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

Zdraljevic, Stefan; Fox, Bennett W.; Strand, Christine; Panda, Oishika; Tenjo, Francisco J.; Brady, Shannon C.; Crombie, Timothy A.; Doench, John G.; Schroeder, Frank C.; Andersen, Erik C.

doi:10.7554/elife.40260

Cited by 72 publications

(96 citation statements)

References 82 publications

(111 reference statements)

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“…We used the GWAS function in the rrBLUP package to perform genome-wide mapping with the following command: rrBLUP::GWAS (pheno = trait_file, geno = Pruned_Markers, K = KINSHIP, min.MAF = 0.05, n.core = 1, P3D = FALSE, plot = FALSE). Genomic regions associated with the bacteria responses were determined as previously defined 84 , but with +/-150 SNVs from the rightmost and leftmost markers above the Bonferroni significance threshold. The workflow for performing GWA mapping can be found on github.com/elifesciences-publications/cegwas2-nf.…”

Section: Genome-wide Association Mappings and Enrichment Analysismentioning

confidence: 99%

Balancing selection maintains hyper-divergent haplotypes inC. elegans

Lee¹,

Zdraljevic²,

Stevens³

et al. 2020

Preprint

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Summary paragraphThe mating system of a species profoundly influences its evolutionary trajectory1–3. Across diverse taxa, selfing species have evolved independently from outcrossing species thousands of times4. The transition from outcrossing to selfing significantly decreases the effective population size, effective recombination rate, and heterozygosity within a species5. These changes lead to a reduction in the genetic diversity, and therefore adaptive potential, by intensifying the effects of random genetic drift and linked selection6,7. Selfing has evolved at least three times independently in the nematode genus Caenorhabditis8, including in the model organism Caenorhabditis elegans, and all three selfing species show substantially reduced genetic diversity relative to outcrossing species8,9. Selfing and outcrossing Caenorhabditis species are often found in the same niches, but we still do not know how selfing species with limited genetic diversity can adapt to and inhabit these same diverse environments. Here, we discovered previously uncharacterized levels and patterns of genetic diversity by examining the whole-genome sequences from 609 wild C. elegans strains isolated worldwide. We found that genetic variation is concentrated in punctuated hyper-divergent regions that cover 20% of the C. elegans reference genome. These regions are enriched in environmental response genes that mediate sensory perception, pathogen response, and xenobiotic stress. Population genomic evidence suggests that these regions have been maintained by balancing selection. Using long-read genome assemblies for 15 wild isolates, we found that hyper-divergent haplotypes contain unique sets of genes and show levels of divergence comparable to that found between Caenorhabditis species that diverged millions of years ago. Taken together, these results suggest that ancient genetic diversity present in the outcrossing ancestor of C. elegans has been maintained by long-term balancing selection since the evolution of selfing. These results provide an example for how species can avoid the evolutionary “dead end” associated with selfing by maintaining ancestral genetic diversity.

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Section: Genome-wide Association Mappings and Enrichment Analysismentioning

confidence: 99%

Balancing selection maintains hyper-divergent haplotypes inC. elegans

Lee¹,

Zdraljevic²,

Stevens³

et al. 2020

Preprint

Self Cite

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“…All the wild strains were obtained from CeNDR (S3 Table) [31] and maintained at 20˚C on nematode growth medium (NGM) plates on a diet of E. coli OP50. Near-isogenic lines (NILs) were generated using a procedure described previously [43] by crossing BRC20067 and DL238. Each NIL strain harbors recombination breakpoints at different locations on chromosome V generated by crossing two single recombinant strains, followed by six times backcrossing with BRC20067 to change the other five chromosomes into the BRC20067 background.…”

Section: Strainsmentioning

confidence: 99%

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

Zdraljevic

Tanny

et al. 2020

PLoS Genet

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Mutations 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. 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. Using genome-wide association (GWA) mapping across wild strains, 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. 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 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 in models of human inborn errors in metabolism.

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“…The Developmental Trait Architecture Consists of Balanced Closely Linked QTL Trait architectures underlying natural variation in C. elegans differ strongly over traits. For example, currently 25 quantitative trait nucleotides (QTNs) are known in C. elegans, capturing a majority of the heritable variation for particular traits [reviewed by Gaertner and Phillips (2010) and Rockman (2012) and studies by Andersen et al (2014); Noble et al (2015), Schmid et al (2015); Cook et al (2016), Greene et al (2016a;2016b), Large et al (2016);Ben-David et al (2017), Sterken et al (2017); Zdraljevic et al (2017Zdraljevic et al ( , 2019, Hahnel et al (2018)]. However, there are also examples of traits that are highly heritable but have only yielded complex or few QTL (let alone QTNs).…”

Section: Introgression Lines Indicate the Presence Of Parental-balancmentioning

confidence: 99%

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

et al. 2020

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The study of expression quantitative trait loci (eQTL) using natural variation in inbred populations has yielded detailed information about the transcriptional regulation of complex traits. Studies on eQTL using recombinant inbred lines (RILs) led to insights on cis and trans regulatory loci of transcript abundance. However, determining the underlying causal polymorphic genes or variants is difficult, but ultimately essential for the understanding of regulatory networks of complex traits. This requires insight into whether associated loci are single eQTL or a combination of closely linked eQTL, and how this QTL micro-architecture depends on the environment. We addressed these questions by testing for independent replication of previously mapped eQTL in Caenorhabditis elegans using new data from introgression lines (ILs). Both populations indicate that the overall heritability of gene expression, number, and position of eQTL differed among environments. Across environments we were able to replicate 70% of the cis-and 40% of the trans-eQTL using the ILs. Testing eight different simulation models, we suggest that additive effects explain up to 60-93% of RIL/IL heritability for all three environments. Closely linked eQTL explained up to 40% of RIL/IL heritability in the control environment whereas only 7% in the heat-stress and recovery environments. In conclusion, we show that reproducibility of eQTL was higher for cis vs. trans eQTL and that the environment affects the eQTL micro-architecture.

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

Cited by 72 publications

References 82 publications

Balancing selection maintains hyper-divergent haplotypes inC. elegans

Balancing selection maintains hyper-divergent haplotypes inC. elegans

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

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

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