Biology subjects

Bell, A. D.

Publications and source records attributed to Bell, A. D..

6 recordsLinked to original sources

bioRxiv2025

Nuclear-encoded tRNA genes harbor substantial allelic diversity in three nematode species

Cytosolic transfer RNAs, which are encoded as hundreds of genes in nuclear genomes, experience exceptionally high mutation rates and have been hypothesized to confer substantial mutational load in natural populations. Although this phenomenon appears universal across multicellular eukaryotes, a comprehensive characterization of standing variation in tRNA repertoires is still lacking in any system. Here, we resolve within-species allelic variation in nuclear-encoded tRNAs in three nematode species: Caenorhabditis elegans, C. briggsae, and C. tropicalis. We show that these genes carry signatures of high rates of historical transcription-associated mutagenesis and of purifying selection, resulting in allelic variation that includes pervasive instances of within-gene mismatches between the amino acid recognized by the tRNA backbone and that indicated by the anticodon. Furthermore, patterns of tRNA genomic organization and variation differ markedly from those of protein-coding regions. Individual genomes harbor distinct complements of tRNA genes with predicted functional differences, an observation that coincides with recent evidence that variation in tRNA expression and regulation contributes to human disease. Our findings offer an entry point for identifying the micro-evolutionary processes that act on tRNA repertoires, and in turn connecting those processes to the macro-evolutionary patterns that have more frequently been the focus of study. Significance statementTransfer RNAs (tRNAs) are ancient and essential molecules that deliver amino acids to the growing polypeptide chain during protein synthesis. Despite their importance, little is known about how the genes encoding tRNAs vary among individuals, even though they accumulate large numbers of mutations due to their high rates of expression. Here, we report that three nematode species, including the model organism C. elegans, show within-species variation in their tRNA gene repertoires, which may cause differences in protein synthesis across individuals. Our findings may represent patterns common across multicellular species and they set the stage for future investigation into how this diversity influences cellular function and organismal fitness.

genetics↗

bioRxiv2024

Stabilizing selection and adaptation shape cis and trans gene expression variation in C. elegans

An outstanding question in the evolution of gene expression is the composition of the underlying regulatory architecture and the processes that shape it. Mutations affecting a genes expression may reside locally in cis or distally in trans; the accumulation of these changes, their interactions, and their modes of inheritance influence how traits are expressed and how they evolve. Here, we interrogated gene expression variation in C. elegans, including the first allele-specific expression analysis in this system, capturing effects in cis and in trans that govern gene expression differences between the reference strain N2 and seven wild strains. We observed extensive compensatory regulation, in which opposite effects in cis and trans at individual genes mitigate expression differences among strains, and that genes with expression differences exhibit strain specificity. As the genomic distance increased between N2 and each wild strain, the number of genes with expression differences also increased. We also report for the first time that expression-variable genes are lower expressed on average than genes without expression differences, a trend that may extend to humans and Drosophila melanogaster and may reflect the selection constraints that govern the universal anticorrelation between gene expression and rate of protein evolution. Together, these and other observed trends support the conclusion that many C. elegans genes are under stabilizing selection for expression level, but we also highlight outliers that may be biologically significant. To provide community access to our data, we introduce an easily accessible, interactive web application for gene-based queries: https://wildworm.biosci.gatech.edu/ase/. Author SummaryGenes are first expressed as RNAs, which act as templates in the synthesis of proteins, the workhorse molecules of the cell. Naturally-occurring mutations can influence how RNA expression occurs; to evaluate how RNA expression varies among individuals and how such patterns evolve, the authors measured expression in wild strains of the nematode C. elegans and in offspring derived from crosses between them. This study describes the architecture of RNA expression variation in this essential model organism and reports novel patterns that may extend to insects and humans.

genetics↗

bioRxiv2023

Beyond the reference: gene expression variation and transcriptional response to RNAi in C. elegans

