Biology subjects

Pearson, A.

Publications and source records attributed to Pearson, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Tumor extracellular vesicle RNA profiling predicts treatment response in pediatric diffuse midline glioma

Detection of reliable markers of therapy response and drug resistance remains a major unmet need in brain cancer, as serial tumor biopsy is often not feasible. This challenge is particularly acute in diffuse midline glioma (DMG), a fatal pediatric brain tumor for which new targeted therapies are entering clinical use, yet tools for real-time molecular analysis of tumor evolution during therapy remain lacking. Here, we demonstrate that plasma tumor-derived extracellular vesicle (EV) profiling provides a minimally invasive and complementary approach for diagnosis and longitudinal molecular monitoring in H3K27M-mutant DMG. Across patient-derived tumor models and clinical plasma samples, EV mRNA levels correlated strongly with parental tumor transcriptomes. EV H3K27M mRNA enabled discrimination of DMG from non-DMG controls, and exploratory EV response-associated mRNAs were linked to radiographic response and progression-free survival in patients receiving ONC201. To enable tumor-selective EV enrichment and multiplexed molecular profiling within a clinically practical workflow, we developed a new integrated platform supporting same-day EV analysis from small plasma volumes. This work represents the first proof-of-concept demonstration of the diagnostic and treatment response relevance of tumor-derived EV RNA in pediatric DMG and establishes a generalizable framework for minimally invasive longitudinal molecular monitoring in diseases where tissue access is inherently limited.

cancer biology↗

bioRxiv2026

Lipid Hydrogen Stable Isotope Probing Reveals Decadal-Scale Generation Times for Archaea in Hot Spring Sediments

Quantifying the lipid biosynthesis rate of archaea in hot spring sediments is necessary to estimate their generation times and environmental significance, with implications for modern biogeochemical cycling and astrobiology. Here, we performed lipid hydrogen stable isotope probing (LH-SIP) experiments on sediments collected from two high-temperature, suboxic, circumneutral hot springs in Yellowstone National Park (USA) and El Tatio Geyserfield (Chile). We determined the incorporation rate of 2H2O into intact polar lipids (IPLs) during short-duration, ex situ incubations, which provides a taxon- and metabolism-agnostic quantification of biosynthesis under near-natural conditions. We targeted isoprenoid glycerol dialkyl glycerol tetraether lipids (iGDGTs) and recovered structures with 0 to 7 cyclopentyl moieties from both springs. We observed minor 2H-uptake into archaeal IPL-iGDGT-derived biphytanes in spring sediments in Yellowstone, corresponding to decadal-scale apparent generation times (16 +/- 3 years), and no detectable uptake in El Tatio sediments, where lipid turnover was slower than could be resolved under the experimental conditions (maximum resolvable apparent generation times ~ 42 +/- 21 years). We conclude that these slow apparent generation times likely reflect substantial dilution by a large standing IPL pool and/or recycling or re-functionalization of relict lipid components, rather than equivalently slow rates of archaeal cell division. These are the first estimates of archaeal lipid production rates in terrestrial hydrothermal systems using LH-SIP incubations and provide critical constraints for interpreting archaeal lipids in modern systems and ancient hot spring deposits.

microbiology↗

bioRxiv2026

Integrated analysis of stemness-associated immune modulatory circuits in squamous cell carcinomas

