Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways

Host genetic landscapes can shape microbiome assembly in the animal gut by contributing to the establishment of distinct physiological environments. However, the genetic determinants contributing to the stability and variation of these microbiome types remain largely undefined. Here, we use the free-living nematode Caenorhabditis elegans to identify natural genetic variation among wild strains of C. elegans strains that drives assembly of distinct microbiomes. To achieve this, we first established a diverse model microbiome that represents the phylogenetic and functional diversity naturally found in the C. elegans microbiome. Using this community, we show that C. elegans utilizes immune, xenobiotic and metabolic signaling pathways to favor the assembly of different microbiome types. Variations in these pathways were associated with the enrichment for specific commensals, including the Alphaproteobacteria Ochrobactrum. Using RNAi and mutant strains, we showed that host selection for Ochrobactrum is mediated specifically by host insulin signaling pathways. Ochrobactrum recruitment is blunted in the absence of daf-2/IGFR and requires the insulin signaling transcription factors daf-16/FOXO and pqm-1/SALL2. Further, the ability of C. elegans to enrich for Ochrobactrum is correlated positively with host outcomes, as animals that develop faster are larger and have higher gut Ochrobactrum colonization as adults. These results highlight a new role for the highly conserved insulin signaling pathways in the regulation of microbiome composition in C. elegans.

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The ancestral C. elegans cuticle suppresses rol-1

10.1101/2020.02.07.938696 ◽

2020 ◽

Author(s):

Luke M. Noble ◽

Asif Miah ◽

Taniya Kaur ◽

Matthew V. Rockman

Keyword(s):

Genetic Variation ◽

Caenorhabditis Elegans ◽

Comparative Genomics ◽

Linkage Mapping ◽

Genetic Background ◽

Gene Editing ◽

Wild Strain ◽

Collagen Gene ◽

Natural Genetic Variation ◽

C Elegans

ABSTRACTGenetic background commonly modifies the effects of mutations. We discovered that worms mutant for the canonical rol-1 gene, identified by Brenner in 1974, do not roll in the genetic background of the wild strain CB4856. Using linkage mapping, association analysis and gene editing, we determined that N2 carries an insertion in the collagen gene col-182 that acts as a recessive enhancer of rol-1 rolling. From population and comparative genomics, we infer the insertion is derived in N2 and related laboratory lines, likely arising during the domestication of Caenorhabditis elegans, and breaking a conserved protein. The ancestral version of col-182 also modifies the phenotypes of four other classical cuticle mutant alleles, and the effects of natural genetic variation on worm shape and locomotion. These results underscore the importance of genetic background and the serendipity of Brenner’s choice of strain.

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Natural variation in the roles of C. elegans autophagy components during microsporidia infection

10.1101/418749 ◽

2018 ◽

Author(s):

Keir M. Balla ◽

Vladimir Lažetić ◽

Emily Troemel

Keyword(s):

Genetic Variation ◽

Caenorhabditis Elegans ◽

Natural Variation ◽

Early Stage ◽

Laboratory Strain ◽

Host Strain ◽

Standard Laboratory ◽

Natural Genetic Variation ◽

C Elegans ◽

Natural Variant

AbstractNatural genetic variation can determine the outcome of an infection, and often reflects the co-evolutionary battle between hosts and pathogens. We previously found that a natural variant of the nematode Caenorhabditis elegans from Hawaii (HW) has increased resistance against natural microsporidian pathogens in the Nematocida genus, when compared to the standard laboratory strain of N2. In particular, HW animals can clear infection, while N2 animals cannot. In addition, HW animals have lower levels of intracellular colonization of Nematocida compared to N2. Here we investigate how this natural variation in resistance relates to autophagy. We found that there is much better targeting of autophagy-related machinery to parasites under conditions where they are cleared. In particular, ubiquitin targeting to Nematocida cells correlates very well with their subsequent clearance in terms of timing, host strain and age, as well as Nematocida species. Furthermore, clearance correlates with targeting of the LGG-2/LC3 autophagy protein to parasite cells, with HW animals having much more efficient targeting of LGG-2 to parasite cells than N2 animals. Surprisingly, however, we found that lgg-2 is not required to clear infection. Instead we found that loss of lgg-2 leads to increased intracellular colonization in the HW background, although interestingly, it does not affect colonization in the N2 background. Altogether our results suggest that there is natural genetic variation in an lgg-2-dependent process that regulates intracellular levels of microsporidia at a very early stage of infection prior to clearance.

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C. elegansharbors pervasive cryptic genetic variation for embryogenesis

10.1101/008532 ◽

2014 ◽

Author(s):

Annalise Paaby ◽

Amelia White ◽

David Riccardi ◽

Kristin Gunsalus ◽

Fabio Piano ◽

...