A universal feature of living systems is that natural variation in genotype underpins variation in phenotype. Yet, research in model organisms is often constrained to a single genetic background, the reference strain. Further, genomic studies that do evaluate wild strains typically rely on the reference strain genome for read alignment, leading to the possibility of biased inferences based on incomplete or inaccurate mapping; the extent of reference bias can be difficult to quantify. As an intermediary between genome and organismal traits, gene expression is well positioned to describe natural variability across genotypes generally and in the context of environmental responses, which can represent complex adaptive phenotypes. C. elegans sits at the forefront of investigation into small-RNA gene regulatory mechanisms, or RNA interference (RNAi), and wild strains exhibit natural variation in RNAi competency following environmental triggers. Here, we examine how genetic differences among five wild strains affect the C. elegans transcriptome in general and after inducing RNAi responses to two germline target genes. Approximately 34% of genes were differentially expressed across strains; 411 genes were not expressed at all in at least one strain despite robust expression in others, including 49 genes not expressed in reference strain N2. Despite the presence of hyper-diverse hotspots throughout the C. elegans genome, reference mapping bias was of limited concern: over 92% of variably expressed genes were robust to mapping issues. Overall, the transcriptional response to RNAi was strongly strain-specific and highly specific to the target gene, and the laboratory strain N2 was not representative of the other strains. Moreover, the transcriptional response to RNAi was not correlated with RNAi phenotypic penetrance; the two germline RNAi incompetent strains exhibited substantial differential gene expression following RNAi treatment, indicating an RNAi response despite failure to reduce expression of the target gene. We conclude that gene expression, both generally and in response to RNAi, differs across C. elegans strains such that choice of strain may meaningfully influence scientific conclusions. To provide a public, easily accessible resource for querying gene expression variation in this dataset, we introduce an interactive website at https://wildworm.biosci.gatech.edu/rnai/.

genetics↗

bioRxiv2021

Strict adherence to Mendel's First Law across a large sample of human sperm genomes

Mendels Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby "selfish" alleles are disproportionately transmitted to the next generation. Evidence of such "transmission distortion" (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data ([~]0.01 x per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.

genomics↗

bioRxiv2021

Diversification of small RNA pathways underlies germline RNAi incompetence in wild C. elegans strains

The discovery that experimental delivery of dsRNA can induce gene silencing at target genes revolutionized genetics research, by both uncovering essential biological processes and creating new tools for developmental geneticists. However, the efficacy of exogenous RNAi varies dramatically within the C. elegans population, raising questions about our understanding of RNAi in the lab relative to its activity and significance in nature. Here, we investigate why some wild-type strains fail to mount a robust RNAi response to germline targets. We observe diversity in mechanism: in some strains, the response is stochastic, either on or off among individuals, while in others the response is consistent but delayed. Increased activity of the Argonaute PPW-1, which is required for germline RNAi in the laboratory strain N2, rescues the response in some strains, but dampens it further in others. Among wild-type strains, genes known to mediate RNAi exhibited very high expression variation relative to other genes in the genome as well as allelic divergence and strain-specific instances of pseudogenization at the sequence level. Our results demonstrate functional diversification in the small RNA pathways in C. elegans, and suggest that RNAi processes are evolving rapidly and dynamically in nature.

evolutionary biology↗

bioRxiv2019

Insights about variation in meiosis from 31,228 human sperm genomes

Meiosis, while critical for reproduction, is also highly variable and error prone: crossover rates vary among humans and individual gametes, and chromosome nondisjunction leads to aneuploidy, a leading cause of miscarriage. To study variation in meiotic outcomes within and across individuals, we developed a way to sequence many individual sperm genomes at once. We used this method to sequence the genomes of 31,228 gametes from 20 sperm donors, identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic anomalies. Different sperm donors varied four-fold in the frequency of aneuploid sperm, and aneuploid chromosomes gained in meiosis I had 36% fewer crossovers than corresponding non-aneuploid chromosomes. Diverse recombination phenotypes were surprisingly coordinated: donors with high average crossover rates also made a larger fraction of their crossovers in centromere-proximal regions and placed their crossovers closer together. These same relationships were also evident in the variation among individual gametes from the same donor: sperm with more crossovers tended to have made crossovers closer together and in centromere-proximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation across chromosomes, gametes, and individuals.

genomics↗