Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model

ABSTRACTMutations in human metabolic genes can lead to rare diseases known as inborn errors of human metabolism. For instance, patients with loss-of-function mutations in either subunit of propionyl-CoA carboxylase suffer from propionic acidemia because they cannot catabolize propionate, leading to its harmful accumulation. Interestingly, both the penetrance and expressivity of metabolic disorders can be modulated by genetic background. However, modifiers of these diseases are difficult to identify because of the lack of statistical power for rare diseases in human genetics. Here, we use a model of propionic acidemia in the nematode Caenorhabditis elegans to identify genetic modifiers of propionate sensitivity. By genome-wide association mapping across wild strains exposed to excess propionate we identify several genomic regions correlated with reduced propionate sensitivity. We find that natural variation in the putative glucuronosyltransferase GLCT-3, a homolog of human B3GAT, partly explains differences in propionate sensitivity in one of these genomic intervals. Using genome-editing, we demonstrate that loss-of-function alleles in glct-3 render the animals less sensitive to propionate. Additionally, we find that C. elegans has an expansion of the glct gene family, suggesting that the number of members of this family could influence sensitivity to excess propionate. Our findings demonstrate that natural variation in metabolic genes that are not directly associated with propionate breakdown can modulate propionate sensitivity. Our study provides a framework for using C. elegans to characterize the contributions of genetic background to inborn errors in human metabolism.

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Faculty Opinions recommendation of Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14195956.15708056 ◽

2012 ◽

Author(s):

Mark Hahn

Keyword(s):

Chloride Channel ◽

Natural Variation ◽

C Elegans

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Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

10.1101/2021.01.05.425329 ◽

2021 ◽

Author(s):

Janneke Wit ◽

Steffen R. Hahnel ◽

Briana C. Rodriguez ◽

Erik Andersen

Keyword(s):

Caenorhabditis Elegans ◽

Mode Of Action ◽

Natural Variation ◽

Treatment Strategies ◽

Parasitic Nematodes ◽

Anthelmintic Drug ◽

C Elegans ◽

Hormetic Effect ◽

Filarial Nematodes

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some variation in emodepside responses can be explained by natural differences in slo-1. This result suggests that other genes in addition to slo-1 underlie emodepside resistance in wild C. elegans strains. Additionally, all assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies. We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across parasitic nematodes.

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Author response: Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism

10.7554/elife.40260.081 ◽

2019 ◽

Author(s):

Stefan Zdraljevic ◽

Bennett William Fox ◽

Christine Strand ◽

Oishika Panda ◽

Francisco J Tenjo ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Natural Variation ◽

Acid Metabolism ◽

Author Response ◽

Arsenic Toxicity ◽

C Elegans ◽

Branched Chain Amino Acid ◽

Branched Chain

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Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans

Science ◽

10.1126/science.1214318 ◽

2012 ◽

Vol 335 (6068) ◽

pp. 574-578 ◽

Cited By ~ 104

Author(s):

R. Ghosh ◽

E. C. Andersen ◽

J. A. Shapiro ◽

J. P. Gerke ◽

L. Kruglyak

Keyword(s):

Chloride Channel ◽

Natural Variation ◽

C Elegans

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Natural Variation in plep-1 Causes Male-Male Copulatory Behavior in C. elegans

Current Biology ◽

10.1016/j.cub.2015.09.019 ◽

2015 ◽

Vol 25 (20) ◽

pp. 2730-2737 ◽

Cited By ~ 25

Author(s):

Luke M. Noble ◽

Audrey S. Chang ◽

Daniel McNelis ◽

Max Kramer ◽

Mimi Yen ◽

...

Keyword(s):

Natural Variation ◽

Copulatory Behavior ◽

C Elegans ◽

Male Copulatory Behavior

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Evolution of sperm competition: Natural variation and genetic determinants of Caenorhabditis elegans sperm size

10.1101/501486 ◽

2018 ◽

Cited By ~ 1

Author(s):

Clotilde Gimond ◽

Anne Vielle ◽

Nuno Silva-Soares ◽

Stefan Zdraljevic ◽

Patrick T. McGrath ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Sperm Competition ◽

Natural Variation ◽

Competitive Ability ◽

Molecular Mechanisms ◽

Genetic Determinants ◽

Heritable Variation ◽

C Elegans ◽

Male Sperm ◽

Sperm Size

ABSTRACTSperm morphology is critical for sperm competition and thus for reproductive fitness. In the male-hermaphrodite nematode Caenorhabditis elegans, sperm size is a key feature of sperm competitive ability. Yet despite extensive research, the molecular mechanisms regulating C. elegans sperm size and the genetic basis underlying its natural variation remain unknown. Examining 97 genetically distinct C. elegans strains, we observe significant heritable variation in male sperm size but genome-wide association mapping did not yield any QTL (Quantitative Trait Loci). While we confirm larger male sperm to consistently outcompete smaller hermaphrodite sperm, we find natural variation in male sperm size to poorly predict male fertility and competitive ability. In addition, although hermaphrodite sperm size also shows significant natural variation, male and hermaphrodite sperm size do not correlate, implying a sex-specific genetic regulation of sperm size. To elucidate the molecular basis of intraspecific sperm size variation, we focused on recently diverged laboratory strains, which evolved extreme sperm size differences. Using mutants and quantitative complementation tests, we demonstrate that variation in the gene nurf-1 – previously shown to underlie the evolution of improved hermaphrodite reproduction – also explains the evolution of reduced male sperm size. This result illustrates how adaptive changes in C. elegans hermaphrodite function can cause the deterioration of a male-specific fitness trait due to a sexually antagonistic variant, representing an example of intralocus sexual conflict with resolution at the molecular level. Our results further provide first insights into the genetic determinants of C. elegans sperm size, pointing at an involvement of the NURF chromatin remodelling complex.

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Signaling by AWC Olfactory Neurons Is Necessary for Caenorhabditis elegans’ Response to Prenol, an Odor Associated with Nematode-Infected Insects

Genetics ◽

10.1534/genetics.120.303280 ◽

2020 ◽

Vol 216 (1) ◽

pp. 145-157

Author(s):

Tiffany Baiocchi ◽

Kyle Anesko ◽

Nathan Mercado ◽

Heenam Park ◽

Kassandra Kin ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Behavioral Ecology ◽

Natural Variation ◽

Isoamyl Alcohol ◽

Life Cycles ◽

C Elegans ◽

Link Type ◽

Genome Wide ◽

Ecological Differences

Chemosensation plays a role in the behaviors and life cycles of numerous organisms, including nematodes. Many guilds of nematodes exist, ranging from the free-living Caenorhabditis elegans to various parasitic species such as entomopathogenic nematodes (EPNs), which are parasites of insects. Despite ecological differences, previous research has shown that both EPNs and C. elegans respond to prenol (3-methyl-2-buten-1-ol), an odor associated with EPN infections. However, it is unclear how C. elegans responds to prenol. By utilizing natural variation and genetic neuron ablation to investigate the response of C. elegans to prenol, we found that the AWC neurons are involved in the detection of prenol and that several genes (including dcap-1, dcap-2, and clec-39) influence response to this odorant. Furthermore, we identified that the response to prenol is mediated by the canonically proposed pathway required for other AWC-sensed attractants. However, upon testing genetically diverse isolates, we found that the response of some strains to prenol differed from their response to isoamyl alcohol, suggesting that the pathways mediating response to these two odorants may be genetically distinct. Further, evaluations leveraging natural variation and genome wide association revealed specific genes that influence nematode behavior and provide a foundation for future studies to better understand the role of prenol in nematode behavioral ecology.

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