Biology subjects

Baer, C. F.

Publications and source records attributed to Baer, C. F..

17 recordsLinked to original sources

bioRxiv2025

Evolution of the rate, spectrum, and fitness effects of mutation under minimal selection in Caenorhabditis elegans

The rate, molecular spectrum, and fitness effects of mutations vary at all levels of the biological hierarchy, from within individual genomes to among taxonomic domains. Understanding the evolutionary factors underpinning that variation is of fundamental importance to biology. Accurate quantification of the properties of mutations requires that other evolutionary forces, especially natural selection, be minimized as much as possible. To investigate the evolution of the mutational process in C. elegans, we propagated a set of 100 "first order" mutation accumulation (O1MA) lines under minimal selection for [~]150 generations, divided each O1MA line into two "second order" MA (O2MA) lines and propagated them for another [~]150 generations, at which time the genome of each O2MA line was sequenced, and a subset of 50 O1MA families was assayed for competitive fitness. Over the course of the experiment, the mean nucleotide substitution mutation rate did not change, but the variance increased. In contrast, the indel mutation rate increased significantly. The two types of mutations fulfill the predictions of different theoretical models for the evolution of mutation rate. These results reinforce previous findings that the rate of indels is more sensitive to endogenous stress than the rate of nucleotide substitutions. Several evolutionary quandaries could be resolved if deleterious mutations interact synergistically (negative epistasis). Evidence for synergistic epistasis is famously inconclusive, although there is reason to think it may be more detectable under competitive conditions. However, a model of constant mutational effects on competitive fitness explains the results significantly better than a model including epistasis.

evolutionary biology↗

bioRxiv2025

High rate of mutation and efficient removal by selection of structural variants from natural populations of Caenorhabditis elegans

The importance of genomic structural variants (SVs) is well-appreciated, but less is known about their mutational properties than of single nucleotide variants (SNVs) and short indels. The reason is simple: the longer the variant, the less likely it will be covered by a single sequencing read, thus the harder it is to map unambiguously to a unique genomic location. Here we report SV mutation rate estimates from six mutation accumulation (MA) lines from two strains of C. elegans using long-read (PacBio) sequencing. The inferred SV mutation rate is [~]0.03/genome/generation, about 1/10 the SNV rate and 1/4 the short indel rate. We identified 40 SV mutations (12 insertions, 28 deletions, 0 inversions) and 52 false positive (FP) variants by manual inspection. Excluding one atypical line (5 mutations, 35 FPs), the signal (mutant) to noise (FP) ratio is approximately 2:1. False negative rates were determined by simulating variants in the reference genome and observing recall. Recall rate ranges from >90% for short indels and declines as SV length increases. Small deletions have nearly the same recall rate as small insertions ([~]100bp), but deletions have higher recall rates than insertions as size increases. The reported SV mutation rate is likely a lower bound. A quarter of identified SV mutations occur in SV hotspots that harbor pre-existing low complexity repeat variation. Comparison of the spectrum of spontaneous SVs to wild isolates implies that natural selection is not only efficient at removing SVs in exons but also effectively removes SVs in intergenic regions.

genetics↗

bioRxiv2024

Pervasive conservation of intron number and other genetic elements revealed by a chromosome-level genomic assembly of the hyper-polymorphic nematode Caenorhabditis brenneri

With within-species genetic diversity estimates that span the gambit of that seen across the entirety of animals, the Caenorhabditis genus of nematodes holds unique potential to provide insights into how population size and reproductive strategies influence gene and genome organization and evolution. Our study focuses on Caenorhabditis brenneri, currently known as one of the most genetically diverse nematodes within its genus and metazoan phyla. Here, we present a high-quality gapless genome assembly and annotation for C. brenneri, revealing a common nematode chromosome arrangement characterized by gene-dense central regions and repeat rich peripheral parts. Comparison of C. brenneri with other nematodes from the Elegans group revealed conserved macrosynteny but a lack of microsynteny, characterized by frequent rearrangements and low correlation iof orthogroup sizes, indicative of high rates of gene turnover. We also assessed genome organization within corresponding syntenic blocks in selfing and outcrossing species, affirming that selfing species predominantly experience loss of both genes and intergenic DNA. Comparison of gene structures revealed strikingly small number of shared introns across species, yet consistent distributions of intron number and length, regardless of population size or reproductive mode, suggesting that their evolutionary dynamics are primarily reflective of functional constraints. Our study provides valuable insights into genome evolution and expands the nematode genome resources with the highly genetically diverse C. brenneri, facilitating research into various aspects of nematode biology and evolutionary processes.

