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. 2013;8(1):e52581.
doi: 10.1371/journal.pone.0052581. Epub 2013 Jan 2.

A conserved mammalian protein interaction network

Åsa Pérez-Bercoff  1 , Corey M Hudson, Gavin C Conant
Affiliations

A conserved mammalian protein interaction network

Åsa Pérez-Bercoff et al. PLoS One. 2013.

Abstract

Physical interactions between proteins mediate a variety of biological functions, including signal transduction, physical structuring of the cell and regulation. While extensive catalogs of such interactions are known from model organisms, their evolutionary histories are difficult to study given the lack of interaction data from phylogenetic outgroups. Using phylogenomic approaches, we infer a upper bound on the time of origin for a large set of human protein-protein interactions, showing that most such interactions appear relatively ancient, dating no later than the radiation of placental mammals. By analyzing paired alignments of orthologous and putatively interacting protein-coding genes from eight mammals, we find evidence for weak but significant co-evolution, as measured by relative selective constraint, between pairs of genes with interacting proteins. However, we find no strong evidence for shared instances of directional selection within an interacting pair. Finally, we use a network approach to show that the distribution of selective constraint across the protein interaction network is non-random, with a clear tendency for interacting proteins to share similar selective constraints. Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. PPI presence and absence at the different nodes in the rooted eutherian phylogenetic tree. A)
At each node, we have shown the predicted percentage of human PPIs present at that node (necessarily 100% at the human tip). The percentages at the other seven tip nodes were inferred by the presence or absence of the orthologs of the two human proteins making up the PPI (Methods). We then inferred the states of the internal nodes under the assumption that a given PPI ortholog pair could appear only once in the phylogeny (Methods). The topology was visualized using FigTree . Branch lengths are the mean Ks value (e.g., number of synonymous substitutions per synonymous site) found across the genes surveyed for that branch of the tree (See Methods). The five colored branches indicate potential origin points for a PPI under our limited parsimony model (Methods), while the two gray branches were used to estimate the rate of PPI loss. The dashed branches indicate the fact the Ks values could not be distinguished for these two branches because the models used produce unrooted trees. B) There is an association between the age of the branch along which a PPI appears (x-axis; estimated via Ks above) and the average interaction degree of the proteins that make up that interaction (y-axis). Note that the blue distance was estimated as one-half the Ks distance between the rodent-primate and horse-dog-cow clade in the unrooted topology of (A). See Methods for details.
Figure 2
Figure 2. Differences between primate-specific and phylogenetically-distributed interactions. A)
Gene sets used in the GO analyses of primate-specific protein interactions. There are 8876 human genes having at least one interaction (for a total of 32,916 PPIs). Among those genes, 1502 interactions (encoded by 1675 genes) are found only in primates. Of those 1675 genes, 1,521 are also involved in other, nonprimate-specific interactions, and 154 are only involved in primate specific interactions. B) Genes involved in primate-specific interactions have, on average, more total interactions (i.e., the genes involved in these interactions tend to have a higher degree k). The distribution of the difference in degree (k) for each gene in a pair of interaction proteins was compared (here referred to as ‘absolute degree difference’, Δk; x-axis). In black are the primate-specific interactions (primatePPIs) while red (dashed-line) shows the remainder of the interactions.
Figure 3
Figure 3. Paired cases of relaxed selective constraints for PPI pairs.
For each clade in Figure 1, we plot the number of cases where both members have either ρ>1.0 (A) or >0.5 (B). P-values are shown for the test of the hypothesis that there are more such shared cases of relaxed constraint than would be expected by chance (χ2 test, Methods). Cases where no P-value is shown had too few observations of ρ>5 for valid statistical conclusions to be drawn.
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