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1. Giant transposons promote strain heterogeneity in a major fungal pathogen

   https://doi.org/10.1128/mbio.01092-25  

   Gluck-Thaler, Emile; Forsythe, Adrian; Puerner, Charles; Gutierrez-Perez, Cecilia; Stajich, Jason E; Croll, Daniel; Cramer, Robert A; Vogan, Aaron A (June 2025, mBio)

   Goldman, Gustavo H (Ed.)

   ABSTRACT Fungal infections are difficult to prevent and treat in large part due to strain heterogeneity, which confounds diagnostic predictability. Yet, the genetic mechanisms driving strain-to-strain variation remain poorly understood. Here, we determined the extent to whichStarships—giant transposons capable of mobilizing numerous fungal genes—generate genetic and phenotypic variability in the opportunistic human pathogenAspergillus fumigatus. We analyzed 519 diverse strains, including 11 newly sequenced with long-read technology and multiple isolates of the same reference strain, to reveal 20 distinctStarshipsthat are generating genomic heterogeneity over timescales relevant for experimental reproducibility.Starship-mobilized genes encode diverse functions, including known biofilm-related virulence factors and biosynthetic gene clusters, and many are differentially expressed during infection and antifungal exposure in a strain-specific manner. These findings support a new model of fungal evolution whereinStarshipshelp generate variation in genome structure, gene content, and expression among fungal strains. Together, our results demonstrate thatStarshipsare a previously hidden mechanism generating genotypic and, in turn, phenotypic heterogeneity in a major human fungal pathogen.IMPORTANCENo “one size fits all” option exists for treating fungal infections in large part due to genetic and phenotypic variability among strains. Accounting for strain heterogeneity is thus fundamental for developing efficacious treatments and strategies for safeguarding human health. Here, we report significant progress toward achieving this goal by uncovering a previously hidden mechanism generating heterogeneity in the human fungal pathogenAspergillus fumigatus: giant transposons, calledStarships, that span dozens of kilobases and mobilize fungal genes as cargo. By conducting a systematic investigation of these unusual transposons in a single fungal species, we demonstrate their contributions to population-level variation at the genome, pangenome, and transcriptome levels. TheStarshipcompendium we develop will not only help predict variation introduced by these elements in laboratory experiments but will serve as a foundational resource for determining howStarshipsimpact clinically relevant phenotypes, such as antifungal resistance and pathogenicity. 

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2. The Gene scb-1 Underlies Variation in Caenorhabditis elegans Chemotherapeutic Responses

   https://doi.org/10.1534/g3.120.401310  

   Evans, Kathryn S.; Andersen, Erik C. (May 2020, G3: Genes|Genomes|Genetics)

   Pleiotropy, the concept that a single gene controls multiple distinct traits, is prevalent in most organisms and has broad implications for medicine and agriculture. The identification of the molecular mechanisms underlying pleiotropy has the power to reveal previously unknown biological connections between seemingly unrelated traits. Additionally, the discovery of pleiotropic genes increases our understanding of both genetic and phenotypic complexity by characterizing novel gene functions. Quantitative trait locus (QTL) mapping has been used to identify several pleiotropic regions in many organisms. However, gene knockout studies are needed to eliminate the possibility of tightly linked, non-pleiotropic loci. Here, we use a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to identify a single large-effect QTL on the center of chromosome V associated with variation in responses to eight chemotherapeutics. We validate this QTL with near-isogenic lines and pair genome-wide gene expression data with drug response traits to perform mediation analysis, leading to the identification of a pleiotropic candidate gene, scb-1 for some of the eight chemotherapeutics. Using deletion strains created by genome editing, we show that scb-1 , which was previously implicated in response to bleomycin, also underlies responses to other double-strand DNA break-inducing chemotherapeutics. This finding provides new evidence for the role of scb-1 in the nematode drug response and highlights the power of mediation analysis to identify causal genes. 

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3. Natural variation in C. elegans short tandem repeats

   https://doi.org/10.1101/gr.277067.122  

   Zhang, Gaotian; Wang, Ye; Andersen, Erik C. (October 2022, Genome Research)

   Short tandem repeats (STRs) represent an important class of genetic variation that can contribute to phenotypic differences. Although millions of single nucleotide variants (SNVs) and short indels have been identified among wild Caenorhabditis elegans strains, the natural diversity in STRs remains unknown. Here, we characterized the distribution of 31,991 STRs with motif lengths of 1–6 bp in the reference genome of C. elegans . Of these STRs, 27,667 harbored polymorphisms across 540 wild strains and only 9691 polymorphic STRs (pSTRs) had complete genotype data for more than 90% of the strains. Compared with the reference genome, the pSTRs showed more contraction than expansion. We found that STRs with different motif lengths were enriched in different genomic features, among which coding regions showed the lowest STR diversity and constrained STR mutations. STR diversity also showed similar genetic divergence and selection signatures among wild strains as in previous studies using SNVs. We further identified STR variation in two mutation accumulation line panels that were derived from two wild strains and found background-dependent and fitness-dependent STR mutations. We also performed the first genome-wide association analyses between natural variation in STRs and organismal phenotypic variation among wild C. elegans strains. Overall, our results delineate the first large-scale characterization of STR variation in wild C. elegans strains and highlight the effects of selection on STR mutations. 

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4. 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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5. 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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