Network analysis of functional genomics data: application to avian sex-biased gene expression

Abstract

Gene expression analysis is often used to investigate the molecular and functional underpinnings of a phenotype. However, differential expression of individual genes is limited in that it does not consider how the genes interact with each other in networks. To address this shortcoming we propose a number of network-based analyses that give additional functional insights into the studied process. These were applied to a dataset of sex-specific gene expression in the chicken gonad and brain at different developmental stages. We first constructed a global chicken interaction network. Combining the network with the expression data showed that most sex-biased genes tend to have lower network connectivity, that is, act within local network environments, although some interesting exceptions were found. Genes of the same sex bias were generally more strongly connected with each other than expected. We further studied the fates of duplicated sex-biased genes and found that there is a significant trend to keep the same pattern of sex bias after duplication. We also identified sex-biased modules in the network, which reveal pathways or complexes involved in sex-specific processes. Altogether, this work integrates evolutionary genomics with systems biology in a novel way, offering new insights into the modular nature of sex-biased genes.

Figure 1

Network of crosstalk, that is, enrichment or depletion of links, between sex-biased and unbiased genes. Positive crosstalk (i.e., enrichment of links) is shown in red and depletion in green. Solid lines indicate significant crosstalk with FDR < 0.05. Edge width and label show the z-score of the crosstalk analysis.

Figure 2

Example of sex-differentiation-driven subfunctionalization. The chicken genes GSTA2 and GSTA3 (glutathione S-transferases 2 and 3; shown as diamonds) originate from a duplication that happened after the divergence from human, making them inparalogs. GSTA2 is male biased, but GSTA3 is female biased in the adult gonad. Their interaction partners in the chicken network are shown with sex bias. Male-biased genes are shown in blue, female-biased in red, unbiased in green, and unknown in grey.

Figure 3

Example of sex bias switching between developmental stages. Shown is an MGclus cluster colored according to sex bias in the embryonic (a) and adult (b) gonads. Male-biased genes are shown in blue, female-biased in red, and unbiased in green.