Experimental evidence that network topology can accelerate the spread of beneficial mutations
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PROVIDER: S-EPMC10693003 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:BackgroundGain-of-function mutations in SCN9A gene that encodes the voltage-gated sodium channel NaV1.7 have been associated with a wide spectrum of painful syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1.7.ResultsWe used homology modeling to build an atomic model of NaV1.7 and a network-based theoretical approach, which can predict interatomic interactions and connectivity arrangements, to investigate how pain-related NaV1.7 mutations may alter specific interatomic bonds and cause connectivity rearrangement, compared to benign variants and polymorphisms. For each amino acid substitution, we calculated the topological parameters betweenness centrality (B ct ), degree (D), clustering coefficient (CC ct ), closeness (C ct ), and eccentricity (E ct ), and calculated their variation (Δ value = mutant value -WT value ). Pathogenic NaV1.7 mutations showed significantly higher variation of |ΔB ct | compared to benign variants and polymorphisms. Using the cut-off value ±0.26 calculated by receiver operating curve analysis, we found that ΔB ct correctly differentiated pathogenic NaV1.7 mutations from variants not causing biophysical abnormalities (nABN) and homologous SNPs (hSNPs) with 76% sensitivity and 83% specificity.ConclusionsOur in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |ΔB ct | value as a potential in-silico marker.
| S-EPMC5324268 | biostudies-literature
Project description:Biological soil crusts (biocrusts) are communities of microbes that inhabit the surface of arid soils and provide essential services to dryland ecosystems. While resistant to extreme environmental conditions, biocrusts are susceptible to anthropogenic disturbances that can deprive ecosystems of these valuable services for decades. Until recently, culture-based efforts to produce inoculum for cyanobacterial biocrust restoration in the southwestern United States focused on producing and inoculating the most abundant primary producers and biocrust pioneers, Microcoleus vaginatus and members of the family Coleofasciculaceae (also called Microcoleus steenstrupii complex). The discovery that a unique microbial community characterized by diazotrophs, known as the cyanosphere, is intimately associated with M. vaginatus suggests a symbiotic division of labor in which nutrients are traded between phototrophs and heterotrophs. To probe the potential use of such cyanosphere members in the restoration of biocrusts, we performed coinoculations of soil substrates with cyanosphere constituents. This resulted in cyanobacterial growth that was more rapid than that seen for inoculations with the cyanobacterium alone. Additionally, we found that the mere addition of beneficial heterotrophs enhanced the formation of a cohesive biocrust without the need for additional phototrophic biomass within native soils that contain trace amounts of biocrust cyanobacteria. Our findings support the hitherto-unknown role of beneficial heterotrophic bacteria in the establishment and growth of biocrusts and allow us to make recommendations concerning biocrust restoration efforts based on the presence of remnant biocrust communities in disturbed areas. Future biocrust restoration efforts should consider cyanobacteria and their beneficial heterotrophic community as inoculants. IMPORTANCE The advancement of biocrust restoration methods for cyanobacterial biocrusts has been largely achieved through trial and error. Successes and failures could not always be traced back to particular factors. The investigation and application of foundational microbial interactions existing within biocrust communities constitute a crucial step toward informed and repeatable biocrust restoration methods.
| S-EPMC8478466 | biostudies-literature
Project description:Amphibians are the most threatened vertebrates today, experiencing worldwide declines. In recent years considerable effort was invested in exposing the causes of these declines. Climate change has been identified as such a cause; however, the expectable effects of predicted milder, shorter winters on hibernation success of temperate-zone Amphibians have remained controversial, mainly due to a lack of controlled experimental studies. Here we present a laboratory experiment, testing the effects of simulated climate change on hibernating juvenile common toads (Bufo bufo). We simulated hibernation conditions by exposing toadlets to current (1.5 °C) or elevated (4.5 °C) hibernation temperatures in combination with current (91 days) or shortened (61 days) hibernation length. We found that a shorter winter and milder hibernation temperature increased survival of toads during hibernation. Furthermore, the increase in temperature and shortening of the cold period had a synergistic positive effect on body mass change during hibernation. Consequently, while climate change may pose severe challenges for amphibians of the temperate zone during their activity period, the negative effects may be dampened by shorter and milder winters experienced during hibernation.