Emerging evidence indicates that a subset of cancer cells enriched for stemness-related gene signatures possess distinct immunomodulatory capacities, enabling these tumor-initiating stem cells (tSCs) to more effectively evade or resist anti-tumor immunity. Despite these advances, the tSC-specific molecular circuits orchestrating their specialized immune privilege program are not well defined. Here, in squamous cell carcinomas of the skin and oral cavity, we comprehensively delineate the unique immune-evasive properties of tSCs and dissect the transcriptional regulation shaping their immunomodulatory programs. By integrating transcriptome profiling, chromatin landscape mapping, genetic perturbation, and single-cell RNA sequencing, we found that the tSC-specific immune program is broadly governed by SOX2, a stemness-associated transcription factor. We demonstrate that SOX2 enables tSCs to sustain immature tumor-associated neutrophils (TANs) and subsequently trigger these myeloid cells to foster the development of tumor-associated macrophages (TAMs). This SOX2-directed tSC-TAN-TAM axis establishes a localized immunosuppressive niche for protecting tSC. SIGNIFICANCEHere, we uncover SOX2 as a master regulator that orchestrates conserved immune modulatory circuits in tSCs to sustain pro-tumor myeloid cell states. These findings place tSCs at the apex of immune landscape remodeling, asserting a central role of stemness-associated program in organizing the immunosuppressive tumor microenvironment.

cancer biology↗

bioRxiv2025

The NOX2-ROS-NLRP3 inflammasome axis in traumatic brain injury

BackgroundPhagocyte NADPH oxidase 2 (NOX2) is an enzyme complex responsible for reactive oxygen species (ROS) production. Chronic NOX2 activity sustains oxidative stress/damage and drives neuroinflammation following traumatic brain injury (TBI). NOX2 acts as a priming signal for NLRP3 inflammasome activation, which also plays a role in secondary injury after TBI. GSK2795039 is a small molecule brain penetrable drug that inhibits NOX2 in a NADPH competitive manner. Here, we investigated whether pharmacological inhibition of NOX2 using GSK2795039 can reduce secondary neuroinflammation after TBI, specifically via inhibition of downstream NLRP3 inflammasome activation, in both resident microglia and infiltrating myeloid cells in the injured brain. MethodsImmortalised microglial (IMG) cells or primary microglia were pre-treated with GSK2795039 (NOX2 inhibitor) or MCC950 (NLRP3 inhibitor) and stimulated with lipopolysaccharide and nigericin to induce NOX2/ROS and NLRP3 inflammasome activation. The controlled cortical impact model, pharmacokinetic analyses, multi-dimensional flow cytometry, histology and neurobehavioral assessments were used to translate in vitro findings to an experimental TBI model in adult male C57BL6/J mice. ResultsThe small molecule NOX2 inhibitor, GSK2795039, attenuated microglial NOX2 activity, thereby reducing ROS, nitrite and cytokine levels, as well as NLRP3 inflammasome components in pro-inflammatory microglia. TBI recruited NOX2/ROS/IL-1{beta}+ neutrophils and inflammatory monocytes into injured brain parenchyma with peak monocytic NOX2/ROS/IL-1{beta} production at 3 days post-injury (DPI), coincident with peak NOX2/ROS/IL-1{beta} expression in microglia. Systemic administration of GSK2795039 (100mg/kg; I.P.) starting 2 hours post-injury attenuated NOX2/IL-1{beta}+ microglial and infiltrating myeloid cell activation at 3 DPI. In addition, NOX2 inhibition reduced numbers of IL-1R+ T cells in the brain of TBI mice, indicating that myeloid-T cell crosstalk was altered by GSK2795039 treatment. Innate and adaptive neuroimmune changes were associated with improvements in motor function post-TBI. In the chronic phase through 28 DPI, pharmacological inhibition of NOX2 by GSK2795039 treatment resulted in modest improvements in neurobehavioral deficits and TBI neuropathology. ConclusionsThese preclinical studies identify the NOX2-ROS-NLRP3 inflammasome axis along with myeloid-T cell crosstalk as effective targets for TBI neuroinflammation. Our translational studies indicate that NOX2 may be a promising therapeutic target for mitigating neuroinflammation in microglia, and peripheral immune cells, following experimental TBI in mice.

neuroscience↗

bioRxiv2024

Lipid hydrogen isotope compositions primarily reflect growth water in the model archaeon Sulfolobus acidocaldarius

