Biology subjects

Thomas, D. C.

Publications and source records attributed to Thomas, D. C..

13 recordsLinked to original sources

bioRxiv2025

Stabilising selection and ecological trade-offs underpin coexistence in a tropical flora

Tropical forests harbour the majority of global plant biodiversity1,2, yet the genomic mechanisms governing the assembly and maintenance of these communities remain poorly understood. Here, we assembled draft genomes for 499 angiosperm species from a lowland rainforest in Singapore, representing 67% of its flora, and integrated these with plant traits and comprehensive forest census data. Across the community, most gene families evolve under stabilising selection, with copy numbers maintained near long-term optima that differ among ecological strategies. These niche-associated genomic attractor states provide a mechanism for convergent adaptation and species coexistence. Modelling stabilising selection also identified a strong trade-off between defence and growth, indicating that pathogen pressure constrains developmental diversification. Consistent with this, species-specific genome space was enriched for resistance genes and transposable elements. In contrast, genomic processes structuring present-day plant community composition differ from those driving deep-time convergence. Genomic comparisons across forest types revealed stronger selection on defence-related pathways in old-growth primary forests and on growth-related processes in regenerating secondary forests, while community-level genomic profiles showed expansions in gene families associated with rapid responses to environmental fluctuations. Stabilising selection therefore links population-level adaptation3,4 with long-term species diversification in the tropics. Niche similarity promotes long-term coexistence, whereas local community structure is shaped by more rapid ecological filtering driven by environmental change. Taken together, these two distinct evolutionary layers provide a genomic framework for understanding how hyperdiverse rainforest floras arise and persist.

genomics↗

bioRxiv2024

Absolute quantification of cerebral metabolites using 2D 1H-MRSI with quantitative MRI-based water reference

PurposeMetabolite concentrations are valuable biomarkers in brain tumors (BT). However, correction of water relaxation effects often requires time-consuming quantitative MRI (qMRI) sequences on top of a lengthy spectroscopic water reference acquisition. The goal of this work was to develop and validate a fast metabolite quantification method where a 2D spectroscopic water reference acquisition is obtained using a fast qMRI protocol and single-voxel STEAM sequence. MethodsA 2D sLASER sequence was acquired for MRSI. An 8-minute qMRI protocol was also acquired. A single-voxel unsuppressed water signal was acquired using a STEAM sequence. The H2O map, obtained from qMRI, was calibrated based on the STEAM-signal to obtain the spectroscopic water reference (proposed method). Five healthy volunteers and one BT patient were scanned at 3T. Concentrations obtained using the proposed and two reference methods, one where water relaxation effects were corrected using literature values (Reference method) and one where they were corrected using qMRI-derived values (Reference method with qMRI) were compared. ResultsIn healthy subjects, WM metabolite concentrations obtained using water relaxation using literature values (Reference method) significantly differed from those using individual-specific corrections (Reference method with qMRI and proposed method). Bland-Altman analyses revealed a very low bias and SD of the differences between the Reference method with qMRI and the proposed-method (Bias<0.5% and SD<10%). The BT regions showed a [~]15% underestimation of metabolite concentrations using the Reference method. ConclusionFor metabolite quantification, accurate water referencing with individual-specific corrections for water relaxation times was obtained in 8 minutes using the proposed method.

neuroscience↗

bioRxiv2023

A disease-associated gene desert orchestrates macrophage inflammatory responses via ETS2

Increasing global rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2 - underscoring an urgent need to better understand disease mechanisms. Here we show how genetics could address this challenge. By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasus arteritis3-6, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Genes regulated by ETS2 were prominently expressed in affected tissues from chr21q22-associated diseases and more enriched for IBD GWAS hits than almost all previously described pathways. Overexpressing ETS2 in resting macrophages produced an activated effector state that phenocopied intestinal macrophages from IBD7, with upregulation of multiple drug targets including TNF and IL-23. Using a database of cellular signatures8, we identify drugs that could modulate this pathway and validate the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this highlights the potential for common genetic associations to improve both the understanding and treatment of human disease.

immunology↗

bioRxiv2022

Reversible restriction of electron flow across cytochrome b6f in dark acclimated cells limited for downstream electron sinks

