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

Abstract

A 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.

Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis

“…Thus, the [psi−]/[ PSI+ ] system serves as an evolutionary capacitor: the [psi−] state canalizes the favorable [psi−] phenotypes in the absence of stress, when no adaptation is needed, while the [ PSI+ ] state is switched on in challenging environments, when adaptation is needed, and then generates novel protein variants that result from stop-codon readthrough ( True and Lindquist 2000 ; Lancaster et al 2010 ; Zabinsky et al 2019 ). Chaperones such as the yeast Hsp90, GroEL in Escherichia coli , and Hsp-110 in Caenorhabditis elegans may have similar functions as evolutionary capacitators, canalizing favorable phenotypes during benign conditions by chaperoning mutated peptides into a standard protein fold, while allowing the expression of these mutations as new protein variants during stress ( Rutherford and Lindquist 1998 ; Tokuriki and Tawfik 2009 ; Jarosz and Lindquist 2010 ; Koneru et al 2021 ).…”

Higher-order epistasis shapes natural variation in germ stem cell niche activity

“…Although experimentally difficult to characterize, molecular and quantitative genetic analyses also suggest the presence of widespread epistatic interactions when measuring developmental phenotypes (e.g. Barkoulas et al, 2013;Chandler et al, 2017;Duveau and Félix, 2012;Gibson and Hogness, 1996;Huang et al, 2012;Koneru et al, 2021;Paaby et al, 2015;Steiner et al, 2007;Vanhaeren et al, 2014;Vonesch et al, 2016). So far, however, there is no information on how specific interactions between natural alleles cause quantitative variation in animal stem cell systems.…”

“…Strong polygenicity and epistasis have been observed for most quantitative phenotypes across distant taxa [3][4][5][6][7][8] but detailed mechanistic dissection of complex epistatic interactions, including higher-order epistasis where three or more loci interact, remains rare [9][10][11][12][13][14][15] . Although experimentally difficult to characterize, molecular and quantitative genetic analyses also suggest that widespread epistatic interactions underlie developmental phenotypes 15,16,19,21,23,25,27,29,31,96 . Yet, so far, there is no information on how interactions among natural alleles cause quantitative variation in animal stem cell systems.…”

Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis

“…The chaperone GroEL in E. coli and HSP-110 in C. elegans may canalise and de-canalise genetic variation in much the same way (Koneru et al, 2021;Tokuriki & Tawfik, 2009).…”

“…This unmasking of beneficial protein variants enhances evolvability, while exposing deleterious protein variants facilitates purging of deleterious mutations from the population (Jarosz & Lindquist, 2010). The chaperone GroEL in E. coli and HSP-110 in C. elegans may canalise and de-canalise genetic variation in much the same way (Koneru et al, 2021; Tokuriki & Tawfik, 2009).…”