The Relationship between Gene Network Structure and Expression Variation among Individuals and Species.

Karen E Sears,Kari Kosog,Richard R Behringer,Jennifer A Maier,John J Rasweiler,Marcelo Rivas-Astroza,Zoi Rapti,Chris J Cretekos,Jonathan D Marcot,Sheng Zhong,Rachel Poe,Artyom Kopp

doi:10.1371/journal.pgen.1005398

Abstract

Variation among individuals is a prerequisite of evolution by natural selection. As such, identifying the origins of variation is a fundamental goal of biology. We investigated the link between gene interactions and variation in gene expression among individuals and species using the mammalian limb as a model system. We first built interaction networks for key genes regulating early (outgrowth; E9.5–11) and late (expansion and elongation; E11-13) limb development in mouse. This resulted in an Early (ESN) and Late (LSN) Stage Network. Computational perturbations of these networks suggest that the ESN is more robust. We then quantified levels of the same key genes among mouse individuals and found that they vary less at earlier limb stages and that variation in gene expression is heritable. Finally, we quantified variation in gene expression levels among four mammals with divergent limbs (bat, opossum, mouse and pig) and found that levels vary less among species at earlier limb stages. We also found that variation in gene expression levels among individuals and species are correlated for earlier and later limb development. In conclusion, results are consistent with the robustness of the ESN buffering among-individual variation in gene expression levels early in mammalian limb development, and constraining the evolution of early limb development among mammalian species.

Highlights

Phenotypic variation within populations is a prerequisite of evolution by natural selection, and in theory has the potential to bias the trajectory and rate of evolutionary change [1,2,3,4,5,6]
Results suggest that the way in which genes interact biases the distribution of variation in gene expression among individuals, and that this in turn biases the distribution of variation among species
In this study we use the mammalian limb as a study system to investigate two questions that address the relationship between developmental processes and phenotypic variation at the level of gene expression dynamics: (1) Does the structure of the gene network affect the distribution of variation in gene expression among individuals?, and (2) Is the distribution of variation in gene expression among individuals correlated with the evolutionary divergence in gene expression among species?

Summary

Introduction

Phenotypic variation within populations is a prerequisite of evolution by natural selection, and in theory has the potential to bias the trajectory and rate of evolutionary change [1,2,3,4,5,6]. Initial budding of the limb from the body and limb outgrowth (embryonic day [E] 9.5 –E11) are regulated by interactions between several genes, including Bmp, Gli, Grem, Shh, AER-Fgf’s (e.g., Fgf, Fgf8), Fgf, and Hox genes (Fig 1A) Knockouts of these genes result in pathological phenotypes ranging from severe (e.g., complete limb agenesis; AER-Fgf’s, Fgf10) to moderate (e.g., limb truncations; Bmp4) to mild (e.g., malformed digits; Shh, Gli, Grem1) [13,14,15,16,17,18]. This structural difference provides two opportunities to investigate the relationship between network structure and gene expression variation among individuals

Methods

Results

Discussion

Conclusion