It is often assumed that the mutation rate is an evolutionarily optimized property of a taxon. The relevant mutation rate is for mutations that affect fitness, U, but the strength of selection on the mutation rate depends on the average effect of a mutation. Determination of U is complicated by the possibility that mutational effects depend on the particular environmental context in which the organism exists. It has been suggested that the effects of deleterious mutations are typically magnified in stressful environments, but most studies confound genotype with environment, so it is unclear to what extent environmental specificity of mutations is specific to a particular starting genotype. We report a study designed to separate effects of species, genotype, and environment on the degradation of fitness resulting from new mutations. Mutations accumulated for .200 generations at 20°in two strains of two species of nematodes that differ in thermal sensitivity. Caenorhabditis briggsae and C. elegans have similar demography at 20°, but C. elegans suffers markedly reduced fitness at 25°. We find little evidence that mutational properties differ depending on environmental conditions and mutational correlations between environments are close to those expected if effects were identical in both environments.T HE importance of deleterious mutations to the evolutionary process is well appreciated (Morgan 1903;Haldane 1927;Fisher 1930;Sturtevant 1937;Kondrashov 1988), and much effort has been expended in understanding the processes by which new mutations arise and their effects on the phenotype and on fitness (reviewed by Simmons and Crow 1977;Drake et al. 1998;Keightley and Eyre-Walker 1999;Lynch et al. 1999;Houle and Kondrashov 2006). Drake, especially, has emphasized the remarkable consistency of the per-genome mutation rate across very broad taxonomic categories, but has also noted that there is considerable variation within those broad taxa (e.g., Drake et al. 1998). The idea that certain mutational properties vary between related species and even within species is venerable (Sturtevant 1937 and references therein), but there is as yet nothing approaching a comprehensive understanding of the variation in mutational properties-rate, distribution of effects, environmental sensitivity, molecular spectrum-of any species or group of closely related species, with the possible exception of the bacterium Escherichia coli (Matic et al. 1997;Sniegowski et al. 1997;Bjedov et al. 2003).An intriguing but almost completely unsubstantiated possibility (but see Nöthel 1987;Bjedov et al. 2003) is that mutation rates are themselves an evolutionarily optimized property (Fisher 1930;Sturtevant 1937;Kimura 1960Kimura , 1967Leigh 1970Leigh , 1973 Kondrashov 1995a,b;Dawson 1998). Because the vast majority of mutations with observable effects are deleterious, it is generally accepted that direct selection (almost) always favors a reduction in the mutation rate, with an optimal mutation rate of zero, at least in sexual taxa (e.g., Leig...

OBJECTIVEPrevious studies have noted a specific association between type 1 diabetes and insufficient levels of vitamin D, as well as polymorphisms within genes related to vitamin D pathways. Here, we examined whether serum levels or genotypes of the vitamin D–binding protein (VDBP), a molecule key to the biologic actions of vitamin D, specifically associate with the disorder.RESEARCH DESIGN AND METHODSA retrospective, cross-sectional analysis of VDBP levels used samples from 472 individuals of similar age and sex distribution, including 153 control subjects, 203 patients with type 1 diabetes, and 116 first-degree relatives of type 1 diabetic patients. Single nucleotide polymorphism (SNP) typing for VDBP polymorphisms (SNP rs4588 and rs7041) was performed on this cohort to determine potential genetic correlations. In addition, SNP analysis of a second sample set of banked DNA samples from 1,502 type 1 diabetic patients and 1,880 control subjects also was used to determine genotype frequencies.RESULTSSerum VDBP levels were highest in healthy control subjects (median 423.5 µg/mL [range 193.5–4,345.0; interquartile range 354.1–]586), intermediate in first-degree relatives (402.9 µg/mL [204.7–4,850.0; 329.6–492.4]), and lowest in type 1 diabetic patients (385.3 µg/mL [99.3–1,305.0; 328.3–473.0]; P = 0.003 vs. control subjects). VDBP levels did not associate with serum vitamin D levels, age, or disease duration. However, VDBP levels were, overall, lower in male subjects (374.7 µg/mL [188.9–1,602.0; 326.9–449.9]) than female subjects (433.4 µg/mL [99.3–4,850.0; 359.4–567.8]; P < 0.0001). It is noteworthy that no differences in genotype frequencies of the VDBP polymorphisms were associated with serum VDBP levels or between type 1 diabetic patients and control subjects.CONCLUSIONSSerum VDBP levels are decreased in those with type 1 diabetes. These studies suggest that multiple components in the metabolic pathway of vitamin D may be altered in type 1 diabetes and, collectively, have the potential to influence disease pathogenesis.

