The genetic basis of natural variation in a phoretic behavior

Lee, Daehan; Yang, Heeseung; Kim, Jun; Brady, Shannon C.; Zdraljevic, Stefan; Zamanian, Mostafa; Kim, Heekyeong; Paik, Young Ki; Kruglyak, Leonid; Andersen, Erik C.; Lee, Jun-Ho

doi:10.1038/s41467-017-00386-x

Cited by 51 publications

(64 citation statements)

References 44 publications

(48 reference statements)

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“…At the end of the boom phase when the local population size is large and nutrients are limited, individual animals enter the dauer stage. Dauers exhibit a stage-specific behavior called nictation, which facilitates phoretic interactions between dauer larvae and more mobile animals to disperse to favorable environments 8,9 . Because dauer larvae are presumed to play a crucial role in the survival and dispersal of the species, it is likely that the decision to enter the dauer stage is under natural selection.…”

Section: Introductionmentioning

confidence: 99%

Selection and gene flow shape niche-associated copy-number variation of pheromone receptor genes

Lee¹,

Zdraljevic²,

Cook

et al. 2019

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From quorum sensing in bacteria to pheromone signaling in social insects, chemical communication mediates interactions among individuals in a local population. In Caenorhabditis elegans , ascaroside pheromones can dictate local population density, in which high levels of pheromones inhibit the reproductive maturation of individuals. Little is known about how genetic diversity in natural population affects the pheromone responses of individuals from diverse habitats. Here, we show that a niche-associated copy-number variation (CNV) of pheromone receptor genes contributes to natural differences in pheromone responses. We found putative loss-of-function deletions that reduce copy number of two duplicated pheromone receptor genes ( srg-36 and srg-37 ), which were shown previously to be selected in population-dense laboratory cultures. A common natural deletion in the less functional copy ( srg-37 ) arose from a single ancestral population that spread throughout the world and underlies reduced pheromone sensitivity across the global C. elegans population. This deletion is enriched in wild strains that were isolated from a rotting fruit niche, where proliferating populations are often found. Taken together, these results demonstrate that selection and gene flow together shape the copy number of pheromone receptor genes in the natural C. elegans population to facilitate local adaptation in diverse niches.

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Section: Introductionmentioning

confidence: 99%

Selection and gene flow shape niche-associated copy-number variation of pheromone receptor genes

Lee¹,

Zdraljevic²,

Cook

et al. 2019

Preprint

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“…We exposed a panel of 296 RIAILs (set 2 RIAILs, see Methods) to all eight chemotherapeutics at a selected concentration that both maximizes among-strain and minimizes within-strain phenotypic variation ( File S2 ). Linkage mapping for all three traits for each of the eight drugs (total of 24 traits) identified 56 QTL from 23 traits (one trait had no significant QTL), several of which have been identified previously (Brady et al 2019;Evans et al 2018;Zdraljevic et al 2017) ( File S3, Figure S2 ). Strikingly, a QTL on the center of chromosome V was linked to variation in responses to all eight compounds ( Figure 1 ).…”

Section: Natural Variation On Chromosome V Underlies Differences In Rmentioning

confidence: 86%

“…We measured C. elegans development and chemotherapeutic sensitivity as a function of animal length (TOF), optical density (EXT), and brood size (n) with a high-throughput assay developed using the COPAS BIOSORT (see Methods) (Zdraljevic et al 2019;Brady et al 2019;Evans et al 2018;Zdraljevic et al 2017;Andersen et al 2015) . We exposed four genetically divergent strains (N2, CB4856, JU258, and DL238) to increasing doses of eight chemotherapeutic compounds.…”

Section: Natural Variation On Chromosome V Underlies Differences In Rmentioning

confidence: 99%

“…A large panel of recombinant inbred advanced intercross lines (RIAILs) derived from two divergent strains, N2 and CB4856 (Rockman and Kruglyak 2009;Andersen et al 2015) , has been leveraged in several linkage mapping analyses (McGrath et al 2009;Lee et al 2017;Singh et al 2016;Zdraljevic et al 2019;Brady et al 2019;Zdraljevic et al 2017;Evans et al 2018;Andersen et al 2014;Viñuela et al 2010;Doroszuk et al 2009;Snoek et al 2014;Rodriguez et al 2012;Glater, Rockman, and Bargmann 2014;Rockman, Skrovanek, and Kruglyak 2010;Zamanian et al 2018a;Bendesky et al , 2012Schmid et al 2015;Balla et al 2015;Kammenga et al 2007;Gutteling, Doroszuk, et al 2007;Li et al 2006;Reddy et al 2009;Seidel et al 2011;Seidel, Rockman, and Kruglyak 2008) . Quantitative genetic analysis using these panels and a high-throughput phenotyping assay has facilitated the discovery of numerous QTL (Zamanian et al 2018b) , several quantitative trait genes (QTG) (Brady et al 2019) and quantitative trait nucleotides (QTN) (Zdraljevic et al 2019(Zdraljevic et al , 2017 underlying fitness-related traits in the nematode. Additionally, three pleiotropic genomic regions were recently found to influence responses to a diverse group of toxins (Evans et al 2018) .…”

