Publications
103 results found
Burr SP, Klimm F, Glynos A, et al., 2023, Cell lineage-specific mitochondrial resilience during mammalian organogenesis, Cell, Vol: 186, Pages: 1212-1229.E21, ISSN: 0092-8674
Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments.
Insalata F, Hoitzing H, Aryaman J, et al., 2022, Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-8, ISSN: 0027-8424
The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.
Klimm F, Jones NS, Schaub MT, 2022, Modularity maximisation for graphons, SIAM Journal on Applied Mathematics, ISSN: 0036-1399
Networks are a widely-used tool to investigate the large-scale connectivitystructure in complex systems and graphons have been proposed as an infinitesize limit of dense networks. The detection of communities or other meso-scalestructures is a prominent topic in network science as it allows theidentification of functional building blocks in complex systems. When suchbuilding blocks may be present in graphons is an open question. In this paper,we define a graphon-modularity and demonstrate that it can be maximised todetect communities in graphons. We then investigate specific synthetic graphonsand show that they may show a wide range of different community structures. Wealso reformulate the graphon-modularity maximisation as a continuousoptimisation problem and so prove the optimal community structure or lackthereof for some graphons, something that is usually not possible for networks.Furthermore, we demonstrate that estimating a graphon from network data as anintermediate step can improve the detection of communities, in comparison withexclusively maximising the modularity of the network. While the choice ofgraphon-estimator may strongly influence the accord between the communitystructure of a network and its estimated graphon, we find that there is asubstantial overlap if an appropriate estimator is used. Our study demonstratesthat community detection for graphons is possible and may serve as aprivacy-preserving way to cluster network data.
Sethi SS, Ewers RM, Jones NS, et al., 2021, Soundscapes predict species occurrence in tropical forests, OIKOS, Vol: 2022, Pages: 1-9, ISSN: 0030-1299
Accurate occurrence data is necessary for the conservation of keystone or endangered species, but acquiring it is usually slow, laborious and costly. Automated acoustic monitoring offers a scalable alternative to manual surveys but identifying species vocalisations requires large manually annotated training datasets, and is not always possible (e.g. for lesser studied or silent species). A new approach is needed that rapidly predicts species occurrence using smaller and more coarsely labelled audio datasets. We investigated whether local soundscapes could be used to infer the presence of 32 avifaunal and seven herpetofaunal species in 20 min recordings across a tropical forest degradation gradient in Sabah, Malaysia. Using acoustic features derived from a convolutional neural network (CNN), we characterised species indicative soundscapes by training our models on a temporally coarse labelled point-count dataset. Soundscapes successfully predicted the occurrence of 34 out of the 39 species across the two taxonomic groups, with area under the curve (AUC) metrics from 0.53 up to 0.87. The highest accuracies were achieved for species with strong temporal occurrence patterns. Soundscapes were a better predictor of species occurrence than above-ground carbon density – a metric often used to quantify habitat quality across forest degradation gradients. Our results demonstrate that soundscapes can be used to efficiently predict the occurrence of a wide variety of species and provide a new direction for data driven large-scale assessments of habitat suitability.
Zhang H, Esposito M, Pezet MG, et al., 2021, Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission, Science Advances, Vol: 7, Pages: 1-12, ISSN: 2375-2548
Heteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild-type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders.
Garrod M, Jones N, 2021, Influencing dynamics on social networks without knowledge of network microstructure, Journal of the Royal Society Interface, Vol: 18, Pages: 1-12, ISSN: 1742-5662
Social network based information campaigns can be used for promoting beneficial health behaviours and mitigating polarisation (e.g. regarding climate change or vaccines). Network-basedintervention strategies typically rely on full knowledge of network structure. It is largely not possibleor desirable to obtain population-level social network data due to availability and privacy issues. Itis easier to obtain information about individuals’ attributes (e.g. age, income), which are jointlyinformative of an individual’s opinions and their social network position. We investigate strategiesfor influencing the system state in a statistical mechanics based model of opinion formation. Using synthetic and data based examples we illustrate the advantages of implementing coarse-grainedinfluence strategies on Ising models with modular structure in the presence of external fields. Ourwork provides a scalable methodology for influencing Ising systems on large graphs and the firstexploration of the Ising influence problem in the presence of ambient (social) fields. By exploitingthe observation that strong ambient fields can simplify control of networked dynamics, our findingsopen the possibility of efficiently computing and implementing public information campaigns usinginsights from social network theory without costly or invasive levels of data collection.