genomics↗

bioRxiv2024

Direct inference of the distribution of fitness effects of spontaneous mutations from recombinant inbred C. elegans mutation accumulation lines

The distribution of fitness effects (DFE) of new mutations plays a central role in evolutionary biology. Estimates of the DFE from experimental Mutation Accumulation (MA) lines are compromised by the complete linkage disequilibrium (LD) between mutations in different lines. To reduce LD, we constructed two sets of recombinant inbred lines from a cross of two C. elegans MA lines. One set of lines ("RIAILs") was intercrossed for ten generations prior to ten generations of selfing; the second set of lines ("RILs") omitted the intercrossing. Residual LD in the RIAILs is much less than in the RILs, which affects the inferred DFE when the sets of lines are analyzed separately. The best-fit model estimated from all lines (RIAILs + RILs) infers a large fraction of mutations with positive effects ([~]40%); models that constrain mutations to have negative effects fit much worse. The conclusion is the same using only the RILs. For the RIAILs, however, models that constrain mutations to have negative effects fit nearly as well as models that allow positive effects. When mutations in high LD are pooled into haplotypes, the inferred DFE becomes increasingly negative-skewed and leptokurtic. We conclude that the conventional wisdom - most mutations have effects near zero, a handful of mutations have effects that are substantially negative and mutations with positive effects are very rare - is likely correct, and that unless it can be shown otherwise, estimates of the DFE that infer a substantial fraction of mutations with positive effects are likely confounded by LD.

evolutionary biology↗

bioRxiv2022

Variation in mutational (co)variances

1Because of pleiotropy, mutations affect the expression and inheritance of multiple traits and are expected to determine the structure of standing genetic variation and phenotypic evolution. It is thus important to find if the M matrix, describing mutational (co)variances between traits, varies between genotypes. We here estimate the M matrix for six locomotion behavior traits in two genotypes of the nematode Caenorhabditis elegans. We find significant mutational variance along at least one phenotypic dimension of the M matrix, but its size and orientation was similar between genotypes. We then tested if the M matrices were similar to one G matrix describing the standing genetic (co)variances of a domesticated population derived by the hybridization of several genotypes and adapted to a lab defined environment for 140 generations. M and G are different in part because the genetic covariances caused by mutational pleiotropy in the two genotypes are smaller than those caused by standing linkage disequilibrium in the lab population. If generalized to other genotypes, these observations indicate that selection is unlikely to shape the evolution of the M matrix for locomotion behavior and suggests that the genetic restructuring due to the hybridization of C. elegans genotypes allows for selection in the lab on new phenotypic dimensions of locomotion behavior, phenotypic dimensions which are inaccessible to natural populations.

evolutionary biology↗

bioRxiv2022

Phenotypic stasis with genetic divergence

1Whether or not genetic divergence on the short-term of tens to hundreds of generations is compatible with phenotypic stasis remains a relatively unexplored problem. We evolved predominantly outcrossing, genetically diverse populations of the nematode Caenorhabditis elegans under a constant and homogeneous environment for 240 generations, and followed individual locomotion behavior. Although founders of lab populations show highly diverse locomotion behavior, during lab evolution the component traits of locomotion behavior - defined as the transition rates in activity and direction - did not show divergence from the ancestral population. In contrast, transition rates genetic (co)variance structure showed a marked divergence from the ancestral state and differentiation among replicate populations during the final 100 generations and after most adaptation had been achieved. We observe that genetic differentiation is a transient pattern during the loss of genetic variance along phenotypic dimensions under drift during the last 100 generations of lab evolution. These results suggest that short-term stasis of locomotion behavior is maintained because of stabilizing selection, while the genetic structuring of component traits is contingent upon drift history.

evolutionary biology↗

bioRxiv2021

Mutation, selection, and the prevalence of the C. elegans mortal germline phenotype

