The effects of protein interactions, gene essentiality and regulatory regions on expression variation

Abstract

Background: Identifying factors affecting gene expression variation is a challenging problem in genetics. Previous studies have shown that the presence of TATA box, the number of cis-regulatory elements, gene essentiality, and protein interactions significantly affect gene expression variation. Nonetheless, the need to obtain a more complete understanding of such factors and how their interactions influence gene expression variation remains a challenge. The growth rates of yeast cells under several DNA-damaging conditions have been studied and a gene's toxicity degree is defined as the number of such conditions that the growth rate of the yeast deletion strain is significantly affected. Since toxicity degree reflects a gene's importance to cell survival under DNA-damaging conditions, we expect that it is negatively associated with gene expression variation. Mutations in both cis-regulatory elements and transcription factors (TF) regulating a gene affect the gene's expression and thus we study the relationship between gene expression variation and the number of TFs regulating a gene. Most importantly we study how these factors interact with each other influencing gene expression variation.

Results: Using yeast as a model system, we evaluated the effects of four separate factors and their interactions on gene expression variation: protein interaction degree, toxicity degree, number of TFs, and the presence of TATA box. Results showed that 1) gene expression variation is negatively correlated with the protein interaction degree in the protein interaction network, 2) essential genes tend to have less expression variation than non-essential genes and gene expression variation decreases with toxicity degree, and 3) the number of TFs regulating a gene is the most important factor influencing gene expression variation (R2 = 8-14%). In addition, the number of TFs regulating a gene was found to be an important factor influencing gene expression variation for both TATA-containing and non-TATA-containing genes, but with different association strength. Moreover, gene expression variation was significantly negatively correlated with toxicity degree only for TATA-containing genes.

Conclusion: The finding that distinct mechanisms may influence gene expression variation in TATA-containing and non-TATA-containing genes, provides new insights into the mechanisms that underlie the evolution of gene expression.

Figure 1

Gene expression variation is negatively correlated with protein interaction degree. The x-axis represents protein physical interaction degree, and the y-axis represents gene expression variation. A) The LOWESS fit to the gene expression variation. B) Bar-plot of the expression variation of all the genes with a given protein interaction degree together with the linear regression fit to the gene expression variation in relation to the interaction degree. The linear coefficient β = -0.0302, R² = 1.41%, and p-value = 9.704e-14. The red dots are the mean expression variation of the genes given the protein physical interaction (PPI) degree. The bar represents the standard deviation of the gene expression variation given PPI degree. To keep the same scale for gene expression variation across the figures, the range of the y-axis is -2.5 to 0.5.

Figure 2

The effect of essentiality, toxicity degree, and protein interaction degree on gene expression variation. A) Bar-plot of the expression variation of all the genes with a given toxicity degree together with the linear regression fit to the expression variation of the genes in relation to the toxicity degree. The linear coefficient β = -0.0629, R² = 0.75%, and the p-value = 4.73e-08. B) The mean expression variation and the linear regression fit to the expression variation with respect to PPI degree for non-essential genes stratified according to toxicity degree and for the essential genes. The β values are -0.0172, -0.0230, -0.0304, -0.0164 and -0.0460 for toxicity degree 0, 1, 2, and 3, and the essential genes, respectively. The corresponding p-values are 0.0313, 0.0141, 0.0011, 0.2248 and 0.0013, respectively. R² is 0.31%, 0.75%, 2.75%, 0.8% and 4.41%, respectively. The labels are the same as those in Figure 1.

Figure 3

The effect of TATA box, number of TFs, and toxicity degree on gene expression variation. A) The relationship between expression variation and toxicity degree stratified by the presence/absence of the TATA box (R² = 2.59%, β = -0.1674, p-value = 7.174e-06 for the TATA-containing gene set; R² = 0.13%, β = -0.0234, p-value = 0.0413 for the non-TATA-containing gene set). B) The relationship between expression variation and the number of TFs up to 25 (R² = 8.28%, β = 0.0654, p-value < 2.2e-16). The labels are the same as those in Figure 1.