Section: Introductionmentioning

confidence: 99%

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A single locus underlies variation inCaenorhabditis eleganschemotherapeutic responses

Evans¹,

Andersen

2020

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Pleiotropy, the concept that a single gene controls multiple distinct traits, is prevalent in most organisms and has broad implications for medicine and agriculture. Identifying the molecular mechanisms underlying pleiotropy has the power to unveil 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 . 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. : bioRxiv preprint / Here, we use linkage mapping to identify a single overlapping QTL on chromosome V that influences the responses to eight chemotherapeutic compounds. We show that these drug-response QTL also overlap with an expression QTL hotspot that contains the gene scb-1 , previously implicated in bleomycin response (Brady et al. 2019) . Although the exact mechanism of scb-1 is yet unknown, it is hypothesized to act in response to stress (Riedel et al. 2013) and has weak homology to a viral hydrolase (Zhang et al. 2018;Kelley et al. 2015) . Together, these data suggest that the importance of scb-1 expression might extend beyond bleomycin response. We validated the QTL using near-isogenic lines (NILs) and performed mediation analysis to predict that scb-1 expression explains the observed QTL for five of the eight drugs. Finally, we directly tested the effect of scb-1 loss of function on chemotherapeutic responses. We discovered that expression of scb-1 underlies differential responses to several chemotherapeutics that cause double-strand DNA breaks, not just bleomycin. This discovery of pleiotropy helps to further define the role of scb-1 by expanding its known functions and provides insights into the molecular mechanisms underlying the nematode drug response. MATERIALS AND METHODS StrainsAnimals were grown at 20°C on modified nematode growth media (NGMA) containing 1% agar and 0.7% agarose to prevent burrowing and fed OP50 (Ghosh et al. 2012) . The two parental str...

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“…The genetic variation among a panel of recombinant inbred advanced intercross lines (RIAILs) generated between the N2 and CB4856 strains of C. elegans Andersen et al 2015) has been leveraged in many linkage mapping analyses (McGrath et al 2009;Bendesky et al ! 4 2011; Lee et al 2017;Bendesky et al 2012;K. D. Singh et al 2016;Schmid et al 2015;Balla et al 2015;Zdraljevic et al 2017;Zamanian et al 2018a;Andersen et al 2014;Viñuela et al 2010;Doroszuk et al 2009;Snoek et al 2014;Rodriguez et al 2012;Kammenga et al 2007;Li et al 2006;Gutteling, Doroszuk, et al 2007;Glater, Rockman, and Bargmann 2014;Reddy et al 2009;Rockman, Skrovanek, and Kruglyak 2010;Seidel et al 2011;Seidel, Rockman, and Kruglyak 2008).…”

Section: Introductionmentioning

confidence: 99%

Common genomic regions underlie natural variation in diverse toxin responses

Brady¹,

Evans²,

Bloom

et al. 2018

Preprint

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Phenotypic complexity is caused by the contributions of environmental factors and multiple genetic loci, interacting or acting independently. Studies of yeast and Arabidopsis found that the majority of natural variation across phenotypes is attributable to independent additive quantitative trait loci (QTL). Detected loci in these organisms explain most of the estimated heritable variation. By contrast, many heritable components underlying phenotypic variation in metazoan models remain undetected. Before the relative impacts of additive and interactive variance components on metazoan phenotypic variation can be dissected, high replication and precise phenotypic measurements are required to obtain sufficient statistical power to detect loci contributing to this missing heritability.Here, we used a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to detect loci underlying responses to 16 different toxins, including heavy metals, chemotherapeutic drugs, pesticides, and neuropharmaceuticals. Using linkage mapping, we identified 82 QTL that underlie variation in responses to these toxins and predicted the relative contributions of additive loci and genetic interactions across various growth parameters. Additionally, we identified three genomic regions that impact responses to multiple classes of toxins. These QTL hotspots could represent common factors impacting toxin responses.We went further to generate near-isogenic lines and chromosome-substitution strains and then experimentally validated these QTL hotspots, implicating additive and interactive loci that underlie toxin-response variation.! 3

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The genetic basis of natural variation in a phoretic behavior

Cited by 51 publications

References 44 publications

Selection and gene flow shape niche-associated copy-number variation of pheromone receptor genes

Selection and gene flow shape niche-associated copy-number variation of pheromone receptor genes

A single locus underlies variation inCaenorhabditis eleganschemotherapeutic responses

Common genomic regions underlie natural variation in diverse toxin responses

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