Genetic divergence and the genetic architecture of complex traits in chromosome substitution strains of mice

Sabrina H Spiezio,Joseph H Nadeau,Toshihiko Shiroishi,Toyoyuki Takada

doi:10.1186/1471-2156-13-38

Abstract

BackgroundThe genetic architecture of complex traits strongly influences the consequences of inherited mutations, genetic engineering, environmental and genetic perturbations, and natural and artificial selection. But because most studies are under-powered, the picture of complex traits is often incomplete. Chromosome substitution strains (CSSs) are a unique paradigm for these genome surveys because they enable statistically independent, powerful tests for the phenotypic effects of each chromosome on a uniform inbred genetic background. A previous CSS survey in mice and rats revealed many complex trait genes (QTLs), large phenotypic effects, extensive epistasis, as well as systems properties such as strongly directional phenotypic changes and genetically-determined limits on the range of phenotypic variation. However, the unusually close genetic relation between the CSS progenitor strains in that study raised questions about the impact of genetic divergence: would greater divergence between progenitor strains, with the corresponding changes in gene regulation and protein function, lead to significantly more distinctive phenotypic features, or alternatively would epistasis and systems constraints, which are pervasive in CSSs, limit the range of phenotypic variation regardless of the extent of DNA sequence variation?ResultsWe analyzed results for an extensive survey of traits in two new panels of CSSs where the donor strains were derived from inbred strains with more distant origins and discovered a strong similarity in genetic and systems properties among the three CSS panels, regardless of divergence time.ConclusionOur results argue that DNA sequence differences between host and donor strains did not substantially affect the architecture of complex traits, and suggest instead that strong epistasis buffered the phenotypic effects of genetic divergence, thereby constraining the range of phenotypic variation.

Highlights

The genetic architecture of complex traits strongly influences the consequences of inherited mutations, genetic engineering, environmental and genetic perturbations, and natural and artificial selection
Because differences in sample sizes and statistical power varied among traits and panels, we examined the frequency distribution of phenotypic effects to test whether significant biases were found among the three Chromosome substitution strains (CSSs) panels, but the distributions were similar suggesting that sample size variation did not substantially affect results (Additional file 1: Figure 1)
To test for epistasis, we examined the cumulative signed phenotypic effect and the corresponding standard error of the mean (SEM) for each of these 22 traits

Summary

Introduction

The genetic architecture of complex traits strongly influences the consequences of inherited mutations, genetic engineering, environmental and genetic perturbations, and natural and artificial selection. The phenotypic consequences of inherited mutations and genetic engineering as well as resilience to systems perturbations and response to natural and artificial selection depend heavily on the genetic architecture of complex traits [1]. This architecture includes features such as the number of genes, the nature of DNA sequence differences, the effects of dominance, the extent of epistasis, and the range of pleiotropic actions [2]. Additional mammalian CSS panels have subsequently been made for mice [12] and rats [13] Their genetic constitution is highly unusual, CSSs have many unique attributes for gene discovery, functional studies, and systems analysis [14,15,16]. By controlling the phenotypic noise of background genetic variation, CSSs have considerable power to identify QTLs and to characterize other genetic features such as epistasis and systems properties such as phenotypic buffering (so-called ‘ceiling and floor’ effects) that are often lost in the background noise of segregating populations [17,18,19,20,21,22,23]

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Results

Conclusion