The stable hydrogen isotope composition ({delta}2H) of lipid biomarkers can track environmental processes and remain stable over geologically relevant time scales, enabling studies of past climate, hydrology, and ecology. Most research has focused on lipids from the domain Eukarya (e.g., plant waxes, long-chain alkanes), and the potential of prokaryotic lipid biomarkers from the domain Archaea to offer unique insights into environments not captured by eukaryotic lipids remains unclear. Here, we investigate the H-isotope composition of biphytanes in Sulfolobus acidocaldarius, a model thermoacidophile and obligate heterotroph. We conducted a series of experiments that varied temperature, pH, shaking rate, electron acceptor availability, or electron donor flux. From these experiments, we quantified the lipid/water H-isotope fractionation (2{varepsilon}L/W) values for core biphytane chains derived from tetraether lipids. The 2{varepsilon}L/W values are consistently negative (-230 to - 180 {per thousand}) and are relatively invariant across all experiments despite a 20-fold change in doubling times and 2-fold change in lipid cyclization. The magnitude and relative invariance of 2{varepsilon}L/W values are consistent with studies on other heterotrophic archaea and suggests archaeal lipids may be faithful recorders of the {delta}2H composition of growth water. Our study highlights the potential of archaeal lipid {delta}2H as a hydrological proxy, offering new insights into environments where traditional proxies, such as plant-derived lipids, are not available, including extreme environments and extraterrestrial settings. ImportanceReconstructing past climates is crucial for understanding Earths environmental history and its responses to changing conditions. This study examines Sulfolobus acidocaldarius, a thermoacidophilic archaeon that thrives in extreme environments like hot springs. These microorganisms incorporate hydrogen water in the growth environment into membrane lipids, creating hydrogen isotope signatures that can reflect hydroclimate conditions. Our findings show that these hydrogen isotope ratios remain consistent even under varying temperature, pH, oxygen levels, and electron donor fluxes, indicating a stable fractionation between lipids and water. This invariance suggests that S. acidocaldarius lipids could serve as a robust proxy for reconstructing ancient water H-isotope values, especially in extreme environments where traditional proxies, such as plant waxes, are absent. This research has broader implications for planetary-scale reconstructions, including potential applications in studying past climates on other planets, such as Mars, where similar microorganisms may have existed in hydrothermal conditions.

microbiology↗

bioRxiv2024

A novel quinone biosynthetic pathway illuminates the evolution of aerobic metabolism

The dominant organisms in modern oxic ecosystems rely on respiratory quinones with high redox potential (HPQs) for electron transport in aerobic respiration and photosynthesis. The diversification of quinones, from low redox potential in anaerobes to HPQs in aerobes, is assumed to have followed Earths surface oxygenation [~]2.3 billion years ago. However, the evolutionary origins of HPQs remain unresolved. Here, we characterize the structure and biosynthetic pathway of a novel ancestral HPQ, methyl-plastoquinone, that is unique to bacteria of the phylum Nitrospirota. Methyl-plastoquinone is structurally related to the two previously known HPQs, plastoquinone from Cyanobacteriota/chloroplasts and ubiquinone from Pseudomonadota/mitochondria, respectively. We demonstrate a common origin of the three HPQ biosynthetic pathways that predates the emergence of Nitrospirota, Cyanobacteriota, and Pseudomonadota. An ancestral HPQ biosynthetic pathway evolved [≥] 3.4 billion years ago in an extinct lineage and was laterally transferred to these three phyla [~]2.5-3.2 billion years ago. We show that Cyanobacteriota and Pseudomonadota were ancestrally aerobic and thus propose that aerobic metabolism using HPQs significantly predates Earths surface oxygenation. Two of the three HPQ pathways were later obtained by eukaryotes through endosymbiosis forming chloroplasts and mitochondria, enabling their rise to dominance in modern oxic ecosystems. Significance statementOxygenic photosynthesis and aerobic respiration by bacteria and eukaryotes rely on respiratory quinones with high redox potential that facilitate membrane-bound electron transport. These quinones are integral to aerobic metabolism and therefore the evolution of aerobic metabolism and quinone biosynthesis must be intertwined. Only two types of high redox potential quinones have been described in bacteria and eukaryotes. Here, we describe the structure and biosynthetic pathway of a third type, methyl-plastoquinone, that is exclusive to bacteria of the phylum Nitrospirota. We then use phylogenetic analysis to show that the three high redox potential quinones have a single evolutionary origin and are much older than previously considered, predating the Great Oxygenation Event, when significant amounts of O2 first accumulated in the atmosphere.

