Nature of epigenetic aging from a single-cell perspective.

Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.

Global coordination level in single-cell transcriptomic data.

Genes are linked by underlying regulatory mechanisms and by jointly implementing biological functions, working in coordination to apply different tasks in the cells. Assessing the coordination level between genes from single-cell transcriptomic data, without a priori knowledge of the map of gene regulatory interactions, is a challenge. A 'top-down' approach has recently been developed to analyze single-cell transcriptomic data by evaluating the global coordination level between genes (called GCL). Here, we systematically analyze the performance of the GCL in typical scenarios of single-cell RNA sequencing (scRNA-seq) data. We show that an individual anomalous cell can have a disproportionate effect on the GCL calculated over a cohort of cells. In addition, we demonstrate how the GCL is affected by the presence of clusters, which are very common in scRNA-seq data. Finally, we analyze the effect of the sampling size of the Jackknife procedure on the GCL statistics. The manuscript is accompanied by a description of a custom-built Python package for calculating the GCL. These results provide practical guidelines for properly pre-processing and applying the GCL measure in transcriptional data.

Connectivity of EEG synchronization networks increases for Parkinson's disease patients with freezing of gait.

Freezing of gait (FoG), a paroxysmal gait disturbance commonly experienced by patients with Parkinson's disease (PD), is characterized by sudden episodes of inability to generate effective forward stepping. Recent studies have shown an increase in beta frequency of local-field potentials in the basal-ganglia during FoG, however, comprehensive research on the synchronization between different brain locations and frequency bands in PD patients is scarce. Here, by developing tools based on network science and non-linear dynamics, we analyze synchronization networks of electroencephalography (EEG) brain waves of three PD patient groups with different FoG severity. We find higher EEG amplitude synchronization (stronger network links) between different brain locations as PD and FoG severity increase. These results are consistent across frequency bands (theta, alpha, beta, gamma) and independent of the specific motor task (walking, still standing, hand tapping) suggesting that an increase in severity of PD and FoG is associated with stronger EEG networks over a broad range of brain frequencies. This observation of a direct relationship of PD/FoG severity with overall EEG synchronization together with our proposed EEG synchronization network approach may be used for evaluating FoG propensity and help to gain further insight into PD and the pathophysiology leading to FoG.

Unveiling the nature of interaction between semantics and phonology in lexical access based on multilayer networks.

An essential aspect of human communication is the ability to access and retrieve information from ones' 'mental lexicon'. This lexical access activates phonological and semantic components of concepts, yet the question whether and how these two components relate to each other remains widely debated. We harness tools from network science to construct a large-scale linguistic multilayer network comprising of phonological and semantic layers. We find that the links in the two layers are highly similar to each other and that adding information from one layer to the other increases efficiency by decreasing the network overall distances, but specifically affecting shorter distances. Finally, we show how a multilayer architecture demonstrates the highest efficiency, and how this efficiency relates to weak semantic relations between cue words in the network. Thus, investigating the interaction between the layers and the unique benefit of a linguistic multilayer architecture allows us to quantify theoretical cognitive models of lexical access.

Age-related loss of gene-to-gene transcriptional coordination among single cells.

A long-standing model holds that stochastic aberrations of transcriptional regulation play a key role in the process of ageing. While transcriptional dysregulation is observed in many cell types in the form of increased cell-to-cell variability, its generality to all cell types remains doubted. Here, we propose a new approach for analysing transcriptional regulation in single-cell RNA sequencing data by focusing on the global coordination between the genes rather than the variability of individual genes or correlations between pairs of genes. Consistently, across very different organisms and cell types, we find a decrease in the gene-to-gene transcriptional coordination in ageing cells. In addition, we find that loss of gene-to-gene transcriptional coordination is associated with high mutational load of a specific, age-related signature and with radiation-induced DNA damage. These observations suggest a general, potentially universal, stochastic attribute of transcriptional dysregulation in ageing.

Mitigation of cascading failures in complex networks.

Cascading failures in many systems such as infrastructures or financial networks can lead to catastrophic system collapse. We develop here an intuitive, powerful and simple-to-implement approach for mitigation of cascading failures on complex networks based on local network structure. We offer an algorithm to select critical nodes, the protection of which ensures better survival of the network. We demonstrate the strength of our approach compared to various standard mitigation techniques. We show the efficacy of our method on various network structures and failure mechanisms, and finally demonstrate its merit on an example of a real network of financial holdings.

Multiple metastable network states in urban traffic.

While abrupt regime shifts between different metastable states have occurred in natural systems from many areas including ecology, biology, and climate, evidence for this phenomenon in transportation systems has been rarely observed so far. This limitation might be rooted in the fact that we lack methods to identify and analyze possible multiple states that could emerge at scales of the entire traffic network. Here, using percolation approaches, we observe such a metastable regime in traffic systems. In particular, we find multiple metastable network states, corresponding to varying levels of traffic performance, which recur over different days. Based on high-resolution global positioning system (GPS) datasets of urban traffic in the megacities of Beijing and Shanghai (each with over 50,000 road segments), we find evidence supporting the existence of tipping points separating three regimes: a global functional regime and a metastable hysteresis-like regime, followed by a global collapsed regime. We can determine the intrinsic critical points where the metastable hysteresis-like regime begins and ends and show that these critical points are very similar across different days. Our findings provide a better understanding of traffic resilience patterns and could be useful for designing early warning signals for traffic resilience management and, potentially, other complex systems.