Photosynthetic organisms frequently experience abiotic stresses that restrict their growth and development. Under such circumstances, most absorbed solar energy cannot be used for CO2 fixation and can cause the photoproduction of reactive oxygen species (ROS) that can damage the photosynthetic reaction centers, photosystems I and II (PSI and PSII), resulting in a decline in primary productivity. This work describes a biological switch in the green alga Chlamydomonas reinhardtii that reversibly restricts photosynthetic electron transport (PET) at the cytochrome b6f complex when reductant and ATP generated by PET are in excess of the capacity of carbon metabolism to utilize these products; we specifically show a restriction at this switch when sta6 mutant cells, which cannot synthesize starch, are limited for nitrogen (growth inhibition) and subjected to a dark-to-light transition. This restriction, which may be a form of photosynthetic control, causes diminished electron flow to PSI, which prevents PSI photodamage. When electron flow is blocked the plastid alternative oxidase (PTOX) may also become activated, functioning as an electron valve that dissipates some of the excitation energy absorbed by PSII thereby lessening PSII photoinhibition. Furthermore, illumination of the cells following the dark acclimation gradually diminishes the restriction at cytochrome b6f complex. Elucidating this photoprotective mechanism and its modulating factors may offer new insights into mechanisms associated with photosynthetic control and offer new directions for optimizing photosynthesis.

plant biology↗

bioRxiv2021

Evidence for alternate stable states in an Ecuadorian Andean Cloud Forest

We analyzed a set of historical data from rapid vegetation inventories in a tropical montane cloud forest in northern Andean Ecuador. Trees in plots from several types of forest were counted and measured, including: (1) primary forest, including mature and recently closed-canopy sites and naturally formed gaps, (2) abandoned pasture, and (3) intensively-farmed sites. The goal of the study was to understand in a specific period of time the similarities and differences among natural and anthropogenic disturbances and their potential long term effect on the forest plant community. We found that mature and intermediate close canopy sites are similar. Also old forest is quite resilient to gap-forming disturbance. Natural gaps are quickly colonized by old-forest-associated plant species, and return to an old-forest-type community of trees in a short time. In contrast, forests regenerating from anthropogenic disturbance appear to have multiple possible states: some regenerating forest sites where the anthropogenic disturbance were low are coming to closely resemble old-forest-type communities, but some where the anthropogenic disturbance was intense appear to be changing in a very different direction, which does not resemble any other vegetation community type currently in the forest. A major predictor of present ecological state is the type of land use before reforestation: pastures can occasionally transition back to the pre-disturbance state of forest. More intensively used sites, many of which are abandoned sugar cane plantations, do not return to a pre-disturbance ecological state, instead forming a new and different kind of forest, dominated by a different community of trees. We examined tree-seedling communities to understand the trajectory of the forest into the future, and find that new forest types may be forming that do not resemble any existing associationsintensive agricultural sites. We also found that Los Cedros is extremely diverse in tree species. We estimate approximately 500 species of tree in only the small southeastern area of the reserve that has been explored scientifically. Additionally, the forest tree community shows extremely rapid distance decay (beta-diversity), approaching near complete turn-over in the limited spatial extent of the study. This suggests that hundreds of other tree species remain to be observed in the reserve, in addition to the 350+ that are directly observed in the present study, including new observations of species with IUCN threatened-endangered status. We also highlight the conservation value of Reserva Los Cedros, which has managed to reverse deforestation within its boundaries despite a general trend of extensive deforestation in the surrounding region, and to protect large, contiguous areas of highly-endangered Andean primary cloud forest habitat.

ecology↗

bioRxiv2021

EROS-mediated control of NOX2 and P2X7 biosynthesis

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

immunology↗

bioRxiv2020

A Library Of Induced Pluripotent Stem Cells From Clinically Well-Characterized, Diverse Healthy Human Individuals

