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A conserved mammalian protein interaction network.

Pérez-Bercoff Å, Hudson CM, Conant GC - PLoS ONE (2013)

Bottom Line: 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.Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.

View Article: PubMed Central - PubMed

Affiliation: Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, Ireland.

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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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 [61]. 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.
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pone-0052581-g001: 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 [61]. 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.

Mentions: Here, we are interested in two primary questions. First, to what extent are human protein interactions evolutionarily ancient? Second, what is the nature of the selection acting on the network structure of the human protein interaction network? To explore these questions, we used previously described human PPI data and inferred orthologous genes from seven other mammals (Figure 1). We reconstruct part of the history of this network, as well as looking for evidence of correlated evolution between interaction partners. In addition to finding strong conservation among the PPIs, we find signals of weak but statistically significant co-evolution among the interacting proteins as well as confirming previous work that showed a tendency of interacting proteins to be under similar selective constraint [29].


A conserved mammalian protein interaction network.

Pérez-Bercoff Å, Hudson CM, Conant GC - PLoS ONE (2013)

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 [61]. 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.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539715&req=5

pone-0052581-g001: 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 [61]. 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.
Mentions: Here, we are interested in two primary questions. First, to what extent are human protein interactions evolutionarily ancient? Second, what is the nature of the selection acting on the network structure of the human protein interaction network? To explore these questions, we used previously described human PPI data and inferred orthologous genes from seven other mammals (Figure 1). We reconstruct part of the history of this network, as well as looking for evidence of correlated evolution between interaction partners. In addition to finding strong conservation among the PPIs, we find signals of weak but statistically significant co-evolution among the interacting proteins as well as confirming previous work that showed a tendency of interacting proteins to be under similar selective constraint [29].

Bottom Line: 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.Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.

View Article: PubMed Central - PubMed

Affiliation: Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, Ireland.

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.

Show MeSH
Related in: MedlinePlus