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07 Sep 2021
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The origin of the allometric scaling of lung ventilation in mammals

Recommended by based on reviews by Oliver Ebenhöh, Megumi Inoue, Elad Noor and Stefan Schuster

How mammals adapt their breath to body activity – and how this depends on body size

How fast and how deep do animals breathe, and how does this depend on how active they are? To answer this question, one needs to dig deeply into how breathing works and what biophysical processes it involves. And one needs to think about body size.

It is impressive how nature adapts the same body plan – e.g. the skeletal structure of mammals – to various shapes and sizes. From mice to whales, also the functioning of most organs remains the same; they are just differently scaled. Scaling does not just mean “making bigger or smaller”. As already noted by Galilei, body shapes change as they are adapted to body dimensions, and the same holds for physiological variables. Many such variables, for instance, heartbeat rates, follow scaling laws of the form y~xa, where x denotes body mass and the exponent a is typically a multiple of ¼ [1]. These unusual exponents – instead of multiples of ⅓, which would be expected from simple geometrical scaling – are why these laws are called “allometric”. Kleiber’s law for metabolic rates, with a scaling exponent of ¾, is a classic example [2]. As shown by G. West, allometric laws can be explained through a few simple steps [1]. In his models, he focused on network-like organs such as the vascular system and assumed that these systems show a self-similar structure, with a fixed minimal unit (for instance, capillaries) but varying numbers of hierarchy levels depending on body size. To determine the flow through such networks, he employed biophysical models and optimality principles (for instance, assuming that oxygen must be transported at a minimal mechanical effort), and showed that the solutions – and the physiological variables – respect the known scaling relations.

The paper “The origin of the allometric scaling of lung ventilation in mammals“ by Noël et al. [3], applies this thinking to the depth and rate of breathing in mammals. Scaling laws describing breathing in resting animals have been known since the 1950s [4], with exponents of 1 (for tidal volume) and -¼ (for breathing frequency). Equipped with a detailed biophysical model, Noël et al. revisit this question, extending these laws to other metabolic regimes. Their starting point is a model of the human lung, developed previously by two of the authors [5], which assumes that we meet our oxygen demand with minimal lung movements. To state this as an optimization problem, the model combines two submodels: a mechanical model describing the energetic effort of ventilation and a highly detailed model of convection and diffusion in self-similar lung geometries. Breathing depths and rates are computed by numerical optimization, and to obtain results for mammals of any size many of the model parameters are described by known scaling laws. As expected, the depth of breathing (measured by tidal volume) scales almost proportionally with body mass and increases with metabolic demand, while the breathing rate decreases with body mass, with an exponent of about -¼. However, the laws for the breathing rate hold only for basal activity; at higher metabolic rates, which are modeled here for the first time, the exponent deviates strongly from this value, in line with empirical data.

Why is this paper important? The authors present a highly complex model of lung physiology that integrates a wide range of biophysical details and passes a difficult test: the successful prediction of unexplained scaling exponents. These scaling relations may help us transfer insights from animal models to humans and in reverse: data for breathing during exercise, which are easy to measure in humans, can be extrapolated to other species. Aside from the scaling laws, the model also reveals physiological mechanisms. In the larger lung branches, oxygen is transported mainly by air movement (convection), while in smaller branches air flow is slow and oxygen moves by diffusion. The transition between these regimes can occur at different depths in the lung: as the authors state, “the localization of this transition determines how ventilation should be controlled to minimize its energetic cost at any metabolic regime”. In the model, the optimal location for the transition depends on oxygen demand [5, 6]: the transition occurs deeper in the lung in exercise regimes than at rest, allowing for more oxygen to be taken up. However, the effects of this shift depend on body size: while small mammals generally use the entire exchange surface of their lungs, large mammals keep a reserve for higher activities, which becomes accessible as their transition zone moves at high metabolic rates. Hence, scaling can entail qualitative differences between species!

Altogether, the paper shows how the dynamics of ventilation depend on lung morphology. But this may also play out in the other direction: if energy-efficient ventilation depends on body activity, and therefore on ecological niches, a niche may put evolutionary pressures on lung geometry. Hence, by understanding how deep and fast animals breathe, we may also learn about how behavior, physiology, and anatomy co-evolve.