Simultaneous TE Analysis of 19 Heliconiine Butterflies Yields Novel Insights into Rapid TE-Based Genome Diversification and Multiple SINE Births and Deaths.

Transposable elements (TEs) play major roles in the evolution of genome structure and function. However, because of their repetitive nature, they are difficult to annotate and discovering the specific roles they may play in a lineage can be a daunting task. Heliconiine butterflies are models for the study of multiple evolutionary processes including phenotype evolution and hybridization. We attempted to determine how TEs may play a role in the diversification of genomes within this clade by performing a detailed examination of TE content and accumulation in 19 species whose genomes were recently sequenced. We found that TE content has diverged substantially and rapidly in the time since several subclades shared a common ancestor with each lineage harboring a unique TE repertoire. Several novel SINE lineages have been established that are restricted to a subset of species. Furthermore, the previously described SINE, Metulj, appears to have gone extinct in two subclades while expanding to significant numbers in others. This diversity in TE content and activity has the potential to impact how heliconiine butterflies continue to evolve and diverge.

Effects of mating patterns on genealogical trees: Assessment of the high carrier rate of Familial Mediterranean Fever in rural Israeli districts.

We investigate the spread from ancestors to descendants, under a model of sexual reproduction, of hereditary elements distinguishing individuals from their fellow human beings. These hereditary elements, termed labels, are either symbolic, implying a socio-cultural or ethnic self-determined category, or biological, i.e. a DNA sequence (for example founder mutations). The impact of various modes of preferential (assortative) mating on the dissemination of a known ancestral label was studied for both kinds of labels, the symbolic and the biological. For the socio-cultural based labeling, both mathematical modeling and simulation studies were carried out, and disclosed a marked delay in the spread of the labels in future generations, compared to the case where mating was random. The transmission of biological labels (founder mutations) from an ancestor to descendants under various modes and degrees of assortative mating was investigated by simulations and supplemented by an in-depth analysis of allele frequencies of Familial Mediterranean Fever (FMF) in an Israeli Muslim Arab village. The high carrier frequency of FMF in this village was satisfactorily explained solely by the presence of a founder effect and a pronounced high factor of selective mating, causing segregation and consanguinity among its inhabitants. Contribution of further evolutionary mechanisms such as heterozygote advantage, drift, differential reproductive success or selection pressure was not essential to explain these results.

Flexibility of thought in high creative individuals represented by percolation analysis.

Flexibility of thought is theorized to play a critical role in the ability of high creative individuals to generate novel and innovative ideas. However, this has been examined only through indirect behavioral measures. Here we use network percolation analysis (removal of links in a network whose strength is below an increasing threshold) to computationally examine the robustness of the semantic memory networks of low and high creative individuals. Robustness of a network indicates its flexibility and thus can be used to quantify flexibility of thought as related to creativity. This is based on the assumption that the higher the robustness of the semantic network, the higher its flexibility. Our analysis reveals that the semantic network of high creative individuals is more robust to network percolation compared with the network of low creative individuals and that this higher robustness is related to differences in the structure of the networks. Specifically, we find that this higher robustness is related to stronger links connecting between different components of similar semantic words in the network, which may also help to facilitate spread of activation over their network. Thus, we directly and quantitatively examine the relation between flexibility of thought and creative ability. Our findings support the associative theory of creativity, which posits that high creative ability is related to a flexible structure of semantic memory. Finally, this approach may have further implications, by enabling a quantitative examination of flexibility of thought, in both healthy and clinical populations.

Integrating networks and comparative genomics reveals retroelement proliferation dynamics in hominid genomes.

Retroelements (REs) are mobile DNA sequences that multiply and spread throughout genomes by a copy-and-paste mechanism. These parasitic elements are active in diverse genomes, from yeast to humans, where they promote diversity, cause disease, and accelerate evolution. Because of their high copy number and sequence similarity, studying their activity and tracking their proliferation dynamics is a challenge. It is particularly difficult to pinpoint the few REs in a genome that are still active in the haystack of degenerate and suppressed elements. We develop a computational framework based on network theory that tracks the path of RE proliferation throughout evolution. We analyze SVA (SINE-VNTR-Alu), the youngest RE family in human genomes, to understand RE dynamics across hominids. Integrating comparative genomics and network tools enables us to track the course of SVA proliferation, identify yet unknown active communities, and detect tentative "master REs" that played key roles in SVA propagation, providing strong support for the fundamental "master gene" model of RE proliferation. The method is generic and thus can be applied to REs of any of the thousands of available genomes to identify active RE communities and master REs that were pivotal in the evolution of their host genomes.