microbiology↗

bioRxiv2024

Environmental controls on crenarchaeol distributions in hydrothermal springs

Thermophilic archaea synthesize cellular membranes composed primarily of isoprenoid glycerol dibiphytanyl glycerol tetraethers (iGDGTs). Cells can adjust the packing of their lipids by increasing the number of cyclopentyl rings during lipid synthesis, thereby decreasing membrane permeability and fluidity to maintain cellular function at high temperature, acidic pH, or nutrient limitation. Archaea of the class Nitrososphaeria synthesize an iGDGT, crenarchaeol, with four cyclopentyl rings and a cyclohexyl ring, the function of which is unknown. Structural modeling suggests the cyclohexyl ring may increase membrane fluidity, potentially optimizing membranes for mesophilic conditions. To begin to investigate this hypothesis, iGDGT composition was quantified in forty-one thermal springs in Yellowstone National Park (YNP), USA, and contextualized within a global thermal spring iGDGT compilation with pH values of 1.1 to 10.1 and temperatures of 16 to 95{degrees}C. pH was the strongest predictor of both crenarchaeol relative abundance and the number of cyclopentyl rings per iGDGT. Crenarchaeol relative abundance exhibited a nonlinear relationship with pH and temperature, with highest relative abundances at pH 7.4 and 46{degrees}C, then decreasing above and below these values. These observations are consistent with the hypothesis that the cyclohexyl ring of crenarchaeol optimizes archaeal cellular membranes for circumneutral and moderate temperature environmental conditions. ImportanceArchaea change the composition of their membrane lipids to alter the fluidity of their membranes to maintain cell homeostasis when confronted with environmental stress. Some archaea of the class Nitrososphaeria produce a lipid, crenarchaeol, with a unique six-membered ring, the effect of which on archaeal membrane dynamics remains unknown. In this study, we identify pH as the most important geochemical variable for archaeal membrane response in Yellowstone National Park thermal springs. In addition, the lipid distributions indicate that crenarchaeol production is highest in circumneutral and mesophilic environments. The YNP results are supported by similar trends across global thermal springs.

microbiology↗

bioRxiv2024

Crystal structure of a bacterial photoactivated adenylate cyclase determined at room temperature by serial femtosecond crystallography

OaPAC is a recently discovered blue-light using flavin adenosine dinucleotide (BLUF) photoactivated adenylate cyclase from the cyanobacterium Oscillatoria acuminata that uses adenosine triphosphate and translates the light signal into the production of cyclic adenosine monophosphate. Here, we report the crystal structures of the enzyme in the absence of its natural substrate determined from room temperature serial crystallography data collected at both an X-ray free electron laser and a synchrotron and we compare them with the cryo macromolecular crystallography structures obtained at a synchrotron by us and others. These results reveal slight differences in the structure of the enzyme due to data collection at different temperatures and X-ray sources. We further investigate the effect of the Y6 mutation in the blue-light using flavin adenosine dinucleotide domain, a mutation which results in a rearrangement of the hydrogen-bond network around the flavin and a notable rotation of the side-chain of the critical Q48 residue. These studies pave the way for ps - ms time-resolved serial crystallography experiments at X-ray free electron lasers and synchrotrons in order to determine the early structural intermediates and correlate them with the well-studied ps - ms spectroscopic intermediates. SynopsisStructures of the dark-adapted state of a photoactivated adenylate cyclase are determined from serial crystallography (SX) data collected at room temperature at an X-ray free electron laser (XFEL) and a synchrotron and are compared with cryo macromolecular crystallography (MX) synchrotron structures obtained by us and others. These structures of the wild-type enzyme in combination with the cryo MX synchrotron structure of a light-sensor domain mutant provide insight into the hydrogen bond network rearrangement upon blue-light illumination and pave the way for the determination of structural intermediates of the enzyme by time-resolved SX.