C. elegans strains with the heat-sensitive mortal germline (Mrt) phenotype become progressively sterile over the course of a few tens of generations when maintained at temperatures near the upper range of C. elegans tolerance. Mrt is transgenerationally-heritable, and proximately under epigenetic control. Previous studies have suggested that Mrt presents a relatively large mutational target, and that Mrt is not uncommon in natural populations of C. elegans. The Mrt phenotype is not monolithic. Some strains exhibit a strong Mrt phenotype, in which individuals invariably become sterile over a few generations, whereas other strains show a weaker (less penetrant) phenotype in which the onset of sterility is slower and more stochastic. We present results in which we (1) quantify the rate of mutation to the Mrt phenotype, and (2) quantify the frequency of Mrt in a collection of 95 wild isolates. Over the course of ~16,000 meioses, we detected one mutation to a strong Mrt phenotype, resulting in a point estimate of the mutation rate UMrt{approx} 6x10-5/genome/generation. We detected no mutations to a weak Mrt phenotype. 6/95 wild isolates have a strong Mrt phenotype, and although quantification of the weak Mrt phenotype is inexact, the weak Mrt phenotype is not rare in nature. We estimate a strength of selection against mutations conferring the strong Mrt phenotype [Formula], similar to selection against mutations affecting competitive fitness. The appreciable frequency of weak Mrt variants in nature combined with the low mutation rate suggests that Mrt may be maintained by balancing selection.

genetics↗

bioRxiv2021

Mutation, selection, and quantitative genetic architecture of susceptibility to bacterial pathogens in C. elegans

Understanding the evolutionary and genetic underpinnings of susceptibility to pathogens is of fundamental importance across a wide swathe of biology. Much theoretical and empirical effort has focused on genetic variants of large effect, but pathogen susceptibility often appears to be a polygenic complex trait. Here we investigate the quantitative genetics of survival over 120 hours of exposure ("susceptibility") of C. elegans to three bacterial pathogens of varying virulence, along with the standard laboratory food, the OP50 strain of E. coli. We compare the genetic (co)variance input by spontaneous mutations accumulated under minimal selection to the standing genetic (co)variance in a set of 47 wild isolates. Three conclusions emerge. First, mutations increase susceptibility to pathogens, and susceptibility is uncorrelated with fitness in the absence of pathogens. Second, the orientation in trait space of the heritable (co)variance of wild isolates is sufficiently explained by mutation. However, with the possible exception of S. aureus, pathogen susceptibility is clearly under purifying, directional, selection of magnitude roughly similar to that of competitive fitness in the MA conditions. The results provide no evidence for fitness tradeoffs between pathogen susceptibility and fitness in the absence of pathogens.

evolutionary biology↗

bioRxiv2021

Mutability of mononucleotide repeats, not oxidative stress, explains the discrepancy between laboratory-accumulated mutations and the natural allele-frequency spectrum in C. elegans

Important clues about natural selection can be gleaned from discrepancies between the properties of segregating genetic variants and of mutations accumulated experimentally under minimal selection, provided the mutational process is the same in the lab as in nature. The ratio of transitions to transversions (Ts/Tv) is consistently lower in C. elegans mutation accumulation (MA) experiments than in nature, which has been argued to be in part due to increased oxidative stress in the lab environment. Using whole-genome sequence data from a set of C. elegans MA lines carrying a mutation (mev-1) that increases the cellular titer of reactive oxygen species (ROS), leading to increased endogenous oxidative stress, we find that the base-substitution spectrum is similar between mev-1 lines, its wild-type progenitor (N2), and another set of MA lines derived from a different wild strain (PB306). By contrast, the rate of short insertions is greater in the mev-1 lines, consistent with studies in other organisms in which environmental stress led to an increase in the rate of insertion-deletion mutations. Further, the mutational properties of mononucleotide repeats in all strains are qualitatively different from those of non-mononucleotide sequence, both for indels and base-substitutions, and whereas the non-mononucleotide spectra are fairly similar between MA lines and wild isolates, the mononucleotide spectra are very different. The discrepancy in mutational spectra between lab MA experiments and natural variation is likely due to a consistent (but unknown) effect of the lab environment that manifests itself via different modes of mutability and/or repair at mononucleotide loci.

evolutionary biology↗

bioRxiv2020

The distribution of mutational effects on fitness in Caenorhabditis elegans inferred from standing genetic variation

The distribution of fitness effects for new mutations is one of the most theoretically important but difficult to estimate properties in population genetics. A crucial challenge to inferring the distribution of fitness effects (DFE) from natural genetic variation is the sensitivity of the site frequency spectrum to factors like population size change, population substructure, and non-random mating. Although inference methods aim to control for population size changes, the influence of non-random mating remains incompletely understood, despite being a common feature of many species. We report the distribution of fitness effects estimated from 326 genomes of Caenorhabditis elegans, a nematode roundworm with a high rate of self-fertilization. We evaluate the robustness of DFE inferences using simulated data that mimics the genomic structure and reproductive life history of C. elegans. Our observations demonstrate how the combined influence of self-fertilization, genome structure, and natural selection can conspire to compromise estimates of the DFE from extant polymorphisms. These factors together tend to bias inferences towards weakly deleterious mutations, making it challenging to have full confidence in the inferred DFE of new mutations as deduced from standing genetic variation in species like C. elegans. Improved methods for inferring the distribution of fitness effects are needed to appropriately handle strong linked selection and selfing. These results highlight the importance of understanding the combined effects of processes that can bias our interpretations of evolution in natural populations.

