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Evolutionary conservation and network structure characterize genes of phenotypic relevance for mitosis in human.

ABSTRACT: The impact of gene silencing on cellular phenotypes is difficult to establish due to the complexity of interactions in the associated biological processes and pathways. A recent genome-wide RNA knock-down study both identified and phenotypically characterized a set of important genes for the cell cycle in HeLa cells. Here, we combine a molecular interaction network analysis, based on physical and functional protein interactions, in conjunction with evolutionary information, to elucidate the common biological and topological properties of these key genes. Our results show that these genes tend to be conserved with their corresponding protein interactions across several species and are key constituents of the evolutionary conserved molecular interaction network. Moreover, a group of bistable network motifs is found to be conserved within this network, which are likely to influence the network stability and therefore the robustness of cellular functioning. They form a cluster, which displays functional homogeneity and is significantly enriched in genes phenotypically relevant for mitosis. Additional results reveal a relationship between specific cellular processes and the phenotypic outcomes induced by gene silencing. This study introduces new ideas regarding the relationship between genotype and phenotype in the context of the cell cycle. We show that the analysis of molecular interaction networks can result in the identification of genes relevant to cellular processes, which is a promising avenue for future research.

SUBMITTER: Ostaszewski M

PROVIDER: S-EPMC3342260 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Evolutionary conservation in genes underlying human psychiatric disorders.

Project description:Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained.

| S-EPMC4018557 | biostudies-literature

Using genomics to characterize evolutionary potential for conservation of wild populations.

Project description:Genomics promises exciting advances towards the important conservation goal of maximizing evolutionary potential, notwithstanding associated challenges. Here, we explore some of the complexity of adaptation genetics and discuss the strengths and limitations of genomics as a tool for characterizing evolutionary potential in the context of conservation management. Many traits are polygenic and can be strongly influenced by minor differences in regulatory networks and by epigenetic variation not visible in DNA sequence. Much of this critical complexity is difficult to detect using methods commonly used to identify adaptive variation, and this needs appropriate consideration when planning genomic screens, and when basing management decisions on genomic data. When the genomic basis of adaptation and future threats are well understood, it may be appropriate to focus management on particular adaptive traits. For more typical conservations scenarios, we argue that screening genome-wide variation should be a sensible approach that may provide a generalized measure of evolutionary potential that accounts for the contributions of small-effect loci and cryptic variation and is robust to uncertainty about future change and required adaptive response(s). The best conservation outcomes should be achieved when genomic estimates of evolutionary potential are used within an adaptive management framework.

| S-EPMC4231592 | biostudies-literature

Evolutionary conservation of RecA genes in relation to protein structure and function.

Project description:Functional and structural regions inferred from the Escherichia coli R ecA protein crystal structure and mutation studies are evaluated in terms of evolutionary conservation across 63 RecA eubacterial sequences. Two paramount segments invariant in specific amino acids correspond to the ATP-binding A site and the functionally unassigned segment from residues 145 to 149 immediately carboxyl to the ATP hydrolysis B site. Not only are residues 145 to 149 conserved individually, but also all three-dimensional structural neighbors of these residues are invariant, strongly attesting to the functional or structural importance of this segment. The conservation of charged residues at the monomer-monomer interface, emphasizing basic residues on one surface and acidic residues on the other, suggests that RecA monomer polymerization is substantially mediated by electrostatic interactions. Different patterns of conservation also allow determination of regions proposed to interact with DNA, of LexA binding sites, and of filament-filament contact regions. Amino acid conservation is also compared with activities and properties of certain RecA protein mutants. Arginine 243 and its strongly cationic structural environment are proposed as the major site of competition for DNA and LexA binding to RecA. The conserved acidic and glycine residues of the disordered loop L1 and its proximity to the RecA acidic monomer interface suggest its involvement in monomer-monomer interactions rather than DNA binding. The conservation of various RecA positions and regions suggests a model for RecA-double-stranded DNA interaction and other functional and structural assignments.

