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

Sneha L Koneru,Michalis Barkoulas,Dimitris Katsanos,Mark Hintze

doi:10.1038/s41467-021-23567-1

Sneha L Koneru, Michalis Barkoulas + Show 2 more

Open Access

https://doi.org/10.1038/s41467-021-23567-1

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Journal: Nature Communications	Publication Date: May 31, 2021
Citations: 8	License type: open-access

Affiliation: Imperial College London

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.

Highlights

A fundamental question in medical genetics is how the genetic background modifies the phenotypic outcome of mutations
To investigate whether the genetic background can influence the phenotypic outcome of mutations affecting seam cell development, we introduced genetic perturbations targeting seam cell regulators, known from previous research in N2, into two wild isolates of C. elegans
Over the course of these experiments, we discovered that a putative null mutation in the GATA transcription factor egl-18, which acts downstream of the Wnt signalling pathway to maintain the seam cell fate[18,19], led to a milder decrease in seam cell number (SCN) in the CB4856 background compared to N2 (Fig. 1b)

Summary

Introduction

A fundamental question in medical genetics is how the genetic background modifies the phenotypic outcome of mutations. 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. Investigating how the effects of genetic mutations may vary across genetic backgrounds is important to uncover new gene functions and understand how genetic modifiers can shape phenotypic traits We study this problem using seam cell development in C. elegans as a simplified model of stem cell patterning[8]. We have recently shown that seam cell development is robust to standing genetic variation, with genetically divergent C. elegans isolates displaying a comparable seam cell number (SCN) to the lab reference strain[12]. This is called cryptic genetic variation and is a hidden source of variation that can influence many phenotypes and complex disease[13,15,16]

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