Modification of Gene Duplicability during the Evolution of Protein Interaction Network

D’Antonio M, Ciccarelli FD, Modification of Gene Duplicability during the Evolution of Protein Interaction Network, PLoS Comput Biol 7(4), 2011, doi:10.1371/journal.pcbi.1002029

Duplications of genes encoding highly connected and essential proteins are selected against in several species but not in human, where duplicated genes encode highly connected proteins. To understand when and how gene duplicability changed in evolution, we compare gene and network properties in four species (Escherichia coli, yeast , fly, and human) that are representative of the increase in evolutionary complexity, defined as progressive growth in the number of genes, cells, and cell types. We find that the origin and conservation of a gene significantly correlates with the properties of the encoded protein in the protein-protein interaction network. All four species preserve a core of singleton and central hubs that originated early in evolution, are highly conserved, and accomplish basic biological functions. Another group of hubs appeared in metazoans and duplicated in vertebrates, mostly through vertebrate-specific whole genome duplication. Such recent and duplicated hubs are frequently targets of microRNA and show tissue-selective expression, suggesting that these are alternative mechanisms to control their dosage. Our study shows how networks modified during evolution and contributes to explaining the occurrence of somatic genetic diseases, such as cancer, in terms of network perturbations.

These are three different ways of controlling gene dosage. The duplication of the entire genome maintains the dosage balance between inter-actors and allows the duplication of dosage-sensitive genes in yeast and in vertebrates. Similarly, miRNAs play a pervasive role in the post-transcriptional regulation of gene expression in higher eukaryotes, particularly in those biological processes that require a fine-tuned control of the gene dosage, such as signal transduction. Finally, tissue selectivity represents yet another mechanism of gene dosage control because paralogs expressed in different tissues do not interfere with each other.

There are several indications that, despite being robust towards gene duplication, recent hubs remain sensitive to gene dosage modifications. First, human duplicated hubs rapidly underwent alternative ways to control their dosage, for example through tissue-selective expression and miRNA regulation. Second, ohnologs do not undergo further small-scale duplications and copy number variations. Finally, genes that carry disease-related germ line mutations are depicted in hubs and somatic mutations of hubs are often associated with cancer.

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