Biology subjects

Goyal, A.

Publications and source records attributed to Goyal, A..

53 records · Page 3Linked to original sources

bioRxiv2021

RTT109 AND Fun30 proteins mediate epigenetic regulation of the DNA damage response pathway in C. albicans

Fun30, an ATP-dependent chromatin remodeller, from S. cerevisiae mediates both regulation of gene expression as well as DNA damage response/repair. In this paper, we have characterized the biochemical and physiological function of Fun30 from the opportunistic fungi, C. albicans. Biochemically, the protein shows DNA-stimulated ATPase activity. Physiologically, the protein co-regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathway. The expression of FUN30, in turn, is regulated by histone H3 acetylation catalysed by Rtt109 encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1 and RAD5 expression; ChIP experiments showed Fun30 but not H3ac regulates the expression of these genes in response to oxidative stress. In contrast, on treatment with MMS, the expression of RAD9 is upregulated and this upregulation is co-regulated by both Fun30 and H3 acetylation catalysed by Rtt109. Thus, Fun30 and H3 acetylation mediate the response of the fungal cell to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.

molecular biology↗

bioRxiv2021

Complementary resource preferences spontaneously emerge in diauxic microbial communities

Many microbes grow diauxically, utilizing the available resources one at a time rather than simultaneously. The properties of communities of microbes growing diauxically remain poorly understood, largely due to a lack of theory and models of such communities. Here, we develop and study a minimal model of diauxic microbial communities assembling in a serially diluted culture. We find that unlike co-utilizing communities, diauxic community assembly repeatably and spontaneously leads to communities with complementary resource preferences, i.e., communities where species prefer different resources as their top choice. Simulations and theory explain that the emergence of complementarity is driven by the disproportionate contribution of the top choice resource to the growth of a diauxic species. Additionally, we develop a geometric approach for analyzing serially diluted communities, with or without diauxie, which intuitively explains several additional emergent community properties, such as the apparent lack of species which grow fastest on a resource other than their most preferred resource. Overall, our work provides testable predictions for the assembly of natural as well as synthetic communities of diauxically shifting microbes.

ecology↗

bioRxiv2021

Interactions between strains govern the eco-evolutionary dynamics of microbial communities

Genomic data has revealed that genotypic variants of the same species, i.e., strains, coexist and are abundant in natural microbial communities. However, it is not clear if strains are ecologically equivalent, or if they exhibit distinct interactions and dynamics. Here, we address this problem by tracking 10 microbial communities from the pitcher plant Sarracenia purpurea in the laboratory for more than 300 generations. Using metagenomic sequencing, we reconstruct their dynamics over time and across scales, from distant phyla to closely related genotypes. We find that interactions between naturally occurring strains govern eco-evolutionary dynamics. Surprisingly, even fine-scale variants differing only by 100 base pairs can exhibit vastly different dynamics. We show that these differences may stem from ecological interactions in the communities, which are specific to strains, not species. Finally, by analyzing genomic differences between strains, we identify major functional hubs such as transporters, regulators, and carbohydrate-catabolizing enzymes, which might be the basis for strain-specific interactions. Our work shows that strains are the relevant level of diversity at which to study the long-term dynamics of microbiomes.

microbiology↗

bioRxiv2020

Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells

{beta}-thalassemia pathology is not only due to loss of {beta}-globin (HBB), but also erythrotoxic accumulation and aggregation of the {beta}-globin binding partner, -globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in {beta}-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize {beta}-globin:-globin mRNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in mice, establishing proof-of-concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing {beta}-thalassemia.

molecular biology↗

bioRxiv2020

A simple linear relationship between resource availability and microbial community diversity

