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1. CaeNDR, the Caenorhabditis Natural Diversity Resource

   https://doi.org/10.1093/nar/gkad887  

   Crombie, Timothy A.; McKeown, Ryan; Moya, Nicolas D.; Evans, Kathryn S.; Widmayer, Samuel J.; LaGrassa, Vincent; Roman, Natalie; Tursunova, Orzu; Zhang, Gaotian; Gibson, Sophia B.; et al (October 2023, Nucleic Acids Research)

   Abstract Studies of model organisms have provided important insights into how natural genetic differences shape trait variation. These discoveries are driven by the growing availability of genomes and the expansive experimental toolkits afforded to researchers using these species. For example, Caenorhabditis elegans is increasingly being used to identify and measure the effects of natural genetic variants on traits using quantitative genetics. Since 2016, the C. elegans Natural Diversity Resource (CeNDR) has facilitated many of these studies by providing an archive of wild strains, genome-wide sequence and variant data for each strain, and a genome-wide association (GWA) mapping portal for the C. elegans community. Here, we present an updated platform, the Caenorhabditis Natural Diversity Resource (CaeNDR), that enables quantitative genetics and genomics studies across the three Caenorhabditis species: C. elegans, C. briggsae and C. tropicalis. The CaeNDR platform hosts several databases that are continually updated by the addition of new strains, whole-genome sequence data and annotated variants. Additionally, CaeNDR provides new interactive tools to explore natural variation and enable GWA mappings. All CaeNDR data and tools are accessible through a freely available web portal located at caendr.org. 

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2. The impact of species-wide gene expression variation on Caenorhabditis elegans complex traits

   https://doi.org/10.1038/s41467-022-31208-4  

   Zhang, Gaotian; Roberto, Nicole M.; Lee, Daehan; Hahnel, Steffen R.; Andersen, Erik C. (June 2022, Nature Communications)

   Abstract Phenotypic variation in organism-level traits has been studied inCaenorhabditis eleganswild strains, but the impacts of differences in gene expression and the underlying regulatory mechanisms are largely unknown. Here, we use natural variation in gene expression to connect genetic variants to differences in organismal-level traits, including drug and toxicant responses. We perform transcriptomic analyses on 207 genetically distinctC. eleganswild strains to study natural regulatory variation of gene expression. Using this massive dataset, we perform genome-wide association mappings to investigate the genetic basis underlying gene expression variation and reveal complex genetic architectures. We find a large collection of hotspots enriched for expression quantitative trait loci across the genome. We further use mediation analysis to understand how gene expression variation could underlie organism-level phenotypic variation for a variety of complex traits. These results reveal the natural diversity in gene expression and possible regulatory mechanisms in this keystone model organism, highlighting the promise of using gene expression variation to understand how phenotypic diversity is generated. 

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3. An atlas of gene expression variation across the Caenorhabditis elegans species

   https://doi.org/10.1101/2022.02.06.479320  

   Zhang, Gaotian; Roberto, Nicole M.; Lee, Daehan; Hahnel, Steffen R; Andersen, Erik C. (February 2022, bioRxiv)

   Phenotypic variation in diverse organism-level traits have been studied in Caenorhabditis elegans wild strains, but differences in gene expression and the underlying variation in regulatory mechanisms are largely unknown. Here, we use natural variation in gene expression to connect genetic variants to differences in organismal- level traits, including drug and toxicant responses. We performed transcriptomic analysis on 207 genetically distinct C. elegans wild strains to study natural regulatory variation of gene expression. Using this massive dataset, we performed genome-wide association mappings to investigate the genetic basis underlying gene expression variation and revealed complex genetic architectures. We found a large collection of hotspots enriched for expression quantitative trait loci across the genome. We further used mediation analysis to understand how gene expression variation could underlie organism-level phenotypic variation for a variety of complex traits. These results reveal the natural diversity in gene expression and possible regulatory mechanisms in this keystone model organism, highlighting the promise of gene expression variation in shaping phenotypic diversity. 

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4. Transposon-mediated genic rearrangements underlie variation in small RNA pathways

   https://doi.org/10.1126/sciadv.ado9461  

   Zhang, Gaotian; Félix, Marie-Anne; Andersen, Erik C (September 2024, Science Advances)

   Transposable elements (TEs) can alter host gene structure and expression, whereas host organisms develop mechanisms to repress TE activities. In the nematodeCaenorhabditis elegans, a small interfering RNA pathway dependent on the helicase ERI-6/7 primarily silences retrotransposons and recent genes of likely viral origin. By studying gene expression variation among wildC. elegansstrains, we found that structural variants and transposon remnants likely underlie expression variation ineri-6/7and the pathway targets. We further found that multiple insertions of the DNA transposons,Polintons,reshuffled theeri-6/7locus and induced inversion oferi-6in some wild strains. In the inverted configuration, gene function was previously shown to be repaired by unusual trans-splicing mediated by direct repeats. We identified that these direct repeats originated from terminal inverted repeats ofPolintons. Our findings highlight the role of host-transposon interactions in driving rapid host genome diversification among natural populations and shed light on evolutionary novelty in genes and splicing mechanisms. 

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5. Beyond the reference: gene expression variation and transcriptional response to RNA interference in Caenorhabditis elegans

   https://doi.org/10.1093/g3journal/jkad112  

   Bell, Avery Davis; Chou, Han Ting; Valencia, Francisco; Paaby, Annalise B (May 2023, G3: Genes, Genomes, Genetics)

   Kim, J (Ed.)

   Abstract Though natural systems harbor genetic and phenotypic variation, research in model organisms is often restricted to a reference strain. Focusing on a reference strain yields a great depth of knowledge but potentially at the cost of breadth of understanding. Furthermore, tools developed in the reference context may introduce bias when applied to other strains, posing challenges to defining the scope of variation within model systems. Here, we evaluate how genetic differences among 5 wild Caenorhabditis elegans strains affect gene expression and its quantification, in general and after induction of the RNA interference (RNAi) response. Across strains, 34% of genes were differentially expressed in the control condition, including 411 genes that were not expressed at all in at least 1 strain; 49 of these were unexpressed in reference strain N2. Reference genome mapping bias caused limited concern: despite hyperdiverse hotspots throughout the genome, 92% of variably expressed genes were robust to mapping issues. The transcriptional response to RNAi was highly strain- and target-gene-specific and did not correlate with RNAi efficiency, as the 2 RNAi-insensitive strains showed more differentially expressed genes following RNAi treatment than the RNAi-sensitive reference strain. We conclude that gene expression, generally and in response to RNAi, differs across C. elegans strains such that the choice of strain may meaningfully influence scientific inferences. Finally, we introduce a resource for querying gene expression variation in this dataset at https://wildworm.biosci.gatech.edu/rnai/. 

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