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Jordan, I. King

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Author: Koonin, Eugene V. ×

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Global similarity and local divergence in human and mouse gene co-expression networks

2006-09-12 , Tsaparas Panayiotis , Mariño-Ramírez, Leonardo , Bodenreider, Olivier , Koonin, Eugene V. , Jordan, I. King

Background: A genome-wide comparative analysis of human and mouse gene expression patterns was performed in order to evaluate the evolutionary divergence of mammalian gene expression. Tissue-specific expression profiles were analyzed for 9,105 human-mouse orthologous gene pairs across 28 tissues. Expression profiles were resolved into species-specific coexpression networks, and the topological properties of the networks were compared between species. Results: At the global level, the topological properties of the human and mouse gene coexpression networks are, essentially, identical. For instance, both networks have topologies with small-world and scale-free properties as well as closely similar average node degrees, clustering coefficients, and path lengths. However, the human and mouse coexpression networks are highly divergent at the local level: only a small fraction (<10%) of coexpressed gene pair relationships are conserved between the two species. A series of controls for experimental and biological variance show that most of this divergence does not result from experimental noise. We further show that, while the expression divergence between species is genuinely rapid, expression does not evolve free from selective (functional) constraint. Indeed, the coexpression networks analyzed here are demonstrably functionally coherent as indicated by the functional similarity of coexpressed gene pairs, and this pattern is most pronounced in the conserved human-mouse intersection network. Numerous dense network clusters show evidence of dedicated functions, such as spermatogenesis and immune response, that are clearly consistent with the coherence of the expression patterns of their constituent gene members. Conclusion: The dissonance between global versus local network divergence suggests that the interspecies similarity of the global network properties is of limited biological significance, at best, and that the biologically relevant aspects of the architectures of gene coexpression are specific and particular, rather than universal. Nevertheless, there is substantial evolutionary conservation of the local network structure which is compatible with the notion that gene coexpression networks are subject to purifying selection.

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Essential genes are more evolutionarily conserved than non-essential genes in bacteria

2002-06 , Jordan, I. King , Rogozin, Igor B. , Wolf, Yuri I. , Koonin, Eugene V.

The “knockout-rate” prediction holds that essential genes should be more evolutionarily conserved than are nonessential genes. This is because negative (purifying) selection acting on essential genes is expected to be more stringent than that for nonessential genes, which are more functionally dispensable and/or redundant. However, a recent survey of evolutionary distances between Saccharomyces cerevisiae and Caenorhabditis elegans proteins did not reveal any difference between the rates of evolution for essential and nonessential genes. An analysis of mouse and rat orthologous genes also found that essential and nonessential genes evolved at similar rates when genes thought to evolve under directional selection were excluded from the analysis. In the present study, we combine genomic sequence data with experimental knockout data to compare the rates of evolution and the levels of selection for essential versus nonessential bacterial genes. In contrast to the results obtained for eukaryotic genes, essential bacterial genes appear to be more conserved than are nonessential genes over both relatively short (microevolutionary) and longer (macroevolutionary) time scales. Rates of evolution vary tremendously among protein-coding genes. Molecular evolutionary studies have revealed an ∼1000-fold range of nonsynonymous substitution rates (Li and Graur 1991). The strength of negative (purifying) selection is thought to be the most important factor in determining the rate of evolution for the protein-coding regions of a gene (Kimura 1983; Ohta 1992; Li 1997). Consistent with this idea, Alan Wilson and colleagues (1997) proposed that essential genes should evolve more slowly than nonessential genes. This is the so-called “knockout-rate” prediction (Hurst and Smith 1999). “Essential” and “nonessential” are classic molecular genetic designations that relate to the functional significance of a gene with respect to its effect on organismic fitness. A gene is considered to be essential if a knock-out results in (conditional) lethality or infertility. On the other hand, nonessential genes are those for which knock-outs yield viable and fertile individuals. It was reasoned that purifying selection should be more intense for essential genes because they are, by definition, less functionally dispensable and/or redundant than are nonessential genes. Given the role of purifying selection in determining evolutionary rates, the greater levels of purifying selection on essential genes should be manifest as a lower rate of evolution relative to that of nonessential genes. To systematically evaluate the relationship between the fitness effects of genes and their rates of evolution, a combination of a substantial amount of experimental knock-out data and sequence data from numerous genes is required. Only recently has enough data accumulated to allow for tests of the straightforward and seemingly intuitive knock-out rate prediction. However, examinations of sequence data with respect to this prediction have yielded equivocal results. For example, a survey of substitution rates for mouse and rat orthologous genes appeared to indicate a slower rate of evolution for essential genes. But when genes thought to evolve under directional selection were excluded from the analysis, essential and nonessential genes were found to evolve at similar rates (Hurst and Smith 1999). A more recent analysis of the evolutionary distances between Saccharomyces cerevisiae and Caenorhabditis elegans proteins did indicate that the fitness effect of a protein influences its rate of evolution (Hirsh and Fraser 2001). Nevertheless, this study (Hirsh and Fraser 2001) was also unable to reveal any difference between the rates of evolution for essential and nonessential genes. The results from both of these studies were taken to indicate that the fitness differences between essential and nonessential genes do not influence evolutionary rates to the extent that was expected. However, the studies relied on the analyses of relatively few genes (n = 175 and n = 287, respectively) and comparisons between species that diverged at least tens of millions of years ago. It might be the case that these results reflect a lack of power and sensitivity of the approaches that were used. The recent availability of complete genome sequences from different strains of the same bacterial species provides an opportunity to address the issue with an unprecedented level of resolution. In the present study, to test the knockout-rate prediction, the relationship between the fitness class of genes (essential versus nonessential) and their rate of evolution was assessed for three bacterial species: Escherichia coli, Helicobacter pylori, and Neisseria meningitidis, for each of which at least two complete genome sequences are available.