| S-EPMC4882615 | biostudies-literature
Project description:BackgroundThe maintenance of sexuality is a classic problem in evolutionary biology because it is a less efficient mode of reproduction compared with asexuality; however, many organisms are sexual. Theoretical work suggests sex facilitates natural selection, and experimental data support this. However, there are fewer experimental studies that have attempted to determine the mechanisms underlying the advantage of sex. Two main classes of hypotheses have been proposed to explain its advantage: detrimental mutation clearance and beneficial mutation accumulation. Here we attempt to experimentally differentiate between these two classes by evolving Saccharomyces cerevisiae populations that differ only in their ability to undergo sex, and also manipulate mutation rate. We cannot manipulate the types of mutation that occur, but instead propagate populations in both stressful and permissive environments and assume that the extent of detrimental mutation clearance and beneficial mutation incorporation differs between them.ResultsAfter 300 mitotic generations interspersed with 11 rounds of sex we found there was no change or difference in fitness between sexuals and asexuals propagated in the permissive environment, regardless of mutation rate. Sex conferred a greater extent of adaptation in the stressful environment, and wild-type and elevated mutation rate sexual populations adapted equivalently. However, the asexual populations with an elevated mutation rate appeared more retarded in their extent of adaptation compared to asexual wild-type populations.ConclusionsSex provided no advantage in the permissive environment where beneficial mutations were rare. We could not evaluate if sex functioned to clear detrimental mutations more effectively or not here as no additional fitness load was observed in the mutator populations. However, in the stressful environment, where detrimental mutations were likely of more consequence, and where beneficial mutations were apparent, sex provided an advantage. In the stressful environment asexuals were increasingly constrained in their extent of adaptation with increasing mutation rate. Sex appeared to facilitate adaptation not just by more rapidly combining beneficial mutations, but also by unlinking beneficial from detrimental mutations: sex allowed selection to operate on both types of mutations more effectively compared to asexual populations.
| S-EPMC3342131 | biostudies-literature
Project description:Biological invasions are a major threat to biological diversity, agriculture, and human health. To predict and prevent new invasions, it is crucial to develop a better understanding of the drivers of the invasion process. The analysis of 4,533 border interception events revealed that at least 51 different alien ant species were intercepted at US ports over a period of 70 years (1914-1984), and 45 alien species were intercepted entering New Zealand over a period of 68 years (1955-2013). Most of the interceptions did not originate from species' native ranges but instead came from invaded areas. In the United States, 75.7% of the interceptions came from a country where the intercepted ant species had been previously introduced. In New Zealand, this value was even higher, at 87.8%. There was an overrepresentation of interceptions from nearby locations (Latin America for species intercepted in the United States and Oceania for species intercepted in New Zealand). The probability of a species' successful establishment in both the United States and New Zealand was positively related to the number of interceptions of the species in these countries. Moreover, species that have spread to more continents are also more likely to be intercepted and to make secondary introductions. This creates a positive feedback loop between the introduction and establishment stages of the invasion process, in which initial establishments promote secondary introductions. Overall, these results reveal that secondary introductions act as a critical driver of increasing global rates of invasions.
| S-EPMC6003495 | biostudies-literature
Project description:The conventional approach to investigating functional connectivity in the block-designed study usually concatenates task blocks or employs residuals of task activation. While providing many insights into brain functions, the block design adds more manipulation in functional network analysis that may reduce the purity of the blood oxygenation level-dependent signal. Recent studies utilized one single long run for task trials of the same condition, the so-called continuous design, to investigate functional connectivity based on task functional magnetic resonance imaging. Continuous brain activities associated with the single-task condition can be directly utilized for task-related functional connectivity assessment, which has been examined for working memory, sensory, motor, and semantic task experiments in previous research. But it remains unclear how the block and continuous design influence the assessment of task-related functional connectivity networks. This study aimed to disentangle the separable effects of block/continuous design and working memory load on task-related functional connectivity networks, by using repeated-measures analysis of variance. Across 50 young healthy adults, behavioral results of accuracy and reaction time showed a significant main effect of design as well as interaction between design and load. Imaging results revealed that the cingulo-opercular, fronto-parietal, and default model networks were associated with not only task activation, but significant main effects of design and load as well as their interaction on intra- and inter-network functional connectivity and global network topology. Moreover, a significant behavior-brain association was identified for the continuous design. This work has extended the evidence that continuous design can be used to study task-related functional connectivity and subtle brain-behavioral relationships.