Keyword(s):

Genetic Variation ◽

Gene Networks ◽

Genetic Basis ◽

Disease Susceptibility ◽

Disease Risk ◽

Natural Populations ◽

Cryptic Genetic Variation ◽

Natural Genetic Variation ◽

C Elegans ◽

In The Wild

Conditionally functional mutations are an important class of natural genetic variation, yet little is known about their prevalence in natural populations or their contribution to disease risk. Here, we describe a vast reserve of cryptic genetic variation, alleles that are normally silent but which affect phenotype when the function of other genes is perturbed, in the gene networks ofC. elegansembryogenesis. We find evidence that cryptic-effect loci are ubiquitous and segregate at intermediate frequencies in the wild. The cryptic alleles demonstrate low developmental pleiotropy, in that specific, rather than general, perturbations are required to reveal them. Our findings underscore the importance of genetic background in characterizing gene function and provide a model for the expression of conditionally functional effects that may be fundamental in basic mechanisms of trait evolution and the genetic basis of disease susceptibility.

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Natural Genetic Variation and an Alternative Physiological State Modify Polyglutamine Aggregation and Toxicity in C. elegans

10.17918/sm5b-t730 ◽

2021 ◽

Author(s):

Jasmine Jancola Alexander-Floyd

Keyword(s):

Genetic Variation ◽

Physiological State ◽

Natural Genetic Variation ◽

C Elegans ◽

Polyglutamine Aggregation

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Natural variants in C. elegans atg-5 3’UTR uncover divergent effects of autophagy on polyglutamine aggregation in different tissues

10.1101/670042 ◽

2019 ◽

Author(s):

J Alexander-Floyd ◽

S Haroon ◽

M Ying ◽

AA Entezari ◽

C Jaeger ◽

...

Keyword(s):

Genetic Variation ◽

Protein Misfolding ◽

Age Of Onset ◽

Wild Strain ◽

Model Organism ◽

Muscle Cells ◽

Cell Types ◽

Natural Genetic Variation ◽

C Elegans ◽

Modifier Locus

AbstractDiseases caused by protein misfolding and aggregation, in addition to cell selectivity, often exhibit variation among individuals in the age of onset, progression, and severity of disease. Genetic variation has been shown to contribute to such clinical variation. We have previously found that protein aggregation-related phenotypes in a model organism, C. elegans, can be modified by destabilizing polymorphisms in the genetic background and by natural genetic variation. Here, we identified a large modifier locus in a Californian wild strain of C. elegans, DR1350, that alters the susceptibility of the head muscle cells to polyglutamine (polyQ) aggregation, and causes an increase in overall aggregation, without changing the basal activity of the muscle proteostasis pathways known to affect polyQ aggregation. We found that the two phenotypes were genetically separable, and identified regulatory variants in a gene encoding a conserved autophagy protein ATG-5 (ATG5 in humans) as being responsible for the overall increase in aggregation. The atg-5 gene conferred a dosage-dependent enhancement of polyQ aggregation, with DR1350-derived atg-5 allele behaving as a hypermorph. Examination of autophagy in animals bearing the modifier locus indicated enhanced response to an autophagy-activating treatment. Because autophagy is known to be required for the clearance of polyQ aggregates, this result was surprising. Thus, we tested whether directly activating autophagy, either pharmacologically or genetically, affected the polyQ aggregation in our model. Strikingly, we found that the effect of autophagy on polyQ aggregation was tissue-dependent, such that activation of autophagy decreased polyQ aggregation in the intestine, but increased it in the muscle cells. Our data show that cryptic genetic variants in genes encoding proteostasis components, although not causing visible phenotypes under normal conditions, can have profound effects on the behavior of aggregation-prone proteins, and suggest that activation of autophagy may have divergent effects on the clearance of such proteins in different cell types.

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Natural Genetic Variation in a Multigenerational Phenotype in C. Elegans

SSRN Electronic Journal ◽

10.2139/ssrn.3155658 ◽

2018 ◽

Cited By ~ 1

Author(s):

Lise Frrzal ◽

Emilie Demoinet ◽

Christian Braendle ◽

Eric Miska ◽

Marie-Anne FFlix

Keyword(s):

Genetic Variation ◽

Natural Genetic Variation ◽

C Elegans

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Population Genetics ofCaenorhabditis elegans: The Paradox of Low Polymorphism in a Widespread Species

Genetics ◽

10.1093/genetics/163.1.147 ◽

2003 ◽

Vol 163 (1) ◽

pp. 147-157 ◽

Cited By ~ 6

Author(s):

Arjun Sivasundar ◽

Jody Hey

Keyword(s):

Genetic Variation ◽

Microsatellite Loci ◽

Population Expansion ◽

Widespread Species ◽

C Elegans ◽

Model Research ◽

The World ◽

Natural Isolates ◽

History Of ◽

Low Levels

AbstractCaenorhabditis elegans has become one of the most widely used model research organisms, yet we have little information on evolutionary processes and recent evolutionary history of this widespread species. We examined patterns of variation at 20 microsatellite loci in a sample of 23 natural isolates of C. elegans from various parts of the world. One-half of the loci were monomorphic among all strains, and overall genetic variation at microsatellite loci was low, relative to most other species. Some population structure was detected, but there was no association between the genetic and geographic distances among different natural isolates. Thus, despite the nearly worldwide occurrence of C. elegans, little evidence was found for local adaptation in strains derived from different parts of the world. The low levels of genetic variation within and among populations suggest that recent colonization and population expansion might have occurred. However, the patterns of variation are not consistent with population expansion. A possible explanation for the observed patterns is the action of background selection to reduce polymorphism, coupled with ongoing gene flow among populations worldwide.

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