Contribution of trans regulatory eQTL to cryptic genetic variation in C. elegans

AbstractA fundamental question in medical genetics is how the genetic background modifies the phenotypic outcome of key mutations. We address this question by focusing on the epidermal seam cells, which display stem cell properties in Caenorhabditis elegans. We demonstrate that a null mutation in the GATA transcription factor egl-18, which is involved in seam cell fate maintenance, is more tolerated and thus has lower expressivity in the divergent CB4856 isolate from Hawaii than the lab reference strain N2 from Bristol. We identify multiple quantitative trait loci (QTLs) underlying the difference in mutation expressivity between the two isolates. These QTLs reveal cryptic genetic variation, which acts to reinforce seam cell fate through potentiating Wnt signalling. Within one QTL region, a single amino acid deletion in the heat shock protein HSP-110 in CB4856 lowers egl-18 mutation expressivity. Our work underscores that natural variation in conserved heat shock proteins can shape mutation expressivity.

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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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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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Cryptic genetic variation in a heat shock protein modifies the outcome of a mutation affecting epidermal stem cell development in C. elegans

Nature Communications ◽

10.1038/s41467-021-23567-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sneha L. Koneru ◽

Mark Hintze ◽

Dimitris Katsanos ◽

Michalis Barkoulas

Keyword(s):

Genetic Variation ◽

Stem Cell ◽

Heat Shock ◽

Heat Shock Protein ◽

Cell Fate ◽

Cell Development ◽

Wnt Signalling ◽

Single Amino Acid ◽

Cryptic Genetic Variation ◽

Seam Cell

AbstractA fundamental question in medical genetics is how the genetic background modifies the phenotypic outcome of mutations. We address this question by focusing on the seam cells, which display stem cell properties in the epidermis of Caenorhabditis elegans. We demonstrate that a putative null mutation in the GATA transcription factor egl-18, which is involved in seam cell fate maintenance, is more tolerated in the CB4856 isolate from Hawaii than the lab reference strain N2 from Bristol. We identify multiple quantitative trait loci (QTLs) underlying the difference in phenotype expressivity between the two isolates. These QTLs reveal cryptic genetic variation that reinforces seam cell fate through potentiating Wnt signalling. Within one QTL region, a single amino acid deletion in the heat shock protein HSP-110 in CB4856 is sufficient to modify Wnt signalling and seam cell development, highlighting that natural variation in conserved heat shock proteins can shape phenotype expressivity.

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The distribution of mutational effects on fitness in Caenorhabditis elegans inferred from standing genetic variation

10.1101/2020.10.26.355446 ◽

2020 ◽

Author(s):

Kimberly J. Gilbert ◽

Stefan Zdraljevic ◽

Daniel E. Cook ◽

Asher D. Cutter ◽

Erik C. Andersen ◽

...

Keyword(s):

Genetic Variation ◽

Caenorhabditis Elegans ◽

Population Size ◽

Genomic Structure ◽

Random Mating ◽

Population Substructure ◽

C Elegans ◽

Fitness Effects ◽

Self Fertilization ◽

New Mutations

ABSTRACTThe distribution of fitness effects for new mutations is one of the most theoretically important but difficult to estimate properties in population genetics. A crucial challenge to inferring the distribution of fitness effects (DFE) from natural genetic variation is the sensitivity of the site frequency spectrum to factors like population size change, population substructure, and non-random mating. Although inference methods aim to control for population size changes, the influence of non-random mating remains incompletely understood, despite being a common feature of many species. We report the distribution of fitness effects estimated from 326 genomes of Caenorhabditis elegans, a nematode roundworm with a high rate of self-fertilization. We evaluate the robustness of DFE inferences using simulated data that mimics the genomic structure and reproductive life history of C. elegans. Our observations demonstrate how the combined influence of self-fertilization, genome structure, and natural selection can conspire to compromise estimates of the DFE from extant polymorphisms. These factors together tend to bias inferences towards weakly deleterious mutations, making it challenging to have full confidence in the inferred DFE of new mutations as deduced from standing genetic variation in species like C. elegans. Improved methods for inferring the distribution of fitness effects are needed to appropriately handle strong linked selection and selfing. These results highlight the importance of understanding the combined effects of processes that can bias our interpretations of evolution in natural populations.

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