The relationship between the number of available nutrients and community diversity is a central question for ecological research that remains unanswered. Here, we studied the assembly of hundreds of soil-derived microbial communities on a wide range of well-defined resource environments, from single carbon sources to combinations of up to 16. We found that, while single resources supported multispecies communities varying from 8 to 40 taxa, mean community richness increased only one-by-one with additional resources. Cross-feeding could reconcile these seemingly contrasting observations, with the metabolic network seeded by the supplied resources explaining the changes in richness due to both the identity and the number of resources, as well as the distribution of taxa across different communities. By using a consumer-resource model incorporating the inferred cross-feeding network, we provide further theoretical support to our observations and a framework to link the type and number of environmental resources to microbial community diversity.

ecology↗

bioRxiv2020

Horizontal gene transfer becomes disadvantageous in rapidly fluctuating environments

Horizontal gene transfer (HGT) allows organisms to share genetic material with non-offspring, and is typically considered beneficial for evolving populations. Recent unexplained observations suggest that HGT rates in nature are linked with environmental dynamics, being high in static environments but surprisingly low in fluctuating environments. Here, using a geometric model of adaptation, we show that this trend might arise from evolutionary constraints. During adaptation in our model, a population of phenotype vectors aligns with a potentially fluctuating environmental vector while experiencing mutation, selection, drift and HGT. Simulations and theory reveal that HGT shapes a trade-off between the adaptation speed of populations and their fitness. This trade-off gives rise to an optimal HGT rate which decreases sharply with the rate of environmental fluctuations. Our results are consistent with data from natural populations, and strikingly suggest that HGT may sometimes carry a significant disadvantage for populations.

evolutionary biology↗

bioRxiv2020

Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung. One Sentence SummaryWe developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.

microbiology↗

bioRxiv2020

Ecology-guided prediction of cross-feeding interactions in the human gut microbiome

Understanding a complex microbial ecosystem such as the human gut microbiome requires information about both microbial species and the metabolites they produce and secrete. These metabolites are exchanged via a large network of cross-feeding interactions, and are crucial for predicting the functional state of the microbiome. However, till date, we only have information for a part of this network, limited by experimental throughput. Here, we propose an ecology-based computational method, GutCP, using which we predict hundreds of new experimentally untested cross-feeding interactions in the human gut microbiome. GutCP utilizes a mechanistic model of the gut microbiome with the explicit exchange of metabolites and their effects on the growth of microbial species. To build GutCP, we combined metagenomic and metabolomic measurements from the gut microbiome with optimization techniques from machine learning. Close to 65% of the cross-feeding interactions predicted by GutCP are supported by evidence from genome annotation; we provide these predictions for experimentally testing. Our method has the potential to greatly improve existing models of the human gut microbiome, as well as our ability to predict the metabolic profile of the gut.

ecology↗

bioRxiv2020

In Arabidopsis, low blue light enhances phototropism by releasing cryptochrome 1-mediated inhibition of PIF4 expression

Shade-avoiding plants including Arabidopsis thaliana display a number of growth responses elicited by shade cues including elongation of stem-like structures and repositioning of leaves. Shade also promotes phototropism of de-etiolated seedlings through repression of phytochrome B (phyB) presumably to enhance capture of unfiltered sunlight. Light cues indicative of shade include a reduction in the blue and red portions of the solar spectrum and a low red to far-red ratio. Here we show that in Arabidopsis seedlings both low blue and a low red to far-red ratio are required to rapidly enhance phototropism. However, prolonged low blue treatments through reduced cryptochrome 1 (cry1) activation are sufficient to promote phototropism. The enhanced phototropic response of cry1 mutants in the lab and in response to natural canopies depends on PHYTOCHROME INTERACTING FACTORs (PIFs). In favorable light conditions, cry1 limits the expression of PIF4 while in low blue light PIF4 expression increases, which contributes to phototropic enhancement. The analysis of a quantitative DII auxin reporter indicates that low blue light leads to enhanced auxin levels in the hypocotyl and, upon phototropic stimulation, a steeper auxin gradient across the hypocotyl. We conclude that phototropic enhancement by canopy shade results from the combined activities of phytochrome B and cry1 that converge on PIF regulation. ONE SENTENCE SUMMARYThe persistent depletion of blue light in natural canopy shade relieves the inhibitory effect of cryptochrome 1 on PIF4, enhancing phototropism in de-etiolated Arabidopsis seedlings. Financial supportThis work was supported by the University of Lausanne and a grant from the Swiss National Science foundation (n{degrees} 310030B_179558 to C.F.); Human Frontier Science Program organization (HFSP) Grant RPG0054-2013, ANR-12-BSV6-0005 grant (AuxiFlo) to T.V.; The University of Buenos Aires (Grant 20020100100437 to J. J. C.), and Agencia Nacional de Promocion Cientifica y Tecnologica of Argentina (Grant PICT-2018-01695 to J. J. C.). Alessandra Boccaccini and Martina Legris are funded by Marie Curie fellowships H2020-MSCA-IF-2017 grants CRoSh 796283 and Flat-Leaf 796443 respectively.

