Baer, Charles F. et al. (2013) International Worm Meeting "Revisiting the effects of spontaneous mutations on the (micro)environmental variance in Caenorhabditis."

Farhadifar, Reza, Baer, Charles F., Andersen, Erik C., Needleman, Daniel

[International Worm Meeting, 2013]

An obvious feature of living organisms is that their development is robust to variation in the environmental circumstances in which the organism finds itself - within limits. That is, the phenotype is more or less "canalized" (canalized "robust"). The "more or less" is of considerable interest to evolutionary biologists, for a variety of reasons, i.e., under what environmental or genetic circumstances does development become more or less canalized? Environmental canalization can be quantified as the phenotypic variation among genetically identical individuals raised in a uniform environment - the "(micro)environmental variance" in the lingo of quantitative genetics, V(E). Here we provide quantitative estimates of the effects of spontaneous mutations on V(E) for a variety of phenotypic traits subject to different selective regimes. Three general quantitative trends emerge. First, in almost all cases, mutation accumulation tends to de-canalize the phenotype (i.e., V(E) increases), typically at a rate similar to the rate of change of the trait itself. Second, there is a strong positive association between the rate of increase of V(E) for a trait and the mutational variance, V(M) for the trait itself. Third, and most intriguingly, mutations affecting V(E) for a trait appear to be usually under stronger selection than mutations affecting the trait itself.

Baer, Charles F. et al. (2009) International Worm Meeting "Mutational and environmental variance and the transcriptional (?) control of phenotypic canalization in C. elegans."

Baer, Charles F., Denver, Dee R.

[International Worm Meeting, 2009]

The development of many phenotypic traits is canalized (robust) with respect to environmental variation, i.e., the same phenotype develops irrespective of the environmental circumstances in which the developing individual finds itself. Canalization is adaptive when natural selection favors the same phenotype in different environmental contexts. We have previously documented that spontaneous mutations de-canalize several phenotypic traits - fecundity, body volume, and vulval development - in a predictable way. Canalization of a phenotypic trait necessarily requires variability in some underlying mechanism, but the nature of the controls is rarely known. Here we present evidence that the accumulation of spontaneous mutations actually REDUCES environmental variance in gene expression. We compared transcript abundance of > 7000 genes in four lines of C. elegans that had accumulated mutations for ~280 generations ("MA lines") to that of the common (presumably unmutated) ancestor of those lines, using standard dye-swap microarray methodology. Contrary to our a priori expectation, MA lines exhibited significantly LESS environmental variance for transcript abundance than did their common ancestor. This unexpected result is consistent with what would be predicted if variability in gene expression provides the controlling mechanism underlying phenotypic canalization. These results must be considered highly preliminary for several reasons, which we discuss, but a plausible mechanism underlying phenotypic canalization is obvious.

Charles F Baer et al. (2003) International Worm Meeting "Comparative mutation accumulation in Rhabditid nematodes"

Michael Lynch, Charles F Baer

[International Worm Meeting, 2003]

The rate and effects of spontaneous mutations are of tremendous theoretical and practical importance in many areas of biology, but there are reliable data for only three multicellular taxa: C. elegans, Drosophila melanogaster, and Arabidopsis thaliana, and the interpretation of the data is highly controversial. Classical experiments in Drosophila suggest a mutational degradation of fitness of about 1% per generation, which implies a mutation rate on the order of one new deleterious mutation per diploid genome per generation. Conversely, data from the N2 strain of C. elegans and Arabidopsis and some new data from Drosophila melanogaster suggest that the genomic mutation rate may be an order of magnitude less than previously thought. The large phylogenetic distance between these taxa and the lack of systematically replicated studies precludes generalization, even within species. Here I report results from an experiment in which spontaneous mutations were allowed to accumulate for 100 generations in two strains of three species of androdioecious Rhabditid nematodes (C. elegans, C. briggsae, Oscheius myriophila), with the goal of partitioning the variance in mutational properties (decline in fitness, genomic mutation rate, and average effect of new mutations) within and among taxa. The results are quite clear: relative to the classical Drosophila experiments, in Rhabditid nematodes the decline in fitness and the genomic mutation rate are uniformly low, and there is relatively little variation within or among species. Two important conclusions follow: (1) the mutational properties of taxa may be conserved over long periods of evolutionary time, suggestive of strong stabilizing selection on the mutation rate. (2) Alternatively, the mutational properties of some taxa (e.g., D. melanogaster) may be much more variable than others (e.g., Rhabditid nematodes), in which case generalization from studies in a few model organisms may not be justified.

