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

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

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

<div><p>Abstract</p><p>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.</p></div

Effects of removals of gene-to-gene interactions in simulations on gene expression level.

<p>Asterisks indicate values that differ more than 10% from values generated by the unaltered model. The total number of values that differ more than 10% are shown in the last column and row. In total, 14 of 77 (18%) possible expression levels are affected by alterations in the ESN, while 52 of 84 (62%) possible expression levels are affected by alterations in the LSN.</p

Variation in gene expression levels within a population of mice and among mammalian species are positively correlated during the Early (ES; A) and Late (LS; B) stages of limb development.

<p><i>Shh</i> also displays the most variation in gene expression levels within and among species in both the ES and LS.</p

Interactions among genes in the (A) Early (ESN) and (B) Late (LSN) stage networks that were computationally modeled in this study are shown.

<p>Networks were based on Bénazet et al. (2009) and Sheth et al. (2013). Note that some aspects of the ESN and LSN differ.</p

Overall patterns of gene expression are positively correlated among all examined mammals during the Early (ES; A) and Late (LS; B) stages of limb development.

<p>Opos. = opossum. (C) The Mean Spearman correlation of gene expression patterns between species is higher for the Early (ES) than Late (LS) stage of limb development. This difference is significant (<i>P</i> < 0.05) when more than 90% of orthologous genes are sampled (indicated by asterisks). Whiskers represent the 95% confidence intervals for the data.</p

Relationships between among individual variation in gene expression (Y-axes) and gene sensitivity to network perturbation (X-axes; A and B) and ability to impact the network when perturbed (X-axes; C and D) are shown for the early (ES; A and C) and late (LS; B and D) stages of limb development.

<p>The scale for the Y-axis is the same for all plots, and the scale along the X-axis is the same for A and B, and for C and D. Variance in gene expression level tends to be lower for ES than LS genes. Variance in gene expression level is also more strongly correlated with gene sensitivity in ES genes, and gene impact in LS genes. Overall, the relationship between variance in gene expression and gene sensitivity tends to be more positive, and the relationship between variance in gene expression and gene impact more negative.</p