evolutionary biology↗

bioRxiv2020

Natural selection imposed by mechanical properties of a biomaterial results in novel cellular phenotypes

Mechanical properties such as substrate stiffness are a ubiquitous feature of a cells environment. Many types of animal cells exhibit canonical phenotypic plasticity when grown on substrates of differing stiffness, in vitro and in vivo. Whether such plasticity is a multivariate optimum due to hundreds of millions of years of animal evolution, or instead is a compromise between conflicting selective demands, is unknown. We addressed these questions by means of experimental evolution of populations of mouse fibroblasts propagated for ~90 cell generations on soft or stiff substrates. The ancestral cells grow twice as fast on stiff substrate as on soft substrate and exhibit the canonical phenotypic plasticity. Soft-selected lines derived from a genetically diverse ancestral population increased growth rate on soft substrate to the ancestral level on stiff substrate and evolved the same multivariate phenotype. The pattern of plasticity in the soft-selected lines was opposite of the ancestral pattern, suggesting that reverse plasticity underlies the observed rapid evolution. Conversely, growth rate and phenotypes did not change in selected lines derived from clonal cells. Overall, our results suggest that the changes were the result of genetic evolution and not phenotypic plasticity per se. Whole-transcriptome analysis revealed consistent differentiation between ancestral and soft-selected populations, and that both emergent phenotypes and gene expression tended to revert in the soft-selected lines. However, the selected populations appear to have achieved the same phenotypic outcome by means of at least two distinct transcriptional architectures related to mechano-transduction and proliferation.

evolutionary biology↗

bioRxiv2020

Short-term heritable variation cancels hundreds of generations of mutational variance for metabolic traits in Caenorhabditis elegans

Metabolic disorders have a large heritable component, and have increased over the past few generations. Genome-wide association studies of metabolic traits typically find a substantial unexplained fraction of total heritability, suggesting an important role of spontaneous mutation. An alternative explanation is that epigenetic effects contribute significantly to the heritable variation. Here we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematode Caenorhabditis elegans, including both the activity and concentration of two metabolic enzymes and the standing pools of their associated metabolites. The only prior studies on the effects of mutation on metabolic enzyme activity, in Drosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life-history traits. However, those studies were not designed to account for short-term heritable effects. We find that the short-term heritable variance for most traits is of similar magnitude as the variance among MA lines. This result suggests that the potential heritable effects of epigenetic variation in metabolic disease warrant additional scrutiny.

evolutionary biology↗

bioRxiv2019

Selection and drift determine phenotypic stasis despite genetic divergence

1Evolutionary theory suggests that phenotypic stasis is explained by natural selection and genetic drift, or by constraints imposed by mutation and recombination of standing genetic variation. We performed experimental evolution from standing genetic variation with the nematode Caenorhabditis elegans, measuring individual locomotion in outcrossing populations for 240 generations. We find that, in our constant environment, locomotion bias shows no directional divergence, due to both stabilizing and disruptive selection on specific combinations of component traits. Despite phenotypic stasis, the genetic variance-covariance structure between component traits shows clear divergence from the ancestral state and extensive differentiation among replicated populations facing the same environment. Analysis of mutation accumulation experiments and genome-sequenced recombinant inbred lines from the experimental populations indicates that the evolution of the genetic variance-covariance structure is independent of de novo mutation or major effect QTL; being instead explained by the joint action of selection and drift in generating subtle linkage disequilibrium differences between small effect QTL among replicate populations. These findings indicate that phenotypic evolution is repeatable because of selection, even if the genetic structuring of component traits within lineages is mostly contingent upon drift history.

evolutionary biology↗

bioRxiv2018

Head-to-Head Comparison of Three Methods of Quantifying Competitive Fitness in C. elegans