| S-EPMC177882 | biostudies-other

Deep evolutionary conservation of autism-related genes

Project description:E.O. Wilson proposed in Sociobiology that similarities between human and animal societies reflect common mechanistic and evolutionary roots. When introduced in 1975 this controversial hypothesis was beyond science’s ability to test and remains unproven. We used genomic analyses to determine whether superficial behavioral similarities in humans and the highly social honey bee reflect common molecular mechanisms. Here we report that gene expression signatures for individual bees unresponsive to various salient social stimuli are significantly enriched for autism spectrum disorder-related genes. These signatures occur in the mushroom bodies, a high-level integration center of the insect brain. Further, our finding of enrichment was unique to autism spectrum disorders; brain gene expression signatures from other honey bee behaviors do not show this enrichment, nor do data sets from other human behavioral and health conditions. These results demonstrate deep conservation for genes associated with a human social pathology and individual differences in insect social behavior, thus providing an example of how comparative genomics can be used to test sociobiological theory.

2017-06-21 | GSE87001 | GEO

Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs.

Project description:Positional cloning has already produced the sequences of more than 70 human genes associated with specific diseases. In addition to their medical importance, these genes are of interest as a set of human genes isolated solely on the basis of the phenotypic effect of the respective mutations. We analyzed the protein sequences encoded by the positionally cloned disease genes using an iterative strategy combining several sensitive computer methods. Comparisons to complete sequence databases and to separate databases of nematode, yeast, and bacterial proteins showed that for most of the disease gene products, statistically significant sequence similarities are detectable in each of the model organisms. Only the nematode genome encodes apparent orthologs with conserved domain architecture for the majority of the disease genes. In yeast and bacterial homologs, domain organization is typically not conserved, and sequence similarity is limited to individual domains. Generally, human genes complement mutations only in orthologous yeast genes. Most of the positionally cloned genes encode large proteins with several globular and nonglobular domains, the functions of some or all of which are not known. We detected conserved domains and motifs not described previously in a number of proteins encoded by disease genes and predicted functions for some of them. These predictions include an ATP-binding domain in the product of hereditary nonpolyposis colon cancer gene (a MutL homolog), which is conserved in the HS90 family of chaperone proteins, type II DNA topoisomerases, and histidine kinases, and a nuclease domain homologous to bacterial RNase D and the 3'-5' exonuclease domain of DNA polymerase I in the Werner syndrome gene product.

| S-EPMC20866 | biostudies-literature

Evolutionary conservation of RNA sequence and structure.

Project description:An RNA structure prediction from a single-sequence RNA folding program is not evidence for an RNA whose structure is important for function. Random sequences have plausible and complex predicted structures not easily distinguishable from those of structural RNAs. How to tell when an RNA has a conserved structure is a question that requires looking at the evolutionary signature left by the conserved RNA. This question is important not just for long noncoding RNAs which usually lack an identified function, but also for RNA binding protein motifs which can be single stranded RNAs or structures. Here we review recent advances using sequence and structural analysis to determine when RNA structure is conserved or not. Although covariation measures assess structural RNA conservation, one must distinguish covariation due to RNA structure from covariation due to independent phylogenetic substitutions. We review a statistical test to measure false positives expected under the null hypothesis of phylogenetic covariation alone (specificity). We also review a complementary test that measures power, that is, expected covariation derived from sequence variation alone (sensitivity). Power in the absence of covariation signals the absence of a conserved RNA structure. We analyze artifacts that falsely identify conserved RNA structure such as the misuse of programs that do not assess significance, the use of inappropriate statistics confounded by signals other than covariation, or misalignments that induce spurious covariation. Among artifacts that obscure the signal of a conserved RNA structure, we discuss the inclusion of pseudogenes in alignments which increase power but destroy covariation. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Evolution and Genomics > Computational Analyses of RNA RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.

