Positive selection at the protein network periphery: Evaluation in terms of structural constraints and cellular context

Abstract

Because of recent advances in genotyping and sequencing, human genetic variation and adaptive evolution in the primate lineage have become major research foci. Here, we examine the relationship between genetic signatures of adaptive evolution and network topology. We find a striking tendency of proteins that have been under positive selection (as compared with the chimpanzee) to be located at the periphery of the interaction network. Our results are based on the analysis of two types of genome evolution, both in terms of intra-and interspecies variation. First, we looked at single-nucleotide polymorphisms and their fixed variants, single-nucleotide differences in the human genome relative to the chimpanzee. Second, we examine fixed structural variants, specifically large segmental duplications and their polymorphic precursors known as copy number variants. We propose two complementary mechanisms that lead to the observed trends. First, we can rationalize them in terms of constraints imposed by protein structure: We find that positively selected sites are preferentially located on the exposed surface of proteins. Because central network proteins (hubs) are likely to have a larger fraction of their surface involved in interactions, they tend to be constrained and under negative selection. Conversely, we show that the interaction network roughly maps to cellular organization, with the periphery of the network corresponding to the cellular periphery (i.e., extracellular space or cell membrane). This suggests that the observed positive selection at the network periphery may be due to an increase of adaptive events on the cellular periphery responding to changing environments.protein structure ͉ network centrality ͉ single-nucleotide change ͉ copy number variant ͉ structural variant W ith the advent of genomic sequence data and, more recently, large-scale genetic variation data (1, 2), it has become possible to examine genes or genomic regions for signs of recent evolutionary adaptation in our genome, characterized as signatures of positive selection (3, 4). Typically, tests for positive selection predict adaptation by testing and rejecting the hypothesis of neutral mutation (5) or variation for a given genomic region.Despite considerable advances in the field of genetics, the actual molecular relationship of recent evolutionary events with biophysical properties of associated proteins such as structural characteristics and network connectivity (i.e., protein interactions) has as yet not been studied in detail. Understanding the extent of recent mutations, polymorphisms, and adaptation beyond their effect on the gene level is crucial because most complex cellular processes only come about through the interplay and interactions of many different proteins. On the other hand, although recent proteomic surveys have suggested that proteins with many interaction partners are subject to considerable structural constraints, the connection with human genome variation has not yet been considered. Thus, by combining knowledge fr...

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