Abstract

For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis.

Highlights

  • In any given genetic pathway, or even in a single gene, different mutations can have a wide range of phenotypic effects, and these effects are often modulated by the environment and alleles at other genes throughout the genome [1,2,3,4,5,6,7]

  • Identifying how the genomic and environmental context alter the expression of mutations is critical for making reliable inferences about how genes function. Studies on this context dependence have largely been limited to single mutations in single genes

  • Given our knowledge of context dependence for one allele, can we predict the degree of background dependence for other alleles in that gene or among genes with related functions [9]? Or are the background effects so complex and multifaceted that this remains an impossible task? can variation in the phenotypic consequences of multiple alleles, and variable expression of a single allele in different contexts, be explained by similar developmental underpinnings?

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Summary

Introduction

In any given genetic pathway, or even in a single gene, different mutations (whether they are natural variants or lab-induced lesions) can have a wide range of phenotypic effects, and these effects are often modulated by the environment and alleles at other genes throughout the genome (the genetic background) [1,2,3,4,5,6,7]. Investigations of allelic complementation patterns led to discoveries of mechanisms for gene regulation such as pairing-dependence (transvection; [11,12,13]), position effects [14], and dominant negative interactions [15]

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