Cryptic genetic variation in a heat shock protein shapes the expressivity of a mutation affecting stem cell behaviour in Caenorhabditis elegans

Biological systems constantly accumulate genetic variation, which normally remains cryptic, that is without phenotypic consequences, at least in unperturbed conditions. Revealing how cryptic genetic variation shapes biological system behaviour represents key challenges in developmental and evolutionary systems biology. Here, we investigate this problem by focusing on epidermal seam cell development in C. elegans. Seam cell development has been used over the years as an experimental model to study stem cell behaviour in invertebrates. However, seam cell development has only been studied so far in a single C. elegans genetic background, the most commonly used lab reference strain N2 from Bristol, UK. Therefore, it remains unknown whether genetic variation present in wild C. elegans isolates is able to modulate seam cell development. We sought to investigate in this manuscript how identical mutations influence epidermal stem cell patterning when introduced to different genetic backgrounds of C.elegans. We report that null mutations in the GATA transcription factor EGL-18, which acts downstream of the Wnt signalling pathway as a direct POP-1TCF target, have lower expressivity leading to higher stem cell maintenance in the wild C. elegans isolate CB4856 from Hawaii when compared to N2 animals We fine map one of these genomic regions and through CRISPR-mediated genome-editing we demonstrate that natural variation in a conserved heat shock protein belonging to the Hsp70 gene superfamily contributes to the difference in mutation expressivity. These findings will be of interest to developmental biologists and evolutionary geneticists. Furthermore, our work proposes that natural variation in heat shock proteins can act as genetic modifier of the conserved Wnt signalling pathway, which has much broader implications for Wnt-dependent stem cell biology and mutation-driven stem cell disease.