A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22-61. The hiPSCs match the karyotype and short tandem repeat identity of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of Mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-seq derived cell clusters and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

cell biology↗

bioRxiv2020

Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability

Polymerase {delta}-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, moonlighting protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism, DNA replication and repair, and reactive oxygen species generation. POLDIP2 is found in multiple cellular compartments, potentially shuttled depending on its role. How POLDIP2 binds to and coordinates many different proteins is currently unknown. Towards this goal, we present the crystal structure of the mitochondrial fragment of POLDIP2 to 2.8 [A]. POLDIP2 exhibited a compact two-domain {beta}-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised canonical DUF525 (ApaG) and YccV-like domains, but with the conserved domain linker packed tightly, resulting in an extended YccV module. A central channel through POLDIP2 was observed which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Finally we build models of POLDIP2 interacting in complex with two of its partners in genome stability, PrimPol and PCNA. These indicate that dynamic flexibility of the POLDIP2 N-terminal and loop regions are critical to mediate protein-protein interactions.

biochemistry↗

bioRxiv2020

On the automatic annotation of gene functions using observational data and phylogenetic trees

MotivationGene function annotation is important for a variety of downstream analyses of genetic data. Yet experimental characterization of function remains costly and slow, making computational prediction an important endeavor. In this paper we use a probabilistic evolutionary model built upon phylogenetic trees and experimental Gene Ontology functional annotations that allows automated prediction of function for unannotated genes. ResultsWe have developed a computationally efficient model of evolution of gene annotations using phylogenies based on a Bayesian framework using Markov Chain Monte Carlo for parameter estimation. Unlike previous approaches, our method is able to estimate parameters over many different phylogenetic trees and functions. The resulting parameters agree with biological intuition, such as the increased probability of function change following gene duplication. The method performs well on leave-one-out validation, and we further validated some of the predictions in the experimental scientific literature. AvailabilityOur method has been implemented as an R package and it is available online at https://github.com/USCBiostats/aphylo. Code needed to reproduce the tables and figures can be found in https://github.com/USCbiostats/aphylo-simulations. Author summaryUnderstanding the individual role that genes play in life is a key issue in biomedical-sciences. While information regarding gene functions is continuously growing, the number of genes with unknown biological purpose is yet greater. Because of this, scientists have dedicated much of their time to build and design tools that automatically infer gene functions. In this paper, we present yet another attempt to do such. While very simple, our model of gene-function evolution has some key features that have the potential to generate an impact in the field: (a) compared to other methods, ours is highly-scalable, which means that it is possible to simultaneously analyze hundreds of what are known as gene-families, compromising thousands of genes, (b) supports our biological intuition as our models data-driven results coherently agree with what theory dictates regarding how gene-functions evolved, (c) notwithstanding its simplicity, the models prediction accuracy is comparable to other more complex alternatives, and (d) perhaps most importantly, it can be used to both support new annotations and to suggest areas in which existing annotations show inconsistencies that may indicate errors or controversies.

bioinformatics↗

bioRxiv2020

Incorporating Prior Knowledge into Regularized Regression

MotivationAssociated with genomic features like gene expression, methylation, and genotypes, used in statistical modeling of health outcomes, there is a rich set of meta-features like functional annotations, pathway information, and knowledge from previous studies, that can be used post-hoc to facilitate the interpretation of a model. However, using this meta-feature information a-priori rather than post-hoc can yield improved prediction performance as well as enhanced model interpretation. ResultsWe propose a new penalized regression approach that allows a-priori integration of external meta-features. The method extends LASSO regression by incorporating individualized penalty parameters for each regression coefficient. The penalty parameters are in turn modeled as a log-linear function of the meta-features and are estimated from the data using an approximate empirical Bayes approach. Optimization of the marginal likelihood on which the empirical Bayes estimation is based is performed using a fast and stable majorization-minimization procedure. Through simulations, we show that the proposed regression with individualized penalties can outperform the standard LASSO in terms of both parameters estimation and prediction performance when the external data is informative. We further demonstrate our approach with applications to gene expression studies of bone density and breast cancer. Availability and implementationThe methods have been implemented in the R package xtune freely available for download from CRAN.

bioinformatics↗

bioRxiv2019

The soursop genome and comparative genomics of basalangiosperms provide new insights on evolutionaryincongruence

