The Effect of Insertions and Deletions on Wirings in Protein-Protein Interaction Networks: A Large-Scale Study

School of Computing Science, Simon Fraser University, Burnaby, Canada.
Journal of computational biology: a journal of computational molecular cell biology (Impact Factor: 1.74). 03/2009; 16(2):159-67. DOI: 10.1089/cmb.2008.03TT
Source: PubMed


Although insertions and deletions (indels) are a common type of sequence variation, their origin and their functional consequences have not yet been fully understood. It has been known that indels preferably occur in the loop regions of the affected proteins. Moreover, it has recently been demonstrated that indels are significantly more strongly correlated with functional changes than substitutions. In sum, there is substantial evidence that indels, not substitutions, are the predominant evolutionary factor when it comes to structural changes in proteins. As a consequence it comes natural to hypothesize that sizable indels can modify protein interaction interfaces, causing a gain or loss of protein-protein interactions, thereby significantly rewiring the interaction networks. In this paper, we have analyzed this relationship in a large-scale study. We have computed all paralogous protein pairs in Saccharomyces cerevisiae (Yeast) and Drosophila melanogaster (Fruit Fly), and sorted the respective alignments according to whether they contained indels of significant lengths as per a pair Hidden Markov Model (HMM)-based framework of a recent study. We subsequently computed well known centrality measures for proteins that participated in indel alignments (indel proteins) and those that did not. We found that indel proteins indeed showed greater variation in terms of these measures. This demonstrates that indels have a significant influence when it comes to rewiring of the interaction networks due to evolution, which confirms our hypothesis. In general, this study may yield relevant insights into the functional interplay of proteins and the evolutionary dynamics behind it.

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    • "The differential regions within these proteins can range from single amino acid changes to the insertion or deletion (indels) of multiple amino acids (Thorne, 2000). Indels have been shown to have a greater effect on protein structure and function than single amino acid changes that result from substitutions (Hormozdiari et al., 2009; Salari et al., 2008), and can also create a unique ligand binding site on the protein surface (Studer et al., 2013). It has been shown that indels rarely affect the structural scaffold of a protein, but much more often alter peripheral elements (Studer et al., 2013), which may lead to changes in binding sites that facilitate specific ligand binding. "
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    ABSTRACT: Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite's protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented illustrating the close proximity of the indel to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. The study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns.
    No preview · Article · Jan 2016 · Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases
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    • "Indels, especially frame shifting insertions and deletions, are expected to have large effects on protein functions, since they may change the reading frame of a gene thus change amino acids and probably the functions of proteins. It has been shown that indels cause more severe functional changes in proteins than SNPs [8] and also have significant influence on protein-protein interaction interfaces [9]. As revealed by the Human Gene Mutation Database [3], approximately half (57%) of the human (gene sequence level) disease variations are associated with single nucleotide substitutions, and about a quarter (22%) are associated with small indels [3,10]. "
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    ABSTRACT: With the development of sequencing technologies, more and more sequence variants are available for investigation. Different classes of variants in the human genome have been identified, including single nucleotide substitutions, insertion and deletion, and large structural variations such as duplications and deletions. Insertion and deletion (indel) variants comprise a major proportion of human genetic variation. However, little is known about their effects on humans. The absence of understanding is largely due to the lack of both biological data and computational resources. This paper presents a new indel functional prediction method HMMvar based on HMM profiles, which capture the conservation information in sequences. The results demonstrate that a scoring strategy based on HMM profiles can achieve good performance in identifying deleterious or neutral variants for different data sets, and can predict the protein functional effects of both single and multiple mutations. This paper proposed a quantitative prediction method, HMMvar, to predict the effect of genetic variation using hidden Markov models. The HMM based pipeline program implementing the method HMMvar is freely available at
    Full-text · Article · Jan 2014 · BMC Bioinformatics
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    • "8) (Sarma et al. 2008; Muraki et al. 2010). The surface loops in protein sequences play important roles in mediating protein– protein interactions (Akiva et al. 2008; Singh and Gupta 2009; Hormozdiari et al. 2009). Hence, it is likely that the identified CSIs in the BchL, BchN, and BchB proteins are also involved in mediating protein–protein interaction that are specific and essential for different groups of phototrophs. "
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    ABSTRACT: The origin of photosynthesis and how this capability has spread to other bacterial phyla remain important unresolved questions. I describe here a number of conserved signature indels (CSIs) in key proteins involved in bacteriochlorophyll (Bchl) biosynthesis that provide important insights in these regards. The proteins BchL and BchX, which are essential for Bchl biosynthesis, are derived by gene duplication in a common ancestor of all phototrophs. More ancient gene duplication gave rise to the BchX-BchL proteins and the NifH protein of the nitrogenase complex. The sequence alignment of NifH-BchX-BchL proteins contain two CSIs that are uniquely shared by all NifH and BchX homologs, but not by any BchL homologs. These CSIs and phylogenetic analysis of NifH-BchX-BchL protein sequences strongly suggest that the BchX homologs are ancestral to BchL and that the Bchl-based anoxygenic photosynthesis originated prior to the chlorophyll (Chl)-based photosynthesis in cyanobacteria. Another CSI in the BchX-BchL sequence alignment that is uniquely shared by all BchX homologs and the BchL sequences from Heliobacteriaceae, but absent in all other BchL homologs, suggests that the BchL homologs from Heliobacteriaceae are primitive in comparison to all other photosynthetic lineages. Several other identified CSIs in the BchN homologs are commonly shared by all proteobacterial homologs and a clade consisting of the marine unicellular Cyanobacteria (Clade C). These CSIs in conjunction with the results of phylogenetic analyses and pair-wise sequence similarity on the BchL, BchN, and BchB proteins, where the homologs from Clade C Cyanobacteria and Proteobacteria exhibited close relationship, provide strong evidence that these two groups have incurred lateral gene transfers. Additionally, phylogenetic analyses and several CSIs in the BchL-N-B proteins that are uniquely shared by all Chlorobi and Chloroflexi homologs provide evidence that the genes for these proteins have also been laterally transferred between these groups. Other results and observations reported here indicate that the genes for the BchL-N-B proteins in Proteobacteria are derived from the Clade C Cyanobacteria, whereas those in Chlorobi were acquired from Chloroflexus or related bacteria by means of LGTs. Some implications of these observations regarding the origin and spread of photosynthesis are discussed.
    Full-text · Article · May 2012 · Molecular Biology and Evolution
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