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Deep evolutionary conservation of autism-related genes.

Project description:E. O. Wilson proposed in Sociobiology that similarities between human and animal societies reflect common mechanistic and evolutionary roots. When introduced in 1975, this controversial hypothesis was beyond science's ability to test. We used genomic analyses to determine whether superficial behavioral similarities in humans and the highly social honey bee reflect common molecular mechanisms. Here, we report that gene expression signatures for individual bees unresponsive to various salient social stimuli are significantly enriched for autism spectrum disorder-related genes. These signatures occur in the mushroom bodies, a high-level integration center of the insect brain. Furthermore, our finding of enrichment was unique to autism spectrum disorders; brain gene expression signatures from other honey bee behaviors do not show this enrichment, nor do datasets from other human behavioral and health conditions. These results demonstrate deep conservation for genes associated with a human social pathology and individual differences in insect social behavior, thus providing an example of how comparative genomics can be used to test sociobiological theory.

| S-EPMC5594688 | biostudies-literature

Limited Evolutionary Conservation of the Phenotypic Effects of Antibiotic Resistance Mutations.

Project description:Multidrug-resistant clinical isolates are common in certain pathogens, but rare in others. This pattern may be due to the fact that mutations shaping resistance have species-specific effects. To investigate this issue, we transferred a range of resistance-conferring mutations and a full resistance gene into Escherichia coli and closely related bacteria. We found that resistance mutations in one bacterial species frequently provide no resistance, in fact even yielding drug hypersensitivity in close relatives. In depth analysis of a key gene involved in aminoglycoside resistance (trkH) indicated that preexisting mutations in other genes-intergenic epistasis-underlie such extreme differences in mutational effects between species. Finally, reconstruction of adaptive landscapes under multiple antibiotic stresses revealed that mutations frequently provide multidrug resistance or elevated drug susceptibility (i.e., collateral sensitivity) only with certain combinations of other resistance mutations. We conclude that resistance and collateral sensitivity are contingent upon the genetic makeup of the bacterial population, and such contingency could shape the long-term fate of resistant bacteria. These results underlie the importance of species-specific treatment strategies.

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Trade-offs predicted by metabolic network structure give rise to evolutionary specialization and phenotypic diversification.

Project description:Mitigating trade-offs between different resource-utilization functions is key to an organism's ecological and evolutionary success. These trade-offs often reflect metabolic constraints with a complex molecular underpinning; therefore, their consequences for evolutionary processes have remained elusive. Here, we investigate how metabolic architecture induces resource utilization constraints and how these constraints, in turn, elicit evolutionary specialization and diversification. Guided by the metabolic network structure of the bacterium Lactococcus cremoris, we selected two carbon sources (fructose and galactose) with predicted co-utilization constraints. By evolving L. cremoris on either fructose, galactose or a mix of both sugars, we imposed selection favoring divergent metabolic specializations or co-utilization of both resources, respectively. Phenotypic characterization revealed the evolution of either fructose or galactose specialists in the single-sugar treatments. In the mixed sugar regime, we observed adaptive diversification: both specialists coexisted, and no generalist evolved. Divergence from the ancestral phenotype occurred at key pathway junctions in the central carbon metabolism. Fructose specialists evolved mutations in the fbp and pfk genes that appear to balance anabolic and catabolic carbon fluxes. Galactose specialists evolved increased expression of pgmA (the primary metabolic bottleneck of galactose metabolism) and silencing of ptnABCD (the main glucose transporter) and ldh (regulator/enzyme of downstream carbon metabolism). Overall, our study shows how metabolic network architecture and historical contingency serve to predict targets of selection and inform the functional interpretation of evolved mutations. The elucidation of the relationship between molecular constraints and phenotypic trade-offs contributes to an integrative understanding of evolutionary specialization and diversification.

| S-EPMC9206417 | biostudies-literature

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

Project description:The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

| S-EPMC3477654 | biostudies-literature

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