plant biology↗

bioRxiv2019

Horizontal gene transfer drives the evolution of dependencies in bacteria

Many naturally-occurring bacteria lead a lifestyle of metabolic dependency, i.e., they depend on others for crucial resources. We do not understand what factors drive bacteria towards this lifestyle, and how. Here, we systematically show that horizontal gene transfer (HGT) plays a crucial role in the evolution of dependencies in bacteria. Across 835 bacterial species, we map gene gain-loss dynamics on a deep evolutionary tree, and assess the impact of HGT and gene loss on bacterial metabolic networks. Our analyses suggest that genes acquired by HGT can affect which genes are later lost. Dependency evolution is contingent on earlier HGT because of two reasons. First, we find that HGT typically adds new catabolic routes to bacterial metabolic networks. This increases the chance of new metabolic interactions between bacteria, which is a prerequisite for dependency evolution. Second, we show that gaining new routes can promote the loss of specific ancestral routes (a mechanism we call "coupled gains and losses", CGLs). Phylogenetic patterns indicate that both types of dependencies -- those mediated by CGLs and those purely by gene loss -- are equally likely. Our results highlight HGT as an important driver of metabolic dependency evolution in bacteria.

microbiology↗

bioRxiv2019

Evidence for a multi-level trophic organization of the human gut microbiome

The human gut microbiome is a complex ecosystem, in which hundreds of microbial species and metabolites coexist, in part due to an extensive network of cross-feeding interactions. However, both the large-scale trophic organization of this ecosystem, and its effects on the underlying metabolic flow, remain unexplored. Here, using a simplified model, we provide quantitative support for a multi-level trophic organization of the human gut microbiome, where microbes consume and secrete metabolites in multiple iterative steps. Using a manually-curated set of metabolic interactions between microbes, our model suggests about four trophic levels, each characterized by a high level-to-level metabolic transfer of byproducts. It also quantitatively predicts the typical metabolic environment of the gut (fecal metabolome) in approximate agreement with the real data. To understand the consequences of this trophic organization, we quantify the metabolic flow and biomass distribution, and explore patterns of microbial and metabolic diversity in different levels. The hierarchical trophic organization suggested by our model can help mechanistically establish causal links between the abundances of microbes and metabolites in the human gut.

microbiology↗

bioRxiv2018

Functionally distinct high and low theta oscillations in the human hippocampus

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in thetas function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