Lima A, Lubatti G, Burgstaller J, et al., 2021, Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development, Nature Metabolism, Vol: 3, Pages: 1091-1108, ISSN: 2522-5812
Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated prior to gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single cell transcriptional profiling of eliminated mouse epiblast cells we identify hallmarks of cell competition and mitochondrial defects. We go on to demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. In the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.
Marshall A, Jones N, 2021, Discovering cellular mitochondrial heteroplasmy heterogeneity with single cell RNA and ATAC sequencing, Biology, Vol: 10, Pages: 1/20-1/20, ISSN: 2079-7737
Next generation sequencing technologies have revolutionised the study of biological systems by enabling the examination of a broad range of tissues. Its application to single cell genomics has generated a dynamic and evolving field with a vast amount of research highlighting heterogeneity in transcriptional, genetic and epigenomic state between cells. However, compared to these aspects of cellular heterogeneity, relatively little has been gleaned from the single cell datasets regarding cellular mitochondrial heterogeneity. Single cell sequencing techniques can provide coverage of the mitochondrial genome which allows researchers to probe heteroplasmies 0at the level of the single cell, and observe interactions with cellular function. In this review we give an overview of two popular single cell modalities — single cell RNA sequencing and single cell ATAC sequencing — whose throughput and widespread usage offers researchers the chance to probe heteroplasmy combined with cell state in detailed resolution across thousands of cells. After summarising these technologies in the context of mitochondrial research, we give an overview of recent methods which have used these approaches for discovering mitochondrial heterogeneity. We conclude by highlighting current limitations of these approaches and open problems for future consideration.
Godoy-Lorite A, Jones N, 2021, Inference and influence of network structure using snapshot social behavior without network data, Science Advances, Vol: 7, ISSN: 2375-2548
Population behavior, like voting and vaccination, depends on the structure of social networks. This structure can differ depending on behavior type and is typically hidden. However, we do often have behavioral data, albeit only snapshots taken at one time point. We present a method jointly inferring a model for both network structure and human behavior using only snapshot population-level behavioral data. This exploits the simplicity of a few parameter model, geometric sociodemographic network model, and a spin-based model of behavior. We illustrate, for the European Union referendum and two London mayoral elections, how the model offers both prediction and the interpretation of the homophilic inclinations of the population. Beyond extracting behavior-specific network structure from behavioral datasets, our approach yields a framework linking inequalities and social preferences to behavioral outcomes. We illustrate potential network-sensitive policies: How changes to income inequality, social temperature, and homophilic preferences might have reduced polarization in a recent election.
Prole DL, Chinnery PF, Jones NS, 2020, Visualizing, quantifying, and manipulating mitochondrial DNA in vivo, Journal of Biological Chemistry, Vol: 295, Pages: 17588-17601, ISSN: 0021-9258
Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause mitochondrial diseases and are implicated in ageing. The mtDNA within cells is organized into nucleoids within the mitochondrial matrix, but how mtDNA nucleoids are formed and regulated within cells remains incompletely resolved. Visualization of mtDNA within cells is a powerful means by which mechanistic insight can be gained. Manipulation of the amount, and sequence of, mtDNA within cells is important experimentally and for developing therapeutic interventions to treat mitochondrial disease. This review details recent developments and opportunities for improvements in the experimental tools and techniques that can be used to visualize, quantify and manipulate the properties of mtDNA within cells.
Lubba CH, Ouyang A, Jones N, et al., 2020, Bladder pressure encoding by sacral dorsal root ganglion fibres: implications for decoding, Journal of Neural Engineering, Vol: 18, Pages: 1-19, ISSN: 1741-2552
Objective: We aim at characterising the encoding of bladder pressure (intravesical pressure) by a population of sensory fibres. This research is motivated by the possibility to restore bladder function in elderly patients or after spinal cord injury using implanted devices, so called bioelectronic medicines. For these devices, nerve-based estimation of intravesical pressure can enable a personalized and on-demand stimulation paradigm, which has promise of being more effective and efficient. In this context, a better understanding of the encoding strategies employed by the body might in the future be exploited by informed decoding algorithms that enable a precise and robust bladder-pressure estimation. Approach: To this end, we apply information theory to microelectrode-array recordings from the cat sacral dorsal root ganglion while filling the bladder, conduct surrogate data studies to augment the data we have, and finally decode pressure in a simple informed approach. Main results: We find an encoding scheme by different main bladder neuron types that we divide into three response types (slow tonic, phasic, and derivative fibres). We show that an encoding by different bladder neuron types, each represented by multiple cells, offers reliability through within-type redundancy and high information rates through semi-independence of different types. Our subsequent decoding study shows a more robust decoding from mean responses of homogeneous cell pools. Significance: We have here, for the first time, established a link between an information theoretic analysis of the encoding of intravesical pressure by a population of sensory neurons to an informed decoding paradigm. We show that even a simple adapted decoder can exploit the redundancy in the population to be more robust against cell loss. This work thus paves the way towards principled encoding studies in the periphery and towards a new generation of informed peripheral nerve decoders for bioelectronic medicines.