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Duplicated genes evolve slower than singletons despite the initial rate increase

2004-07-06 , Jordan, I. King , Wolf, Yuri I. , Koonin, Eugene V.

Background: Gene duplication is an important mechanism that can lead to the emergence of new functions during evolution. The impact of duplication on the mode of gene evolution has been the subject of several theoretical and empirical comparative-genomic studies. It has been shown that, shortly after the duplication, genes seem to experience a considerable relaxation of purifying selection. Results: Here we demonstrate two opposite effects of gene duplication on evolutionary rates. Sequence comparisons between paralogs show that, in accord with previous observations, a substantial acceleration in the evolution of paralogs occurs after duplication, presumably due to relaxation of purifying selection. The effect of gene duplication on evolutionary rate was also assessed by sequence comparison between orthologs that have paralogs (duplicates) and those that do not (singletons). It is shown that, in eukaryotes, duplicates, on average, evolve significantly slower than singletons. Eukaryotic ortholog evolutionary rates for duplicates are also negatively correlated with the number of paralogs per gene and the strength of selection between paralogs. A tally of annotated gene functions shows that duplicates tend to be enriched for proteins with known functions, particularly those involved in signaling and related cellular processes; by contrast, singletons include an over-abundance of poorly characterized proteins. Conclusions: These results suggest that whether or not a gene duplicate is retained by selection depends critically on the pre-existing functional utility of the protein encoded by the ancestral singleton. Duplicates of genes of a higher biological import, which are subject to strong functional constraints on the sequence, are retained relatively more often. Thus, the evolutionary trajectory of duplicated genes appears to be determined by two opposing trends, namely, the post-duplication rate acceleration and the generally slow evolutionary rate owing to the high level of functional constraints.

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Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins

2001-11-20 , Jordan, I. King , Kondrashov, Fyodor A. , Rogozin, Igor B. , Tatusov, Roman L. , Wolf, Yuri I. , Koonin, Eugene V.

Background: Detection of changes in a protein’s evolutionary rate may reveal cases of change in that protein’s function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat). Results: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment. Conclusions: Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.

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No simple dependence between protein evolutionary rate and the number of protein-protein interactions: only the most prolific interactors tend to evolve slowly

2003-01-06 , Jordan, I. King , Wolf, Yuri I. , Koonin, Eugene V.

Background It has been suggested that rates of protein evolution are influenced, to a great extent, by the proportion of amino acid residues that are directly involved in protein function. In agreement with this hypothesis, recent work has shown a negative correlation between evolutionary rates and the number of protein-protein interactions. However, the extent to which the number of protein-protein interactions influences evolutionary rates remains unclear. Here, we address this question at several different levels of evolutionary relatedness. Results Manually curated data on the number of protein-protein interactions among Saccharomyces cerevisiae proteins was examined for possible correlation with evolutionary rates between S. cerevisiae and Schizosaccharomyces pombe orthologs. Only a very weak negative correlation between the number of interactions and evolutionary rate of a protein was observed. Furthermore, no relationship was found between a more general measure of the evolutionary conservation of S. cerevisiae proteins, based on the taxonomic distribution of their homologs, and the number of protein-protein interactions. However, when the proteins from yeast were assorted into discrete bins according to the number of interactions, it turned out that 6.5% of the proteins with the greatest number of interactions evolved, on average, significantly slower than the rest of the proteins. Comparisons were also performed using protein-protein interaction data obtained with high-throughput analysis of Helicobacter pylori proteins. No convincing relationship between the number of protein-protein interactions and evolutionary rates was detected, either for comparisons of orthologs from two completely sequenced H. pylori strains or for comparisons of H. pylori and Campylobacter jejuni orthologs, even when the proteins were classified into bins by the number of interactions. Conclusion The currently available comparative-genomic data do not support the hypothesis that the evolutionary rates of the majority of proteins substantially depend on the number of protein-protein interactions they are involved in. However, a small fraction of yeast proteins with the largest number of interactions (the hubs of the interaction network) tend to evolve slower than the bulk of the proteins.

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Lineage-specific gene expansions in bacterial and archaeal genomes

2001-04 , Jordan, I. King , Makarova, Kira S. , Spouge, John L. , Wolf, Yuri I. , Koonin, Eugene V.

Gene duplication is an important mechanistic antecedent to the evolution of new genes and novel biochemical functions. In an attempt to assess the contribution of gene duplication to genome evolution in archaea and bacteria, clusters of related genes that appear to have expanded subsequent to the diversification of the major prokaryotic lineages (lineage-specific expansions) were analyzed. Analysis of 21 completely sequenced prokaryotic genomes shows that lineage-specific expansions comprise a substantial fraction (∼5%–33%) of their coding capacities. A positive correlation exists between the fraction of the genes taken up by lineage-specific expansions and the total number of genes in a genome. Consistent with the notion that lineage-specific expansions are made up of relatively recently duplicated genes, >90% of the detected clusters consists of only two to four genes. The more common smaller clusters tend to include genes with higher pairwise similarity (as reflected by average score density) than larger clusters. Regardless of size, cluster members tend to be located more closely on bacterial chromosomes than expected by chance, which could reflect a history of tandem gene duplication. In addition to the small clusters, almost all genomes also contain rare large clusters of size 20. Several examples of the potential adaptive significance of these large clusters are explored. The presence or absence of clusters and their related genes was used as the basis for the construction of a similarity graph for completely sequenced prokaryotic genomes. The topology of the resulting graph seems to reflect a combined effect of common ancestry, horizontal transfer, and lineage-specific gene loss.

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