Charles F. Baer et al. (2010) Evolutionary Biology of Caenorhabditis and Other Nematodes "FASTER MUTATIONAL DECAY OF FITNESS IN GONOCHORISTIC THAN IN SELF-FERTILIZING CAENORHABDITIS"

Veronica Grigaltchik, Matthew P Salomon, Joanna Joyner-Matos, Ambuj Upadhyay, Dejerianne Ostrow, Charles F. Baer

[Evolutionary Biology of Caenorhabditis and Other Nematodes, 2010]

Evolutionary theory predicts that, all else equal, the mutation rate should evolve to zero because deleterious mutations are so much more prevalent than beneficial mutations. All else is not equal: the mutation rate is never zero. Further, mutation rate demonstrably varies between and within species. In principle, the strength of natural selection to reduce the mutation rate should be stronger in self-fertilizing organisms than in related outcrossing organisms, perhaps much stronger. However, the relative efficacy of selection on mutation rate relative to the many other factors influencing the evolution of any species is poorly understood - that is, what is the empirical relevance of the theory? To address this question we allowed mutations to accumulate in the relative absence of natural selection for ~100 generations in several sets of "mutation accumulation" (MA) lines in several species of gonochoristic Caenorhabditis (C. remanei, C. brenneri, C. sp5); we have previously conducted similar experiments in self-compatible rhabditids. The results are very clear: in every case the rate of mutational decay is substantially greater in the gonochoristic taxa than in the self-compatible C. elegans (~4X greater) and C. briggsae (~2X greater). Residual heterozygosity in the ancestral controls of these MA lines introduces some complications in interpreting the results, but there is reason to believe the results are not primarily due to inbreeding depression resulting from ancestral variation. The results suggest that natural selection operates to optimize the mutation rate in Caenorhabditis and that the strength (or efficiency) of selection differs consistently on the basis of mating system, as predicted by theory.

Charles F Baer et al. (2005) International Worm Meeting "Comparative mutational biology of Rhabditid nematodes: Rate of decline in fitness and mutational covariance in two thermal environments"

Naomi Phillips, Edward Mezerhane, Thomas Keller, Dustin Blanton, Gigi Ostrow, Charles F Baer, Catherine Steding, Frank Shaw, Laura Levy, Ashley Boggs

[International Worm Meeting, 2005]

Deleterious mutations are of fundamental importance to all aspects of organismal biology. Evolutionary geneticists have expended tremendous effort to estimate the genome-wide rate of mutation and the effects of new mutations on fitness, but the degree to which genomic mutational properties vary within and between taxa is largely unknown, particularly in multicellular organisms. Beginning with two highly inbred strains from each of three species in the nematode family Rhabditidae (Caenorhabditis briggsae, Caenorhabditis elegans, and Oscheius myriophila) we allowed mutations to accumulate in the relative absence of natural selection for over 200 generations. We document significant variation in the rate of decay of fitness due to new mutations between strains and between species: C. briggsae declines in fitness approximately twice as fast as C. elegans or O. myriophila. Estimates of the per-generation mutational decay of fitness were very consistent within strains between assays 100 generations apart. The results were very similar when fitness was assayed at 20C and 25C, although the relative fitness of the unmutated controls differed among species at the two temperatures. We report the mutational correlation between fitness in the different thermal environments. Rate of mutational decay in fitness was positively associated with genomic mutation rate and negatively associated with average mutational effect. These results provide unambiguous experimental evidence for substantial variation in genome-wide properties of mutation both within and between species and reinforce conclusions from previous experiments that the cumulative effects on fitness of new mutations can differ markedly among related taxa.

Miller DM et al. (1992) Worm Breeder's Gazette "unc-4 LacZ Expression in A-Type Motor Neurons"

Miller DM, Niemeyer CJ

[Worm Breeder's Gazette, 1992]

unc-4 LacZ expression in A-type motor neurons David M. Miller and Charles J. Niemeyer, Dept. of Cell Biology, Duke Univ. Medical Ctr, Durham, NC 27710

Johnson, Lindsay M. et al. (2017) International Worm Meeting "Network architecture and the cumulative effects of spontaneous mutations on the C. elegans metabolome."

Chandler, Luke, Johnson, Lindsay M., Baer, Charles F.

[International Worm Meeting, 2017]

A functional metabolic network is key for an organism's survival, and thus for its fitness. Spontaneous mutations reduce fitness, so it stands to reason they affect metabolism in some way. However, not all metabolites are equally important in maintaining organismal function, and the relationship between mutation and an organism's metabolic network has rarely been investigated. By investigating a set of mutation accumulation(MA) lines of Caenorhabditis elegans, we aim to better understand the effect mutations have on the metabolic network. Using a set of 43 MA lines and their ancestor, a pool of 29 metabolites was measured for changes in mean metabolite concentration (?M) and mutational variance (VM). We constructed a metabolic network map of these metabolites for C. elegans from the KEGG database, with the aim of characterizing the relationship between VM, ?M, and heritability found for these 29 metabolites and features of the metabolic network. Initial analysis shows a positive association between the largest k-core grouping of a metabolite and ?M and VM.