Hoffmann T, Jones NS, 2020, Inference of a universal social scale and segregation measures using social connectivity kernels, Journal of the Royal Society Interface, Vol: 17, ISSN: 1742-5662
How people connect with one another is a fundamental question in the social sciences, and the resulting social networks can have a profound impact on our daily lives. Blau offered a powerful explanation: people connect with one another based on their positions in a social space. Yet a principled measure of social distance, allowing comparison within and between societies, remains elusive.We use the connectivity kernel of conditionally-independent edge models to develop a family of segregation statistics with desirable properties: they offer an intuitive and universal characteristic scale on social space (facilitating comparison across datasets and societies), are applicable to multivariate and mixed node attributes, and capture segregation at the level of individuals, pairs of individuals, and society as a whole. We show that the segregation statistics can induce a metric on Blau space (a space spanned by the attributes of the members of society) and provide maps of two societies.Under a Bayesian paradigm, we infer the parameters of the connectivity kernel from eleven ego-network datasets collected in four surveys in the United Kingdom and United States. The importance of different dimensions of Blau space is similar across time and location, suggesting a macroscopically stable social fabric. Physical separation and age differences have the most significant impact on segregation within friendship networks with implications for intergenerational mixing and isolation in later stages of life.
Sethi S, Ewers R, Jones N, et al., 2020, SAFE Acoustics: an open-source, real-time eco-acoustic monitoring network in the tropical rainforests of Borneo, Methods in Ecology and Evolution, Vol: 11, Pages: 1182-1185, ISSN: 2041-210X
1. Automated monitoring approaches offer an avenue to unlocking large‐scale insight into how ecosystems respond to human pressures. However, since data collection and data analyses are often treated independently, there are currently no open‐source examples of end‐to‐end, real‐time ecological monitoring networks. 2. Here, we present the complete implementation of an autonomous acoustic monitoring network deployed in the tropical rainforests of Borneo. Real‐time audio is uploaded remotely from the field, indexed by a central database, and delivered via an API to a public‐facing website.3. We provide the open‐source code and design of our monitoring devices, the central web2py database, and the ReactJS website. Furthermore, we demonstrate an extension of this infrastructure to deliver real‐time analyses of the eco‐acoustic data. 4. By detailing a fully functional, open source, and extensively tested design, our work will accelerate the rate at which fully autonomous monitoring networks mature from technological curiosities, and towards genuinely impactful tools in ecology.
Lechuga-Vieco AV, Latorre-Pellicer A, Johnston IG, et al., 2020, Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics, Science Advances, Vol: 6, Pages: eaba5345-eaba5345, ISSN: 2375-2548
Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.
Sethi S, Jones NS, Fulcher B, et al., 2020, Characterising soundscapes across diverse ecosystems using a universal acoustic feature set, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 17049-17055, ISSN: 0027-8424
Natural habitats are being impacted by human pressures at an alarming rate. Monitoring these ecosystem-level changes often requires labor-intensive surveys that are unable to detect rapid or unanticipated environmental changes. Here we have developed a generalizable, data-driven solution to this challenge using eco-acoustic data. We exploited a convolutional neural network to embed soundscapes from a variety of ecosystems into a common acoustic space. In both supervised and unsupervised modes, this allowed us to accurately quantify variation in habitat quality across space and in biodiversity through time. On the scale of seconds, we learned a typical soundscape model that allowed automatic identification of anomalous sounds in playback experiments, providing a potential route for real-time automated detection of irregular environmental behavior including illegal logging and hunting. Our highly generalizable approach, and the common set of features, will enable scientists to unlock previously hidden insights from acoustic data and offers promise as a backbone technology for global collaborative autonomous ecosystem monitoring efforts.
