EVOLUTION OF PROTEIN INTERACTION NETWORKS THROUGH GENE DUPLICATION

Recent studies on S. cerevisiae showed that essential genes, genes coding for protein complexes and network hubs are singleton, i.e. their duplications are negatively selected. These genes are intrinsically fragile toward perturbations, since dosage modifications yield to alterations in protein function, causing phenotypic aberrations that may affect the whole cell function. Unlike yeast, mammalian duplicated genes mostly encode highly connected proteins, while essentiality is not correlated with duplicability. This difference suggests that dosage-sensitive genes could duplicate at a certain point in evolution, likely favoring the progressive increase in genomic complexity. To understand when and how gene duplicability changed in evolution, we compared gene and network properties in several species from bacteria to primates. The origin and conservation of a gene significantly correlates with the properties of the encoded protein in the protein interaction network. All networks 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 hubs are frequently target 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 explain the occurrence of somatic genetic diseases, such as cancer, in terms of network perturbations. Determining the evolutionary characteristics of cancer genes and their position inside the protein interaction network helps understanding the importance of these properties in tumorigenesis.