1. Variation in Mutational Properties - It has been known since early in the last century that the vast majority of mutations are deleterious, which leads to the paradox "why does the mutation rate not evolve to zero?" The resolution seems to be that at some point the organism reaches the point of diminishing returns (in the currency of fitness), whereby the metabolic cost of a further reduction in mutation rate is greater than the reduced incidence of deleterious mutations is worth. The optimum mutation rate need not be the same in all species, in all genotypes within a species, or for the same genotype under different conditions. A primary focus of research in our lab is to characterize the variability in the properties of spontaneous mutations (the rate, phenotypic effects, and molecular spectrum), toward the end of uncovering general empirical principles governing the evolution of those properties.

Ongoing projects include:

* The rate and molecular spectrum of genomic mutations in Caenorhabditis : In collaboration with Dee Denver at Oregon State University , we are working to characterize the molecular properties of accumulated spontaneous mutations in two genotypes each of C. elegans and C. briggsae by whole-genome sequencing. These data will provide the most detailed picture of the mutational process in any multicellular organism. Funded by NIH grant # R01GM072639-01A2.

* Comparing self-compatible and obligate outcrossing Caenorhabditis : Theory predicts that the strength of natural selection to reduce the deleterious mutation rate is greater in taxa that undergo obligate self-fertilization than in proper random-mating organisms. Nematodes in the genus Caenorhabditis provide the perfect opportunity to test this hypothesis because self-compatibility has independently evolved from an obligate outcrossing ancestor several times. Funded by NIH grant # R01GM072639-01A2.

* Investigating the effects of thermal environment and "stress": Metabolic rate and environmental stress have been repeatedly implicated as determinants of the mutation rate. Metabolic rate in ectotherms has a known functional dependence on temperature, and organisms have optimal temperatures, outside of which they suffer stress. Again, nematodes in the genus Caenorhabditis provide the ideal opportunity to disentangle the two factors. C. elegans and C. briggsae are extremely similar, but C. elegans is much more sensitive to high temperatures. Comparison of the tempertature-dependence of the mutational properties of these two species allows us to unambiguously separate the effects of stress and temperature per se. Funded by NIH grant # R01GM072639-01A2

* Is the mutation rate self-dependent? Deleterious mutations constitute an endogenous source of "stress" to the individual, thus if the mutation rate is increased under conditions of stress, it stands to reason that the mutation rate will be an increasing function of itself, because individuals who carry more mutations that average will produce offspring that have more mutations than average. If this situation is generally true, there are interesting theoretical and practical implications. To test this hypothesis, we are allowing mutations to accumulate in stocks of C. elegans that have known differences in fitness due to the cumulative effects of previously accumulated mutations. Funded by NSF grant # DEB-0717167.

* Role of oxidizing free-radical damage - Reactive oxygen species (ROS) are known mutagens and have been implicated in cancer and aging. The extent to which ROS contribute to the overall heritable mutational damage is unknown, but is believed to be important. In collaboration with former Baer lab postdoc Joanna Joyner-Matos ( Eastern Washington University ), we are investigating the role of ROS damage to DNA and RNA in our existing Caenorhabditis mutation accumulation ("MA") lines; a positive relationship would provide a plausible mechanism for self-dependence of the mutation rate. In addition, we are constructing MA lines of mutant strains of C. elegans that experience more and less ROS damage than wild-type, which will allow us to compare the ROS-generated mutational spectrum to the native wild-type spectrum. Funded by NIH grant # R01GM072639-01A2.

* Evolution of mutational covariance: Recent theoretical work has demonstrated the importance of the mutational covariance structure (the " M -matrix") to phenotypic evolution. For example, if mutations tend to make individuals smaller and grow more slowly, all else equal, the evolution of small size and slow growth is more likely than any other combination of size and growth rate. Suites of trait values whose covariance structure differs from that introduced by mutation are likely to have been shaped by natural selection. Further, natural selection may influence the evolution of the M -matrix itself. With our collaborator Frank Shaw of Hamline University , we are investigating the M -matrix of a suite of traits in our Caenorhabditis MA lines; this project constitutes the first such study in a comparative context.

2. (Under)standing genetic (co)variation in Caenorhabditis - Mutation constantly introduces genetic variation into a population; the standing variation is what remains after natural selection and genetic drift have done their work. Consistent differences between the mutational and genetic (co)variance provide strong evidence for natural selection. Further, different modes of selection have characteristically different signatures. Purifying selection against deleterious alleles results in mutation-selection balance (MSB), balancing selection results in more genetic variation than can be explained by MSB, and selective neutrality leads to genetic variation proportional to the effective population size. The common factor is the mutational variance, V M . Our estimates of V M for multiple traits and species allow us to assess the relative importance of purifying and balancing selection and genetic drift in shaping the standing genetic variation. An interesting preliminary result is that there appears to be about twice as much standing genetic variation for fitness and body size in C. briggsae as in C. elegans , consistent with our finding that the mutational decay in fitness of our C. briggsae MA lines is about twice that of our C. elegans lines. A second preliminary finding is that lifespan in C. briggsae appears to be almost exactly at MSB. This result is interesting because Caenorhabditis cease reproduction long before they die of old age, unlike most other animals but very much like humans.

3. Mutational effects on phenotypic canalization - A canalized trait is one that develops into the same state under different environmental or genetic circumstances. For example, limb number in humans is highly canalized, whereas waist-size is not. Biologists have long known that there is genetic variation for canalization, but the causes of that variation are poorly understood. Building on the theoretical work of Gűnter Wagner, we recently provided the first quantification of the mutational variance for canalization of fecundity and body size in our rhabditid MA lines, concluding that, surprisingly, canalization for the traits appears to be as "evolvable" as the traits themselves. We are currently investigating the canalization of gene expression in the same set of lines.