| S-EPMC10073362 | biostudies-literature
Project description:BACKGROUND:Refinement of candidate gene lists to select the most promising candidates for further experimental verification remains an essential step between high-throughput exploratory analysis and the discovery of specific causal genes. Given the qualitative and semantic complexity of biological data, successfully addressing this challenge requires development of flexible and interoperable solutions for making the best possible use of the largest possible fraction of all available data. RESULTS:We have developed an easily accessible framework that links two established network-based gene prioritization approaches with a supporting isolation forest-based integrative ranking method. The defining feature of the method is that both topological information of the biological networks and additional sources of evidence can be considered at the same time. The implementation was realized as an app extension for the Cytoscape graph analysis suite, and therefore can further benefit from the synergy with other analysis methods available as part of this system. CONCLUSIONS:We provide efficient reference implementations of two popular gene prioritization algorithms - DIAMOnD and random walk with restart for the Cytoscape system. An extension of those methods was also developed that allows outputs of these algorithms to be combined with additional data. To demonstrate the utility of our software, we present two example disease gene prioritization application cases and show how our tool can be used to evaluate these different approaches.
| S-EPMC5501438 | biostudies-literature
Project description:A mutation's degree of pleiotropy (i.e., the number of traits it alters) is predicted to impact the probability of the mutation being detrimental to fitness. For mutations that impact gene expression, mutations acting in cis have been hypothesized to generally be less pleiotropic than mutations affecting the same gene's expression in trans, suggesting that cis-regulatory mutations should be less deleterious and more likely to fix over evolutionary time. Here, we use expression and fitness data from Saccharomyces cerevisiae gene deletion strains to test these hypotheses. By treating deletion of each gene as a cis-regulatory mutation affecting its own expression and deletions of other genes affecting expression of this focal gene as trans-regulatory mutations, we find that cis-acting mutations do indeed tend to be less pleiotropic than trans-acting mutations affecting expression of the same gene. This pattern was observed for the vast majority of genes in the data set and could be explained by the topology of the regulatory network controlling gene expression. Comparing the fitness of cis- and trans-acting mutations affecting expression of the same gene also confirmed that trans-acting deletions tend to be more deleterious. These findings provide strong support for pleiotropy playing a role in the preferential fixation of cis-regulatory alleles over evolutionary time.
| S-EPMC9791367 | biostudies-literature
Project description:The incidence of Alzheimer's disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.
| S-EPMC6594764 | biostudies-literature
Project description:Accurate estimation of parameters of biochemical models is required to characterize the dynamics of molecular processes. This problem is intimately linked to identifying the most informative experiments for accomplishing such tasks. While significant progress has been made, effective experimental strategies for parameter identification and for distinguishing among alternative network topologies remain unclear. We approached these questions in an unbiased manner using a unique community-based approach in the context of the DREAM initiative (Dialogue for Reverse Engineering Assessment of Methods). We created an in silico test framework under which participants could probe a network with hidden parameters by requesting a range of experimental assays; results of these experiments were simulated according to a model of network dynamics only partially revealed to participants.We proposed two challenges; in the first, participants were given the topology and underlying biochemical structure of a 9-gene regulatory network and were asked to determine its parameter values. In the second challenge, participants were given an incomplete topology with 11 genes and asked to find three missing links in the model. In both challenges, a budget was provided to buy experimental data generated in silico with the model and mimicking the features of different common experimental techniques, such as microarrays and fluorescence microscopy. Data could be bought at any stage, allowing participants to implement an iterative loop of experiments and computation.A total of 19 teams participated in this competition. The results suggest that the combination of state-of-the-art parameter estimation and a varied set of experimental methods using a few datasets, mostly fluorescence imaging data, can accurately determine parameters of biochemical models of gene regulation. However, the task is considerably more difficult if the gene network topology is not completely defined, as in challenge 2. Importantly, we found that aggregating independent parameter predictions and network topology across submissions creates a solution that can be better than the one from the best-performing submission.
| S-EPMC3927870 | biostudies-literature