References

[1] West GB, Brown JH, Enquist BJ (1997) A General Model for the Origin of Allometric Scaling Laws in Biology. Science 276 (5309), 122–126. https://doi.org/10.1126/science.276.5309.122

[2] Kleiber M (1947) Body size and metabolic rate. Physiological Reviews, 27, 511–541. https://doi.org/10.1152/physrev.1947.27.4.511

[3] Noël F., Karamaoun C., Dempsey J. A. and Mauroy B. (2021) The origin of the allometric scaling of lung's ventilation in mammals. arXiv, 2005.12362, ver. 6 peer-reviewed and recommended by Peer community in Mathematical and Computational Biology. https://arxiv.org/abs/2005.12362

[4] Otis AB, Fenn WO, Rahn H (1950) Mechanics of Breathing in Man. Journal of Applied Physiology, 2, 592–607. https://doi.org/10.1152/jappl.1950.2.11.592

[5] Noël F, Mauroy B (2019) Interplay Between Optimal Ventilation and Gas Transport in a Model of the Human Lung. Frontiers in Physiology, 10, 488. https://doi.org/10.3389/fphys.2019.00488

[6] Sapoval B, Filoche M, Weibel ER (2002) Smaller is better—but not too small: A physical scale for the design of the mammalian pulmonary acinus. Proceedings of the National Academy of Sciences, 99, 10411–10416. https://doi.org/10.1073/pnas.122352499

27 Jul 2021
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Estimating dates of origin and end of COVID-19 epidemics

Recommended by based on reviews by Bastien Boussau and 1 anonymous reviewer

The importance of model assumptions in estimating the dynamics of the COVID-19 epidemic

In “Estimating dates of origin and end of COVID-19 epidemics”, Bénéteau et al. develop and apply a mathematical modeling approach to estimate the date of the origin of the SARS-CoV-2 epidemic in France. They also assess how long strict control measures need to last to ensure that the prevalence of the virus remains below key public health thresholds. This problem is challenging because the numbers of infected individuals in both tails of the epidemic are low, which can lead to errors when deterministic models are used. To achieve their goals, the authors developed a discrete stochastic model. The model is non-Markovian, meaning that individual infection histories influence the dynamics. The model also accounts for heterogeneity in the timing between infection and transmission and includes stochasticity as well as consideration of superspreader events. By comparing the outputs of their model with several alternative models, Bénéteau et al. were able to assess the importance of stochasticity, individual heterogeneity, and non-Markovian effects on the estimates of the dates of origin and end of the epidemic, using France as a test case. Some limitations of the study, which the authors acknowledge, are that the time from infection to death remains largely unknown, a lack of data on the heterogeneity of transmission among individuals, and the assumption that only a single infected individual caused the epidemic. Despite the acknowledged limitations of the work, the results suggest that cases may be detected long before the detection of an epidemic wave. Also, the approach may be helpful for informing public health decisions such as the necessary duration of strict lockdowns and for assessing the risks of epidemic rebound as restrictions are lifted. In particular, the authors found that estimates of the end of the epidemic following lockdowns are more sensitive to the assumptions of the models used than estimates of its beginning. In summary, this model adds to a valuable suite of tools to support decision-making in response to disease epidemics.

References

Bénéteau T, Elie B, Sofonea MT, Alizon S (2021) Estimating dates of origin and end of COVID-19 epidemics. medRxiv, 2021.01.19.21250080, ver. 3 peer-reviewed and recommended by Peer Community in Mathematical and Computational Biology. https://doi.org/10.1101/2021.01.19.21250080

26 May 2021
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An efficient algorithm for estimating population history from genetic data

Recommended by based on reviews by Fernando Racimo and 1 anonymous reviewer

An efficient implementation of legofit software to infer demographic histories from population genetic data

The estimation of demographic parameters from population genetic data has been the subject of many scientific studies [1]. Among these efforts, legofit was firstly proposed in 2019 as a tool to infer size changes, subdivision and gene flow events from patterns of nucleotidic variation [2]. The first release of legofit used a stochastic algorithm to fit population parameters to the observed data. As it requires simulations to evaluate the fitting of each model, it is computationally intensive and can only be deployed on high-performance computing clusters.

