Modification of Gene Duplicability during the Evolution of Protein Interaction Network

Abstract

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 microRNAs 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. Gene copy number is often tightly controlled because it directly affects the gene dosage. In several species, including yeast, worm, and fly, genes that have a single gene copy (singleton genes) encode proteins with several connections in the protein interaction network (hubs) as well as essential proteins. Surprisingly, in mouse and human essential proteins and hubs are encoded by genes with more than one copy in the genome (duplicated genes). Here we show that these two distinct groups of hubs were acquired at different times during the evolution of protein interaction network and contribute in different ways to the cell life. Singleton hubs are ancestral genes that are conserved from prokaryotes to vertebrates and accomplish basic functions that deal with the cell survival. Duplicated hubs were acquired mostly within metazoans and duplicated through vertebrate-specific whole genome duplication. These genes are involved in processes that are crucial for the organization of multicellularity. Although duplicated, also recent hubs are subject to gene dosage control through microRNAs and tissue-selective expression. The clarification of how the protein interaction network evolves enables us to understand the adaptation to the progressive increase in complexity and to better characterize the genes involved in diseases such as cancer.