biophysics↗

bioRxiv2023

The hydrogen isotope signatures of autotrophy versus heterotrophy recorded in archaeal tetraether lipids

The stable hydrogen isotope composition of archaeal lipids is emerging as a potential paleoenvironmental proxy, adding to the well-established application of plant leaf wax-derived n-alkanes in paleohydrological reconstruction. A handful of studies reported relatively invariant and depleted hydrogen isotope compositions for archaeal lipids despite the range of different organisms and growth conditions explored. However, how modes of metabolism and physiological state (growth phase) affect the hydrogen isotope signatures of archaeal lipids remains poorly understood, limiting our ability to interpret archaeal lipid biomarker records from the environment. Here we conducted water isotope label experiments with a metabolically flexible and well-studied model archaeon Archaeoglobus fulgidus and quantified the hydrogen isotope fractionation between lipids and water in response to different carbon substrates and electron donor-acceptor pairs. The 2H/1H fractionation between lipids and water ({varepsilon}L/W) was overall negative, ranging from -280 to -226 {per thousand}, and overlapped with the ranges observed for other archaea in previous studies. Isotope flux-balance model results suggest that [≥]80 % and [≥]50 % of lipid-bound H in A. fulgidus cultures directly reflect water isotope compositions (i.e., not via organic substrate or H2) during autotrophy and heterotrophy, respectively. The model results also suggest the final saturation during isoprenoid lipid biosynthesis catalyzed by a flavoenzyme geranylgeranyl reductase likely contributes to the large 2H/1H fractionation observed in this study, consistent with previous isotope flux-balance model results for a different archaeon. Finally, we synthesized available data to compare {varepsilon}L/W patterns across all three domains of life: Bacteria, Archaea and Eukarya. Emerging patterns between archaeal and eukaryotic lipids are consistent with the notion of highly fractionating geranylgeranyl reductase, and the patterns between archaeal and bacterial lipids suggest that the general state of energy limitation may also contribute to large, negative values of {varepsilon}L/W observed in prokaryotic lipids. Altogether, these findings lend further support for the potential of archaeal lipid {varepsilon}L/W as a paleohydrological proxy and provide a broader insight into the 2H/1H fractionation mechanisms potentially shared among prokaryotic and eukaryotic lipid biomarkers.

microbiology↗

bioRxiv2023

Mode of carbon and energy metabolism shifts lipid composition in the thermoacidophile Acidianus

The degree of cyclization, or ring index (RI), in archaeal glycerol dibiphytanyl glycerol tetraether (GDGT) lipids was long thought to reflect homeoviscous adaptation to temperature. However, more recent experiments show that other factors (e.g., pH, growth phase, and energy flux) can also affect membrane composition. The main objective of this study was to investigate the effect of carbon and energy metabolism on membrane cyclization. To do so we cultivated Acidianus sp. DS80, a metabolically flexible and thermoacidophilic archaeon, on different electron donor, acceptor and carbon source combinations (S0/Fe3+/CO2, H2/Fe3+/CO2, H2/S0/CO2, or H2/S0/glucose). We show that differences in energy and carbon metabolism can result in over a full unit of change in RI in the thermoacidophile Acidianus sp. DS80. The patterns in RI correlated with the normalized electron transfer rate between electron donor and acceptor and did not always align with thermodynamic predictions of energy yield. In light of this, we discuss other factors that may affect the kinetics of cellular energy metabolism: electron transfer chain (ETC) efficiency, location of ETC reaction components (cytoplasmic vs. extracellular), and the physical state of electron donors and acceptors (gas vs. solid). Furthermore, assimilation of a more reduced form of carbon during heterotrophy appears to decrease the demand for reducing equivalents during lipid biosynthesis, resulting in lower RI. Together, these results point to the fundamental role of the cellular energy state in dictating GDGT cyclization, with those cells experiencing greater energy limitation synthesizing more cyclized GDGTs. ImportanceSome archaea make unique membrane-spanning lipids with different numbers of five or six membered rings in the core structure that modulate membrane fluidity and permeability. Changes in membrane core lipid composition reflect fundamental adaptation strategies of archaea in response to stress, but multiple environmental and physiological factors may affect the needs for membrane fluidity and permeability. In this study, we tested how Acidianus sp. DS80 changed its core lipid composition when grown with different electron donor/acceptor pairs. We show that changes in energy and carbon metabolisms significantly affected the relative abundance of rings in the core lipids of DS80. These observations highlight the need to better constrain metabolic parameters, in addition to environmental factors, that may influence changes in membrane physiology in Archaea. Such consideration would be particularly important for studying archaeal lipids from habitats that experience frequent environmental fluctuations and/or where metabolically diverse archaea thrive.