To overcome this issue, Rogers proposes a new implementation of legofit based on a deterministic algorithm that allows the estimation of demographic histories to be computationally faster and more accurate [3]. The new algorithm employs a continuous-time Markov chain that traces the ancestry of each sample into the past. The calculations are now divided into two steps, the first one being solved numerically. To test the hypothesis that the new implementation of legofit produces a more desirable performance, Rogers generated extensive simulations of genomes from African, European, Neanderthal and Denisovan populations with msprime [4]. Additionally, legofit was tested on real genetic data from samples of said populations, following a previously published study [5].

Based on simulations, the new deterministic algorithm is more than 1600 times faster than the previous stochastic model. Notably, the new version of legofit produces smaller residual errors, although the overall accuracy to estimate population parameters is comparable to the one obtained using the stochastic algorithm. When applied to real data, the new implementation of legofit was able to recapitulate previous findings of a complex demographic model with early gene flow from humans to Neanderthal [5]. Notably, the new implementation generates better discrimination between models, therefore leading to a better precision at predicting the population history. Some parameters estimated from real data point towards unrealistic scenarios, suggesting that the initial model could be misspecified.

Further research is needed to fully explore the parameter range that can be evaluated by legofit, and to clarify the source of any associated bias. Additionally, the inclusion of data uncertainty in parameter estimation and model selection may be required to apply legofit to low-coverage high-throughput sequencing data [6]. Nevertheless, legofit is an efficient, accessible and user-friendly software to infer demographic parameters from genetic data and can be widely applied to test hypotheses in evolutionary biology. The new implementation of legofit software is freely available at https://github.com/alanrogers/legofit

References

[1] Spence JP, Steinrücken M, Terhorst J, Song YS (2018) Inference of population history using coalescent HMMs: review and outlook. Current Opinion in Genetics & Development, 53, 70–76. https://doi.org/10.1016/j.gde.2018.07.002

[2] Rogers AR (2019) Legofit: estimating population history from genetic data. BMC Bioinformatics, 20, 526. https://doi.org/10.1186/s12859-019-3154-1

[3] Rogers AR (2021) An Efficient Algorithm for Estimating Population History from Genetic Data. bioRxiv, 2021.01.23.427922, ver. 5 peer-reviewed and recommended by Peer community in Mathematical and Computational Biology. https://doi.org/10.1101/2021.01.23.427922

[4] Kelleher J, Etheridge AM, McVean G (2016) Efficient Coalescent Simulation and Genealogical Analysis for Large Sample Sizes. PLOS Computational Biology, 12, e1004842. https://doi.org/10.1371/journal.pcbi.1004842

[5] Rogers AR, Harris NS, Achenbach AA (2020) Neanderthal-Denisovan ancestors interbred with a distantly related hominin. Science Advances, 6, eaay5483. https://doi.org/10.1126/sciadv.aay5483

[6] Soraggi S, Wiuf C, Albrechtsen A (2018) Powerful Inference with the D-Statistic on Low-Coverage Whole-Genome Data. G3 Genes|Genomes|Genetics, 8, 551–566. https://doi.org/10.1534/g3.117.300192

24 Dec 2020
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A linear time solution to the Labeled Robinson-Foulds Distance problem

Recommended by based on reviews by Gabriel Cardona, Jean-Baka Domelevo Entfellner , Barbara Holland and 1 anonymous reviewer