Fulcher B, Lubba C, Sethi S, et al., 2020, A self-organizing, living library of time-series data, Scientific Data, Vol: 7, ISSN: 2052-4463
Time-series data are measured across the sciences, from astronomy to biomedicine, but meaningful cross-disciplinary interactions are limited by the challenge of identifying fruitful connections. Here we introduce the web platform, CompEngine, a self-organizing, living library of time-series data, that lowers the barrier to forming meaningful interdisciplinary connections between time series. Using a canonical feature-based representation, CompEngine places all time series in a common feature space, regardless of their origin, allowing users to upload their data and immediately explore diverse data with similar properties, and be alerted when similar data is uploaded in future. In contrast to conventional databases which are organized by assigned metadata, CompEngine incentivizes data sharing by automatically connecting experimental and theoretical scientists across disciplines based on the empirical structure of the data they measure. CompEngine’s growing library of interdisciplinary time-series data also enables the comprehensive characterization of time-series analysis algorithms across diverse types of empirical data.
Insalata F, Hoitzing H, Aryaman J, et al., 2020, Survival of the Densest Explains the Expansion of Mitochondrial Deletions in Skeletal Muscle Fibres, 48th European Mathematical Genetics Meeting (EMGM), Publisher: KARGER, Pages: 211-211, ISSN: 0001-5652
Heaton LLM, Jones NS, Fricker MD, 2020, A mechanistic explanation of the transition to simple multicellularity in fungi., Nature Communications, Vol: 11, ISSN: 2041-1723
Development of multicellularity was one of the major transitions in evolution and occurred independently multiple times in algae, plants, animals, and fungi. However recent comparative genome analyses suggest that fungi followed a different route to other eukaryotic lineages. To understand the driving forces behind the transition from unicellular fungi to hyphal forms of growth, we develop a comparative model of osmotrophic resource acquisition. This predicts that whenever the local resource is immobile, hard-to-digest, and nutrient poor, hyphal osmotrophs outcompete motile or autolytic unicellular osmotrophs. This hyphal advantage arises because transporting nutrients via a contiguous cytoplasm enables continued exploitation of remaining resources after local depletion of essential nutrients, and more efficient use of costly exoenzymes. The model provides a mechanistic explanation for the origins of multicellular hyphal organisms, and explains why fungi, rather than unicellular bacteria, evolved to dominate decay of recalcitrant, nutrient poor substrates such as leaf litter or wood.
Hoffmann T, Peel L, Lambiotte R, et al., 2020, Community detection in networks without observing edges, Science Advances, Vol: 6, ISSN: 2375-2548
We develop a Bayesian hierarchical model to identify communities of time series. Fitting the model provides an end-to-end community detection algorithmthat does not extract information as a sequence of point estimates but propagates uncertainties from the raw data to the community labels. Our approachnaturally supports multiscale community detection as well as the selection ofan optimal scale using model comparison. We study the properties of the algorithm using synthetic data and apply it to daily returns of constituents of theS&P100 index as well as climate data from US cities.
McGrath T, Spreckley E, Rodriguez A, et al., 2019, The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents, PLoS Biology, Vol: 17, Pages: 1-30, ISSN: 1544-9173
Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that capturesthe complexity of feeding behaviour. We construct an accurate stochasticmodel of rodent feeding at the bout level in order to perform quantitativebehavioural analysis. Analysing the different effects on feeding behaviour ofPYY3-36, lithium chloride, GLP-1 and leptin shows the precise behaviouralchanges caused by each anorectic agent. Our analysis demonstrates that thechanges in feeding behaviour evoked by the anorectic agents investigated donot mimic the behaviour of well-fed animals, and that the intermeal intervalis influenced by fullness. We show how robust homeostatic control of feedingthwarts attempts to reduce food intake, and how this might be overcome. Insilico experiments suggest that introducing a minimum intermeal interval ormodulating upper gut emptying can be as effective as anorectic drug administration.
Latorre-Pellicer A, Lechuga-Vieco AV, Johnston IG, et al., 2019, Regulation of mother-to-offspring transmission of mtDNA heteroplasmy, Cell Metabolism, Vol: 30, Pages: 1120-1130.e5, ISSN: 1550-4131
mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.