Organismal fitness is relevant in many contexts in biology. The most meaningful experimental measure of fitness is competitive fitness, when two or more entities (e.g., genotypes) are allowed to compete directly. In theory, competitive fitness is simple to measure: an experimental population is initiated with the different types in known proportions and allowed to evolve under experimental conditions to a predefined endpoint. In practice, there are several obstacles to obtaining robust estimates of competitive fitness in multicellular organisms, the most pervasive of which is simply the time it takes to count many individuals of different types from many replicate populations. Methods by which counting can be automated in high throughput are desirable, but for automated methods to be useful, the bias and technical variance associated with the method must be (a) known, and (b) sufficiently small relative to other sources of bias and variance to make the effort worthwhile.\n\nThe nematode Caenorhabditis elegans is an important model organism, and the fitness effects of genotype and environmental conditions are often of interest. We report a comparison of three experimental methods of quantifying competitive fitness, in which wild-type strains are competed against GFP-marked competitors under standard laboratory conditions. Population samples were split into three replicates and counted (1) \"by eye\" from a saved image, (2) from the same image using CellProfiler image analysis software, and (3) with a large particle flow cytometer (a \"worm sorter\"). From 720 replicate samples, neither the frequency of wild-type worms nor the among-sample variance differed significantly between the three methods. CellProfiler and the worm sorter provide at least a tenfold increase in sample handling speed with little (if any) bias or increase in variance.

evolutionary biology↗

bioRxiv2018

Tempo, mode, and fitness effects of mutation in Caenorhabditis elegans over 400 generations of minimal selection

The mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.\n\nDeleterious mutations are a ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups of Caenorhabditis elegans mutation accumulation (MA) lines that differ in their starting mutation loads. \"First-Order MA\" (O1MA) lines maintained under minimal selection for [~]250 generations were divided into high-fitness and low-fitness groups and sets of \"second-order MA\" (O2MA) lines derived from each O1MA line were maintained for [~]150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate ({micro}bs), but no effect of initial fitness, whereas the indel rate is greater in high-fitness O2MA lines. Overall, {micro}bs is positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 Kb GC content. However, probability of mutation is well-predicted by the three-nucleotide motif. [~]90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the \"drift barrier\" model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic.

evolutionary biology↗

bioRxiv2017

Network Architecture and Mutational Sensitivity of the C. elegans Metabolome

A fundamental issue in evolutionary systems biology is understanding the relationship between the topological architecture of a biological network, such as a metabolic network, and the evolution of the network. The rate at which an element in a metabolic network accumulates genetic variation via new mutations depends on both the size of the mutational target it presents and its robustness to mutational perturbation. Quantifying the relationship between topological properties of network elements and the mutability of those elements will facilitate understanding the variation in and evolution of networks at the level of populations and higher taxa.\n\nWe report an investigation into the relationship between two topological properties of 29 metabolites in the C. elegans metabolic network and the sensitivity of those metabolites to the cumulative effects of spontaneous mutation. The relationship between several measures of network centrality and sensitivity to mutation is weak, but point estimates of the correlation between network centrality and mutational variance are positive, with only one exception. There is a marginally significant correlation between core number and mutational heritability. There is a small but significant negative correlation between the shortest path length between a pair of metabolites and the mutational correlation between those metabolites.\n\nPositive association between the centrality of a metabolite and its mutational heritability is consistent with centrally-positioned metabolites presenting a larger mutational target than peripheral ones, and is inconsistent with centrality conferring mutational robustness, at least in toto. The weakness of the correlation between shortest path length and the mutational correlation between pairs of metabolites suggests that network locality is an important but not overwhelming factor governing mutational pleiotropy. These findings provide necessary background against which the effects of other evolutionary forces, most importantly natural selection, can be interpreted.

systems biology↗

bioRxiv2017

The mutational decay of male and hermaphrodite competitive fitness in the androdioecious nematode C. elegans, in which males are naturally rare

Androdioecious Caenorhabditis have a high frequency of self-compatible hermaphrodites and a low frequency of males. The effects of mutations on male fitness are of interest for two reasons. First, when males are rare, selection on male-specific mutations is less efficient than in hermaphrodites. Second, males may present a larger mutational target than hermaphrodites because of the different ways in which fitness accrues in the two sexes.\n\nWe report the first estimates of male-specific mutational effects in an androdioecious organism. The rate of male-specific inviable or sterile mutations is [≤] 5 x 10-4/generation, below the rate at which males would be lost solely due to those kinds of mutations. The rate of mutational decay of male competitive fitness is ~0.17%/generation; that of hermaphrodite competitive fitness is ~0.11%/generation. The point estimate of ~1.5X faster rate of mutational decay of male fitness is nearly identical to the same ratio in Drosophila. Estimates of mutational variance (VM) for male mating success and competitive fitness are not significantly different from zero, whereas VM for hermaphrodite competitive fitness is similar to that of non-competitive fitness. The discrepancy between the two sexes is probably due to the greater inherent variability of mating relative to internal self-fertilization.

evolutionary biology↗