Deep relationships and the sequence of divergence among major lineages of angiosperms (magnoliids, monocots and eudicots) remain ambiguous and differ depending on analytical approaches and datasets used. Complete genomes potentially provide opportunities to resolve these uncertainties, but two recently published magnoliid genomes instead deliver further conflicting signals. To disentangle key angiosperm relationships, we report a high-quality draft genome for the soursop (Annona muricata, Annonaceae). We reconstructed phylogenomic trees and show that the soursop represents a genomic mosaic supporting different histories, with scaffolds almost exclusively supporting single topologies. However, coalescent methods and a majority of genes support magnoliids as sister to monocots and eudicots, where previous whole genome-based studies remained inconclusive. This result is clear and consistent with recent studies using plastomes. The soursop genome highlights the need for more early diverging angiosperm genomes and critical assessment of the suitability of such genomes for inferring evolutionary history.

evolutionary biology↗

bioRxiv2018

New mining concessions will severely decrease biodiversity and ecosystem services in Ecuador

Ecuador has the worlds highest biodiversity, despite being a tiny fraction of the worlds land area. The threat of extinction for much of this biodiversity has dramatically increased since April 2016, during which time the Ecuadorian government has opened approximately 2.9 million hectares of land for mining exploration, with many of the concessions in previously protected forests. Herein, we describe the system of protected lands in Ecuador, their mining laws, and outline the scale of threat by comparing the mammals, amphibians, reptiles, birds, and orchids from several now threatened protected areas, classed as \"Bosques Protectores\" (BPs), in the NW montane cloud forests. We examine two large (>5,000 ha) BPs, Los Cedros and El Chontal, and two medium BPs, Mashpi (1,178 ha) and Maquipucuna (2,474 ha). Since BP El Chontal is so poorly explored, we used several other small reserves (<500 hectares) in the Intag Valley to gain an idea of its biodiversity. Together, these BPs and reserves form a buffer and a southern corridor for the still-protected Cotacachi-Cayapas Ecological Reserve, which is otherwise now surrounded by mining concessions. We gathered published literature, \"gray literature\", information from reserve records and websites, and our previously unpublished observations to make comparative species tables for each reserve. Our results from these still incompletely known reserves reveal the astonishing losses that mining will incur: eight critically endangered species, including two primates (brown-headed spider monkey and white-fronted capuchin), 37 endangered species, 149 vulnerable and 85 near threatened and a large number of less threatened species Our data show that each of the reserves protects a unique subset of taxa in this land of highly localized endemics. Each of the reserves also generates sustainable income for the local people. The short-term national profits from mining will not compensate for the permanent biodiversity losses, and the long-term ecosystem service and economic losses at the local and regional level.

ecology↗

bioRxiv2017

An agent-based model of the Foraging Ascomycete Hypothesis

Most trees host hundreds of species of fungi asymptomatically in their internal tissues, known collectively as fungal endophytes. The Foraging Ascomycete (FA) hypothesis proposes that some fungal endophytes inhabit the internal leaf tissue of forest trees in order to enhance dispersal to substrates on the forest floor, by using leaves as vectors and as refugia during periods of environmental stress. This dispersal strategy has been termed viaphytism. Following the FA hypothesis, many fungi may therefore be in continuous and cyclical flux between life stages as endophytes in the forest canopy and as wood-decomposing fungi on the forest floor. This cycle may represent a very common and previously-ignored process in the ecology of forests, with implications for forest health. The ecological consequences of the FA hypothesis are complex, so we constructed an agent-based model of the FA hypothesis. Our model is intended to serve as both an explicit conceptual explanation of the FA hypothesis, and as an exploration of the conditions in which a strategy of endophytism accompanied by leaf dispersal may be advantageous for fungi. In a scenario of a viaphytic fungal species on a model forest landscape, without fungal competitors, viaphytism is predicted to be a plausible alternative to dispersal to substrates by spores alone, allowing the fungus to persist reliably on the landscape. In a scenario that allows competition from aggressively dispersed non-viaphytic fungi, the model predicts some competitive benefits to fungal dispersal via leaves. However, these benefits are conditional, requiring sufficient retention through time of endophyte infections by host trees, and sufficient host trees on the landscape. In the model, loss of these fungal populations can result from increased local disturbances of forest canopy, and deforestation.

ecology↗