microbiology↗

bioRxiv2023

Distribution of carbon monoxide (CO) in several tissues from Atlantic bottlenose dolphins (Tursiops truncatus)

Carbon monoxide (CO) is known as "The Silent Killer" due to its toxic effect at high concentrations, leading to an impairment in oxygen storage, delivery, and use. The cytotoxicity of CO is due to its high affinity for transition metals, such as iron, where CO outcompetes oxygen for the heme binding sites on hemoproteins in the body. CO is made in vivo in most organisms as a byproduct of heme degradation via heme oxygenase enzymes. Certain species of deep-diving marine mammals with high quantities of hemoproteins in blood and skeletal muscle have naturally elevated concentrations of CO in these tissues. To date, there exist few data on extravascular tissue CO content in wild animals. This study aims to characterize CO concentrations in nine different tissues from stranded Atlantic bottlenose dolphins (Tursiops truncatus). We found three tissues (liver, skeletal muscle, and spleen) have higher CO concentrations than other tissues. In a subset of samples from animals that tested positive for dolphin morbillivirus, the CO content in their kidney and liver was lower when compared to animals that tested negative. The mean CO concentration found in every tissue from dolphins was higher than those previously reported in healthy rodents. However, the skeletal muscle CO concentrations in dolphins from this study were much lower than those of deep-diving elephant seals. These results highlight the diversity and pattern of CO found in different tissues from bottlenose dolphins and continues to show that the heme oxygenase/carbon monoxide pathway appears to be critical for air-breathing divers.

physiology↗

bioRxiv2023

Local Ancestry Inference for Complex Population Histories

It has become apparent from ancient DNA analysis, that the history of many human populations from across the globe are often complex, involving multiple population split, admixture, migration and isolation events. Local ancestry inference (LAI) aims to identify from which ancestral population chromosomal segments in admixed individuals are inherited. However, ancestry in existing LAI tools is characterised by a discrete population identity, a definition which is limited in the context of a complex demographic history involving multiple admixture events at different times. Moreover, many LAI tools rely on a reference panel of present day genomes that act as proxies for the ancestral populations. For ancient admixture events, these proxy genomes are likely only distantly related to the true ancestral populations. Here we present a new method that leverages advances in ancient DNA sequencing and genealogical inference to address these in issues in LAI. The method applies machine learning to tree sequences inferred for ancient and present day genomes and is based on a deterministic model of population structure, within which we introduce the concept of path ancestry. We show that the method is robust to a variety of demographic scenarios, generalises over model misspecification and that it outperforms a leading local ancestry inference tool. We further describe a downstream method to estimate the time since admixture for individuals with painted chromosomes. We apply the method to a large ancient DNA dataset covering Europe and West Eurasia and show that the inferred admixture ages are a better metric than sample ages alone for understanding movements of people across Europe in the past.

genetics↗

bioRxiv2022

Functional and structural asymmetry suggest a unifying principle for catalysis in integral membrane-bound pyrophosphatases