Comparing reconciled gene trees in linear time

Unlike a species tree, a gene tree results not only from speciation events, but also from events acting at the gene level, such as duplications and losses of gene copies, and gene transfer events [1]. The reconciliation of phylogenetic trees consists in embedding a given gene tree into a known species tree and, doing so, determining the location of these gene-level events on the gene tree [2]. Reconciled gene trees can be seen as phylogenetic trees where internal node labels are used to discriminate between different gene-level events. Comparing them is of foremost importance in order to assess the performance of various reconciliation methods (e.g. [3]).
A paper describing an extension of the widely used Robinson-Foulds (RF) distance [4] to trees with labeled internal nodes was presented earlier this year [5]. This distance, called ELRF, is based on edge edits and coincides with the RF distance when all internal labels are identical; unfortunately, the ELRF distance is very costly to compute. In the present paper [6], the authors introduce a distance called LRF, which is inspired by the TED (Tree Edit Distance [7]) and is based on node edits. As the ELRF, the new distance coincides with the RF distance for identically-labeled internal nodes, but has the additional desirable features of being computable in linear time. Also, in the ELRF distance, an edge can be deleted if only it connects nodes with the same label. The new formulation does not have this restriction, and this is, in my opinion, an improvement since the restriction makes little sense in the comparison of reconciled gene trees.
The authors show the pertinence of this new distance by studying the impact of taxon sampling on reconciled gene trees when internal labels are computed via a method based on species overlap. The linear algorithm to compute the LRF distance presented in the paper has been implemented and the software —written in Python— is freely available for the community to use it. I bet that the LRF distance will be widely used in the coming years!

References

[1] Maddison, W. P. (1997). Gene trees in species trees. Systematic biology, 46(3), 523-536. doi: https://doi.org/10.1093/sysbio/46.3.523
[2] Boussau, B., and Scornavacca, C. (2020). Reconciling gene trees with species trees. Phylogenetics in the Genomic Era, p. 3.2:1–3.2:23. [3] Doyon, J. P., Chauve, C., and Hamel, S. (2009). Space of gene/species trees reconciliations and parsimonious models. Journal of Computational Biology, 16(10), 1399-1418. doi: https://doi.org/10.1089/cmb.2009.0095
[4] Robinson, D. F., and Foulds, L. R. (1981). Comparison of phylogenetic trees. Mathematical biosciences, 53(1-2), 131-147. doi: https://doi.org/10.1016/0025-5564(81)90043-2
[5] Briand, B., Dessimoz, C., El-Mabrouk, N., Lafond, M. and Lobinska, G. (2020). A generalized Robinson-Foulds distance for labeled trees. BMC Genomics 21, 779. doi: https://doi.org/10.1186/s12864-020-07011-0
[6] Briand, S., Dessimoz, C., El-Mabrouk, N. and Nevers, Y. (2020) A linear time solution to the labeled Robinson-Foulds distance problem. bioRxiv, 2020.09.14.293522, ver. 4 peer-reviewed and recommended by PCI Mathematical and Computational Biology. doi: https://doi.org/10.1101/2020.09.14.293522
[7] Zhang, K., and Shasha, D. (1989). Simple fast algorithms for the editing distance between trees and related problems. SIAM journal on computing, 18(6), 1245-1262. doi: https://doi.org/10.1137/0218082

09 Sep 2020
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Bayesian investigation of SARS-CoV-2-related mortality in France

Recommended by based on reviews by Wayne Landis and 1 anonymous reviewer

Modeling the effect of lockdown and other events on the dynamics of SARS-CoV-2 in France

This study [1] used Bayesian models of the number of deaths through time across different regions of France to explore the effects of lockdown and other events (i.e., holding elections) on the dynamics of the SARS-CoV-2 epidemic. The models accurately predicted the number of deaths 2 to 3 weeks in advance, and results were similar to other recent models using different structure and input data. Viral reproduction numbers were not found to be different between weekends and week days, and there was no evidence that holding elections affected the number of deaths directly. However, exploring different scenarios of the timing of the lockdown showed that this had a substantial impact on the number of deaths. This is an interesting and important paper that can inform adaptive management strategies for controlling the spread of this virus, not just in France, but in other geographic areas. For example, the results found that there was a lag period between a change in management strategies (lockdown, social distancing, and the relaxing of controls) and the observed change in mortality. Also, there was a large variation in the impact of mitigation measures on the viral reproduction number depending on region, with lockdown being slightly more effective in denser regions. The authors provide an extensive amount of additional data and code as supplemental material, which increase the value of this contribution to the rapidly growing literature on SARS-CoV-2.

References

[1] Duchemin, L., Veber, P. and Boussau, B. (2020) Bayesian investigation of SARS-CoV-2-related mortality in France. medRxiv 2020.06.09.20126862, ver. 5 peer-reviewed and recommended by PCI Mathematical & Computational Biology. doi: 10.1101/2020.06.09.20126862