Braendle, Christian et al. (2009) International Worm Meeting "Quantifying the robustness and evolvability of a developmental system."

Felix, Marie-Anne, Braendle, Christian, Baer, Charles F

[International Worm Meeting, 2009]

Many developmental processes generate invariant phenotypes despite environmental or mutational perturbations. Such robustness is a fundamental biological property, yet its extent, limits and adaptive significance have rarely been assessed empirically. Here we tested how environmental variation and accumulation of spontaneous random mutation impact the developmental system underlying vulval formation in Caenorhabditis nematodes. In different environments, a correct vulval pattern develops with high precision but rare deviant patterns reveal the system''s limits and how its mechanisms respond to environmental challenges. Key features of the apparent robustness are functional redundancy among vulval precursor cells and tolerance to quantitative variation in Ras, Notch and Wnt pathway activities. These environmental responses and the precision of the vulval patterning process further vary within and between Caenorhabditis species. To quantify how developmental precision responds to mutational perturbations, we used a set of mutation accumulation (MA) lines derived from two C. briggsae and two C. elegans genotypes. Developmental defects and variants increased after MA treatment for all tested genotypes, yet the type and proportion of the mutationally induced variation varied among genotypes. Thus, the mutability of this developmental system evolves, so that the mutationally induced phenotypic space is biased depending on the genetic background. Comparison of the standing genetic variance (VG) for deviant vulva phenotypes with the mutational variance (VM) leads to the conclusion that strong natural selection acts to maintain the robustness of this developmental process.

Johnson, Lindsay M. et al. (2019) International Worm Meeting "Spontaneous mutational variation in metabolic network enzyme activity in C. elegans."

Smith, Olivia, Johnson, Lindsay M., Baer, Charles F., Hahn, Daniel

[International Worm Meeting, 2019]

Human metabolic diseases are becoming increasingly common and understanding the role genetic mutation plays in these diseases is an important first step in treatment. Large GWAS studies conducted on the human metabolome have shown that only a small fraction of the heritability of metabolic traits can be explained by cumulative mQTL. The remainder of the heritability indicates that variation is either due to a few, relatively new, highly deleterious variants, which is unlikely because they would be quickly removed by natural selection, or by many small variants that are not likely to be removed via natural selection. Regardless of how many genes are causing this heritability, it implies that spontaneous mutations are playing a role. Here we will employ C. elegans to analyze the relationship between the cumulative effects of spontaneous mutation on adenosine metabolism and on the function of the associated enzymes. The goals of this project are (1) to associate the effects of spontaneous mutations with variation in the metabolome and (2) quantify the covariance between the activity and concentration of metabolic enzymes in the adenosine pathway and metabolic phenotypes. We will also attempt to correlate mutational and network statistics for those metabolites in the adenosine pathway. Pilot data from four mutation accumulation (MA) lines and their common ancestor (N2) show significant variance for adenosine deaminase activity and concentration, adenosine kinase activity and concentration, as well as concentration of several metabolites in the adenosine pathway.

Salomon, Matthew P. et al. (2013) International Worm Meeting "The rate and spectrum of spontaneous mutations in experimental populations of the nematode Caenorhabditis remanei."

Ostrow, Dejerianne G., Salomon, Matthew P., Matsuba, Chikako, Baer, Charles F.

[International Worm Meeting, 2013]

To what degree natural selection has shaped the rate of spontaneous mutations among different taxa remains an important unresolved question in evolutionary biology. While mutation rates are known to vary among and within taxa, the relative importance of natural selection versus non-adaptive processes has yet to be determined. Classical theory predicts that the strength of natural selection to reduce the deleterious mutation rate should be stronger in asexual and selfing taxa than in outcrossing sexual taxa, leading to an adaptive decrease in mutation rate in the former. However, other theory predicts (1) that "mutator" alleles can hitchhike to high frequency in asexual/selfing taxa, thereby leading to a (non-adaptive) increase in the mutation rate, and (2) the efficiency of selection to reduce mutation rate may be substantially greater in outcrossing than asexual or selfing taxa due to the larger effective population sizes of the former. Whether general trends in exist in nature is currently unknown. Nematodes in the genus Caenorhabditis provide an ideal system to test questions of how mutation rates vary among closely related species with different reproductive strategies. Within the genus the ancestral reproductive state within is outcrossing (gonochorism), however self-fertilization (hermaphroditism) has evolved independently several times. To examine the role of matting system on the evolution of mutation rates we constructed a set of long-term mutation accumulation (MA) lines of the outcrossing species Caenorhabditis remanei. MA lines were maintained by transferring a single male-female pair of worm per generation. After 122 generations of MA, five randomly selected MA lines along with the ancestral control were re-sequenced using Illumina sequencing technology.