Mutational bias is a potentially important agent of evolution, but it is difficult to disentangle the effects of mutation from those of natural selection. Mutation-accumulation experiments, in which mutations are allowed to accumulate at very small population size, thus minimizing the efficiency of natural selection, are the best way to separate the effects of mutation from those of selection. Body size varies greatly among species of nematode in the family rhabditidae; mutational biases are both a potential cause and a consequence of that variation. We report data on the cumulative effects of mutations that affect body size in three species of rhabditid nematode that vary fivefold in adult size. Results are very consistent with previous studies of mutations underlying fitness in the same strains: two strains of Caenorhabditis briggsae decline in body size about twice as fast as two strains of C. elegans, with a concomitant higher point estimate of the genomic mutation rate; the confamilial Oscheius myriophila is intermediate. There is an overall mutational bias, such that mutations reduce size on average, but the bias appears consistent between species. The genetic correlation between mutations that affect size and those underlying fitness is large and positive, on average.T HE importance of mutation to the evolutionary process is universally appreciated by biologists, both in terms of the deleterious effects on fitness (Morgan 1903;Fisher 1930;Haldane 1937;Sturtevant 1937) and as the ultimate source of potentially adaptive genetic variation. It has been recognized for a long time that there is substantial variation in the mutational process at a variety of taxonomic levels, even among genotypes within species (Sturtevant 1937 and references therein;Woodruff et al. 1984;Fry 2004b;Baer et al. 2005;Á vila et al. 2006;Haag-Liautard et al. 2007). The factors responsible for that variation are poorly understood, but there are two classes of potential explanations. First, the mutation rate may be primarily a by-product of intrinsic or extrinsic environmental factors, e.g., temperature, metabolic rate, UV exposure, etc. (Martin and Palumbi 1993;Hebert et al. 2002;Gillooly et al. 2005). Alternatively, the mutation rate may be an evolutionarily optimized property, with either the optimum or the deviation from the optimum varying among taxa (Kimura 1967;Leigh 1973;Kondrashov 1995;Dawson 1998). Elucidating the taxonomic distribution of variation in mutational properties may provide important insights into several disparate areas of evolutionary biology, among them the causes of adaptive radiation (Bjedov et al. 2003;Sikorski and Nevo 2005) and cladogenesis (Shpak 2005), the rate of molecular evolution (Martin and Palumbi 1993;Gillooly et al. 2005), the nature of selection on modifier loci (Kondrashov 1995), the evolution of genetic architecture underlying the phenotype ( Jones et al. 2003), and the evolution of mating system and sexual reproduction (Kondrashov 1988(Kondrashov , 1995Keightley and Otto 2006).Of part...

The genetic variation present in a species depends on the interplay between mutation, population size, and natural selection. At mutation-(purifying) selection balance (MSB) in a large population, the standing genetic variance for a trait (V G ) is predicted to be proportional to the mutational variance for the trait (V M ); V M is proportional to the mutation rate for the trait. The ratio V M /V G predicts the average strength of selection (S ) against a new mutation. Here we compare V M and V G for lifetime reproductive success (% fitness) and body volume in two species of self-fertilizing rhabditid nematodes, Caenorhabditis briggsae and C. elegans, which the evidence suggests have different mutation rates. Averaged over traits, species, and populations within species, the relationship between V G and V M is quite stable, consistent with the hypothesis that differences among groups in standing variance can be explained by differences in mutational input. The average (homozygous) selection coefficient inferred from V M /V G is a few percent, smaller than typical direct estimates from mutation accumulation (MA) experiments. With one exception, the variance present in a worldwide sample of these species is similar to the variance present within a sample from a single locale. These results are consistent with specieswide MSB and uniform purifying selection, but genetic draft (hitchhiking) is a plausible alternative possibility.T HE genetic variation present in a species is a composite function of mutation, population size, and natural selection. The relationship between the standing genetic variance (V G ) and the per-generation input of genetic variance by mutation (the mutational variance, V M ) has a straightforward interpretation under two evolutionary scenarios. Under a deterministic mutation-(purifying) selection balance (MSB) model,where S is the average selection coefficient against a new mutation (Barton 1990;Crow 1993;Houle et al. 1996). The ratioS ) can be interpreted as the ''persistence time'' (t P ) of a new mutation, i.e., the expected number of generations a mutant allele remains in the (infinite) population before it is eliminated by selection (Crow 1993;Houle et al. 1996). The more deleterious the allele, the faster it is removed from the population. At the opposite extreme, under a strict neutral model of mutation-drift equilibrium (MDE), for self-fertilizing taxa, V G % 4N e V M , where N e is the effective population size (Lynch and Hill 1986). For a quantitative trait, V M ¼ UE(a 2 ), where U is the genomic mutation rate and a is the additive phenotypic effect of a new mutation (Lynch and Walsh 1998, p. 329).The unifying factor in these different scenarios is V M . Under both the MSB and MDE scenarios, we expect V G to be proportional to V M and thus the persistence timeto be constant if selection is uniform. Changes in the relationship between V G and V M among groups must be due to differences in natural selection. Thus, if t P differs between groups, the difference must be due to h...

Understanding the genetic basis of susceptibility to pathogens is an important goal of medicine and of evolutionary biology. A key first step toward understanding the genetics and evolution of any phenotypic trait is characterizing the role of mutation. However, the rate at which mutation introduces genetic variance for pathogen susceptibility in any organism is essentially unknown. Here we quantify the per-generation input of genetic variance by mutation (VM) for susceptibility of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa (defined as the median time of death, LT50). VM for LT50 is slightly less than VM for a variety of life-history and morphological traits in this strain of C. elegans, but is well within the range of reported values in a variety of organisms. Mean LT50 did not change significantly over 250 generations of mutation accumulation. Comparison of VM to the standing genetic variance (VG) implies a strength of selection against new mutations of a few tenths of a percent. These results suggest that the substantial standing genetic variation for susceptibility of C. elegans to P. aeruginosa can be explained by polygenic mutation coupled with purifying selection.