transgene. Normally, kappa genes are somatically mutated only in the VJ region, but not in the C region. In B cell hybridomas from mice with this kappa transgene (P5'C), both the VJ region and the C region, but not the region between them, were mutated at similar frequencies, suggesting that the mutation mechanism is related to transcription. The downstream promoter was not occluded by transcripts from the upstream promoter. In fact, the levels of transcripts originating from the two promoters were similar, supporting a mutation model based on initiation of transcripts. Several "hot-spots" of somatic mutation were noted, further demonstrating that this transgene has the hallmarks of somatic mutation of endogenous immunoglobulin genes. A model linking somatic mutation to transcription-coupled DNA repair is proposed.

Host-parasite coevolution has been shown to provide an advantage to recombination, but the selective mechanism underlying this advantage is unclear. One possibility is that recombination increases the frequency of advantageous genotypes that are disproportionately rare because of fluctuating epistasis. However, for this mechanism to work, epistasis for fitness must fluctuate over a very narrow timescale: two to five generations. Alternatively, recombination may speed up the response to directional selection by breaking up linkage disequilibria that decrease additive genetic variance. Here we analyze the results of a numerical simulation of host-parasite coevolution to assess the importance of these two mechanisms. We find that linkage disequilibria may tend to increase, rather than decrease, additive genetic variance. In addition, the sign of epistasis changes every two to five generations under several of the parameter values investigated, and epistasis and linkage disequilibrium are frequently of opposite signs. These results are consistent with the idea that selection for recombination is mediated by fluctuating epistasis. Finally, we explore the conditions under which an allele causing free recombination can spread in a nonrecombining host population and find general agreement between the predictions of a population genetic model of fluctuating epistasis and our simulation model.

Deleterious mutations with very small phenotypic effects could be important for several evolutionary phenomena, but the extent of their contribution has been unknown. Fitness effects of induced mutations in lines of Caenorhabditis elegans were measured using a system for which the number of deleterious point mutations in the DNA can be estimated. In fitness assays, only about 4 percent of the deleterious mutations fixed in each line were detectable. The remaining 96 percent, though cryptic, are significant for mutation load and, potentially, for the evolution of sex.

Proliferation of roots in a nutrient patch can occur either as a result of an increase in root length (morphological response) or by a change in root birth or death rates (demographic responses). In this study we attempted to distinguish between these two mechanisms of response to nutrient patches and to compare the responses of four old-field plant species (two annuals, two perennials). For all four species combined, there were significant increases in root numbers and root length in fertilized patches. Root proliferation in fertilized patches was largely due to increased birth (=branching) rates of new roots. However, there was also a significant increase in root death rates in the fertilized patches which reduced the magnitude of the increase in net root numbers. Plots for individual species suggested they differed in the magnitude and timing of root proliferation in fertilized patches due to differences in root birth and death rates. However, because of the limited sample size in this study, there was only a marginally significant difference among species in root birth rates, and no difference in death rates. Further studies are currently underway to better quantify species differences in the demographic mechanism, as well as magnitude, of response to nutrient patches and if this would affect the ability to exploit small-scale heterogeneity in soil resources.

The level of host exploitation is expected, under theory, to be selected to maximise (subject to constraints) the lifetime reproductive success of the parasite. Here we studied the effect of two castrating trematode species on their intermediate snail host, Potamopyrgus antipodarum. One of the trematode species, Microphallus sp., encysts in the snail host and the encysted larvae "hatch" following ingestion of infected snails by birds. The other species, Notocotylus gippyensis, by contrast, releases swimming larvae; ingestion of the snail host is not required for, and does not aid, transmission to the final host. We isolated field-collected snails for 3 months in the laboratory, and followed the survival of infected and uninfected snails under two conditions: not fed and fed ad libitum. Mortality of the infected hosts was higher than mortality of the uninfected ones, but the response to starvation treatment was parasite species specific. N. gippyensis induced significantly higher mortality in starved snails than did Microphallus. Based on these results, we suggest that host exploitation by different species of trematodes may depend on the type of transmission. Encysting in the snail host may select for a reduced rate of host exploitation so as to increase the probability of transmission to the final host.

We explored the evolution of recombination under antagonistic coevolution, concentrating on the equilibrium frequencies of modifier alleles causing recombination in initially nonrecombining populations. We found that the equilibrium level of recombination in the host depended not only on parasite virulence, but also on the strength of the modifier allele, and on whether or not the modifier was physically linked to the parasite interaction loci. Nonetheless, the maximum level of recombination for linked loci at equilibrium was about 0.3 (60% of free recombination) for interactions with highly virulent parasites; the level decreased for unlinked modifiers, and for lower levels of parasite virulence. We conclude that recombination spreads because it provides a combination of an immediate (next‐generation) fitness benefit and a delayed (two or more generations) increase in the rate of response to directional selection. The relative impact of these two mechanisms depends on the virulence of parasites early in the spread of the modifier, but a trade‐off between the two dictates the equilibrium modifier frequency for all nonzero virulences that we examined. In addition, population mean fitness was higher in populations at intermediate equilibria than populations fixed for free recombination or no recombination. The difference, however, was not enough on its own to overcome the two‐fold cost of producing males.

We review our studies on the mechanism of somatic hypermutation of immunoglobulin genes. Most experiments were carried out using Ig transgenes. We showed in these experiments that all required cis-acting elements are present within the 10-16 kb of a transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region. Several Ig gene enhancers are permissive for somatic mutation. Association of the enhancer with its natural Ig promoter is not necessary. However, the mutation process seems specific for Ig genes. No mutations were found in housekeeping genes from cells with high levels of somatic hypermutation of their Ig genes. The Ig enhancers may provide the Ig gene specificity. An exception may be the BCL6 gene, which was mutated in human but not in mouse B cells. Transcription of a region is required for its mutability. When the transcriptional promoter located upstream of the variable region is duplicated upstream of the constant region, this region also becomes mutable. This suggests a model in which a mutator factor associates with the RNA polymerase at the promoter, travels with the polymerase during elongation, and causes mutations during polymerase pausing. The DNA repair systems, nucleotide excision repair and DNA mismatch repair, are not required. Our recent data with an artificial substrate of somatic mutation suggest that pausing may be due to secondary structure of the DNA or nascent RNA, and the specific mutations to preferences of the mutator factor.