Membrane-bound pyrophosphatases (M-PPases) are homodimeric primary ion pumps that couple the transport of Na+- and/or H+ across membranes to the hydrolysis of pyrophosphate. Their role in the virulence of protist pathogens like Plasmodium falciparum makes them an intriguing target for structural and functional studies. Here, we show the first structure of a K+-independent M-PPase, asymmetric and time-dependent substrate binding in time-resolved structures of a K+-dependent M-PPase, and demonstrate pumping-before-hydrolysis by electrometric studies. We suggest how key residues in helix 12, 13, and the exit channel loops affect ion selectivity and K+-activation due to a complex interplay of residues that are involved in subunit-subunit communication. Our findings not only explain ion selectivity in M-PPases but also why they display half-of-the-sites reactivity. Based on this we propose, for the first time, a unified and testable model for ion pumping, hydrolysis, and energy-coupling in all M-PPases, including those that pump both Na+ and H+.

biochemistry↗

bioRxiv2022

Expanding the stdpopsim species catalog, and lessons learned forrealistic genome simulations

Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic data sets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and to the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than three-fold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

bioinformatics↗

bioRxiv2022

The Selection Landscape and Genetic Legacy of Ancient Eurasians

The Holocene (beginning [~]12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical, and mental health of present-day populations. Using a dataset of >1600 imputed ancient genomes 1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify major selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported, and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in >400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic, and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, while risk alleles for diabetes and Alzheimers disease are enriched for Western Hunter-gatherer ancestry. Our results suggest that ancient selection and migration were major contributors to the distribution of phenotypic diversity in present-day Europeans.

evolutionary biology↗

bioRxiv2022

REM Sleep Movements in Parkinson's Disease: Is the Basal Ganglia Engaged?

To elucidate the role of the basal ganglia during REM sleep movements in Parkinsons disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

neuroscience↗

bioRxiv2022

Population Genomics of Stone Age Eurasia

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. To investigate the cross-continental impacts we shotgun-sequenced 317 primarily Mesolithic and Neolithic genomes from across Northern and Western Eurasia. These were imputed alongside published data to obtain diploid genotypes from >1,600 ancient humans. Our analyses revealed a Great Divide genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers (HGs) were highly genetically differentiated east and west of this zone, and the impact of the neolithisation was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacements of HGs in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, while east of the Urals relatedness remained high until [~]4,000 BP, consistent with persistence of localised HG groups. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive but we demonstrate that HGs from the Middle Don region contributed ancestry to them. Yamnaya-groups later admixed with individuals associated with the Globular Amphora Culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a Neolithic steppe cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

evolutionary biology↗

bioRxiv2021

Dual RNA-Seq analysis of SARS-CoV-2 correlates specific human transcriptional response pathways directly to viral expression

The SARS-CoV-2 pandemic has challenged humankinds ability to quickly determine the cascade of health effects caused by a novel infection. Even with the unprecedented speed at which vaccines were developed and introduced into society, identifying therapeutic interventions and drug targets for patients infected with the virus remains important as new strains of the virus may evolve, or future coronaviruses may emerge, that are resistant to current vaccines. The application of transcriptomic RNA sequencing of infected samples may shed new light on the pathways involved in viral mechanisms and host responses. We describe the application of "dual RNA-seq" analysis to consider both the host and pathogen transcriptomes simultaneously, to investigate for the first time the co-regulation of human and SARS-CoV-2 genes. Together with differential expression analysis, we describe the tissue specificity of SARS-CoV-2 expression, an inferred lipopolysaccharide response, and co-regulation of CXCLs, SPRRs, S100s with SARS-CoV-2 expression. Lipopolysaccharide response pathways in particular offer promise for future therapeutic research and the prospect of subgrouping patients based on chemokine expression that may help explain the vastly different reactions patients have to infection. Taken together these findings illuminate previously unappreciated SARS-CoV-2 expression signatures, identify new therapeutic considerations, and contribute a pipeline for studying multi-transcriptome systems.

bioinformatics↗