neuroscience↗

bioRxiv2018

Metabolic adaptations underlying genome flexibility in prokaryotes

Even across genomes of the same species, prokaryotes exhibit remarkable flexibility in gene content. We do not know whether this flexible or \"accessory\" content is mostly neutral or adaptive, largely due to the lack of explicit analyses of accessory gene function. Here, across 96 diverse prokaryotic species, I show that a considerable fraction (~40%) of accessory genomes harbours beneficial metabolic functions. These functions take two forms: (1) they significantly expand the biosynthetic potential of individual strains, and (2) they help reduce strain-specific metabolic auxotrophies via intra-species metabolic exchanges. I find that the potential of both these functions increases with increasing genome flexibility. Together, these results are consistent with a significant adaptive role for prokaryotic pangenomes.\n\nAuthor SummaryRecent and rapid advancements in genome sequencing technologies have revealed key insights into the world of bacteria and archaea. One puzzling aspect uncovered by these studies is the following: genomes of the same species can often look very different. Specifically, some \"core\" genes are maintained across all intraspecies genomes, but many \"accessory\" genes differ between strains. A major ongoing debate thus asks: do most of these accessory genes provide a benefit to different strains, and if so, in what form? In this study, I suggest that the answer is \"yes, through metabolic interactions\". I show that many accessory genes provide significant metabolic advantages to different strains in different conditions. I achieve this by explicitly conducting a large-scale systematic analysis of 1,339 genomes across 96 diverse species of bacteria and archaea. A surprising prediction of this study that in many ecological niches, co-occurring strains of the same species may help each other survive by exchanging metabolites exclusively produced by these different accessory genes. More pronounced gene differences lead to more underlying metabolic advantages.

ecology↗

bioRxiv2018

PIF transcription factors link a neighbor threat cue to accelerated reproduction in Arabidopsis

Changes in light quality indicative of competition for this essential resource influence plant growth and developmental transitions. Little is known about neighbor proximity-induced acceleration of reproduction. phytochrome B (phyB) senses light cues from plant competitors ultimately leading to the expression of the floral inducers FLOWERING LOCUS (FT) and TWIN SISTER of FT (TSF). Here we show that three PHYTOCHROME INTERACTING FACTOR (PIF) transcriptional regulators act directly downstream of phyB to promote expression of FT and TSF. Neighbor proximity enhances PIF accumulation towards the end of the day coinciding with enhanced floral inducer expression. We present evidence for direct PIF-mediated TSF expression. The relevance of our findings is illustrated by the prior identification of FT, TSF and PIF4 as loci underlying flowering time regulation in nature.\n\nOne Sentence SummaryPIF transcription factors mediate reproductive transition in response to neighbor proximity light cues in Arabidopsis.

plant biology↗

bioRxiv2017

Microbial community structure predicted by the stable marriage problem

Experimental studies of microbial communities routinely reveal that they have multiple stable states. While each of these states is generally resilient, certain perturbations such as antibiotics, probiotics and diet shifts, result in transitions to other states. Can we reliably both predict such stable states as well as direct and control transitions between them? Here we present a new conceptual model -- inspired by the stable marriage problem in game theory and economics -- in which microbial communities naturally exhibit multiple stable states, each state with a different species abundance profile. Our models core ingredient is that microbes utilize nutrients one at a time while competing with each other. Using only two ranked tables, one with microbes nutrient preferences and one with their competitive abilities, we can determine all possible stable states as well as predict inter-state transitions, triggered by the removal or addition of a specific nutrient or microbe. Further, using an example of 7 Bacteroides species common to the human gut utilizing 9 polysaccharides, we predict that mutual complementarity in nutrient preferences enables these species to coexist at high abundances.

ecology↗

bioRxiv2017

The medial temporal lobe organizes memory across time and space: Causal evidence from brain stimulation

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects abilities to remember items using view-independent (allocentric) navigation strategies. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.\n\nSignificance StatementNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

neuroscience↗

bioRxiv2017

Diversity, stability, and reproducibility in stochastically assembled microbial ecosystems

Microbial ecosystems are remarkably diverse, stable, and often consist of a balanced mixture of core and peripheral species. Here we propose a conceptual model exhibiting all these emergent properties in quantitative agreement with real ecosystem data, specifically species abundance and prevalence distributions. Resource competition and metabolic commensalism drive stochastic ecosystem assembly in our model. We demonstrate that even when supplied with just one resource, ecosystems can exhibit high diversity, increasing stability, and partial reproducibility between samples.

ecology↗