Lubba CH, Sethi SS, Knaute P, et al., 2019, catch22: CAnonical time-series CHaracteristics, Data Mining and Knowledge Discovery, Vol: 33, Pages: 1821-1852, ISSN: 1384-5810
Capturing the dynamical properties of time series concisely as interpretable feature vectors can enable efficient clustering and classification for time-series applications across science and industry. Selecting an appropriate feature-based representation of time series for a given application can be achieved through systematic comparison across a comprehensive time-series feature library, such as those in the hctsa toolbox. However, this approach is computationally expensive and involves evaluating many similar features, limiting the widespread adoption of feature-based representations of time series for real-world applications. In this work, we introduce a method to infer small sets of time-series features that (i) exhibit strong classification performance across a given collection of time-series problems, and (ii) are minimally redundant. Applying our method to a set of 93 time-series classification datasets (containing over 147,000 time series) and using a filtered version of the hctsa feature library (4791 features), we introduce a set of 22 CAnonical Time-series CHaracteristics, catch22, tailored to the dynamics typically encountered in time-series data-mining tasks. This dimensionality reduction, from 4791 to 22, is associated with an approximately 1000-fold reduction in computation time and near linear scaling with time-series length, despite an average reduction in classification accuracy of just 7%. catch22 captures a diverse and interpretable signature of time series in terms of their properties, including linear and non-linear autocorrelation, successive differences, value distributions and outliers, and fluctuation scaling properties. We provide an efficient implementation of catch22, accessible from many programming environments, that facilitates feature-based time-series analysis for scientific, industrial, financial and medical applications using a common language of interpretable time-series properties.
Aryaman J, Bowles C, Jones NS, et al., 2019, Mitochondrial network state scales mtDNA genetic dynamics, Genetics, Vol: 212, Pages: 1429-1443, ISSN: 0016-6731
Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.
Burgstaller J, Kolbe T, Havlicek V, et al., 2019, Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations, Nature Communications, Vol: 9, ISSN: 2041-1723
Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.
Hoitzing H, Gammage PA, Haute LV, et al., 2019, Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations, PLoS Computational Biology, Vol: 15, ISSN: 1553-734X
The dynamics of the cellular proportion of mutant mtDNA molecules is crucial for mitochondrial diseases. Cellular populations of mitochondria are under homeostatic control, but the details of the control mechanisms involved remain elusive. Here, we use stochastic modelling to derive general results for the impact of cellular control on mtDNA populations, the cost to the cell of different mtDNA states, and the optimisation of therapeutic control of mtDNA populations. This formalism yields a wealth of biological results, including that an increasing mtDNA variance can increase the energetic cost of maintaining a tissue, that intermediate levels of heteroplasmy can be more detrimental than homoplasmy even for a dysfunctional mutant, that heteroplasmy distribution (not mean alone) is crucial for the success of gene therapies, and that long-term rather than short intense gene therapies are more likely to beneficially impact mtDNA populations.
Brittain R, Jones N, Ouldridge T, 2019, Biochemical Szilard engines for memory-limited inference, New Journal of Physics, Vol: 21, ISSN: 1367-2630
By designing and leveraging an explicit molecular realisation of a measurement-and-feedback-powered Szilard engine, we investigate the extraction of work from complex environments by minimal machines with finite capacity for memory and decision-making. Living systems perform inference to exploit complex structure, or correlations, in their environment, but the physical limits and underlying cost/benefit trade-offs involved in doing so remain unclear. To probe these questions, we consider a minimal model for a structured environment—a correlated sequence of molecules—and explore mechanisms based on extended Szilard engines for extracting the work stored in these non-equilibrium correlations. We consider systems limited to a single bit of memory making binary 'choices' at each step. We demonstrate that increasingly complex environments allow increasingly sophisticated inference strategies to extract more free energy than simpler alternatives, and argue that optimal design of such machines should also consider the free energy reserves required to ensure robustness against fluctuations due to mistakes.
Lubba CH, Le Guen Y, Jarvis S, et al., 2019, Correction to: PyPNS: Multiscale Simulation of a Peripheral Nerve in Python., Neuroinformatics
The original version of this article unfortunately contained a mistake. The following text: "This project has received funding from European Research Council (ERC) Synergy Grant no. 319818." is missing in the Acknowledgments.
Insalata F, Hoitzing H, Jones N, 2019, A mathematical model of expansion of disadvantaged but altruistic mitochondrial mutants in skeletal muscle fibres, Publisher: WILEY, Pages: 61-61, ISSN: 0014-2972
Aryaman J, Johnston I, Jones N, 2019, Mitochondrial heterogeneity, Frontiers in Genetics, Vol: 9, ISSN: 1664-8021
Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly of mitochondria, is increasingly being recognized as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence, intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (which is termed “microheteroplasmy”), and developments in the understanding of inter-cellular mtDNA mutation (“macroheteroplasmy”). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH, and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognized role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.
Lubba CT, Le Guen Y, Jarvis S, et al., 2019, PyPNS: multiscale simulation of a peripheral nerve in Python, Neuroinformatics, Vol: 17, Pages: 63-81, ISSN: 1539-2791
Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help.We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modeled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modeled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin- Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.
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