Biology subjects

Ye, S.

Publications and source records attributed to Ye, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing (MGA-Seq)

Genomic abnormalities, including structural variation (SV), copy number variation (CNV), single-nucleotide polymorphism (SNP), homogenously staining regions (HSR) and extrachromosomal DNA (ecDNA), are strongly associated with cancer, rare diseases and infertility. A robust technology to simultaneously detect these genomic abnormalities is highly desired for clinical diagnosis and basic research. In this study, we developed a simple and cost-effective method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect SNPs, CNVs, SVs, ecDNA and HSRs in a single tube. This method has been successfully applied in both cancer cell lines and clinical tumour samples and revealed that focal amplification in tumour tissue is substantially heterogeneous. Notably, we delineated the architecture of focal amplification and the ecDNA network by MGA-Seq, which facilitated the exploration of the regulation of gene expression in ecDNA. This method could be extensively applied for diagnosis and may greatly facilitate the investigation of the genomic mechanism for genetic diseases.

genomics↗

bioRxiv2022

High-resolution small RNAs landscape provides insights into alkane adaptation in the marine alkane-degrader Alcanivorax dieselolei B-5

Alkanes are widespread in the ocean, and Alcanivorax is one of the most ubiquitous alkane-degrading bacteria in the marine ecosystem. Small RNAs (sRNAs) are usually at the heart of regulatory pathways, but sRNA-mediated alkane metabolic adaptability still remains largely unknown due to the difficulties of identification. Here, differential RNA sequencing (dRNA-seq) modified with a size selection ([~]50-nt to 500-nt) strategy was used to generate high-resolution sRNAs profiling in the model species Alcanivorax dieselolei B-5 under alkane (n-hexadecane) and non-alkane (acetate) conditions. As a result, we identified 549 sRNA candidates at single-nucleotide resolution of 5-ends, with 63.4% of transcription start sites (TSSs) and 36.6% of processing sites (PSSs). These sRNAs originated from almost any locations in the genome, regardless of intragenic (65.8%), antisense (20.6%) and intergenic (6.2%) regions, and RNase E may function in the maturation of sRNAs. Most sRNAs locally distribute across the 15 reference genomes of Alcanivorax, and only 7.5% of sRNAs are broadly conserved in this genus. Expression responses to alkane of several core conserved sRNAs, including 6S RNA, M1 RNA and tmRNA, indicate that they may participate in alkane metabolisms and result in more actively global transcription, RNA processing and stresses mitigation. Two novel CsrA-related sRNAs are identified, which may be involved in the translational activation of alkane metabolism-related genes by sequestering the global repressor CsrA. The relationships of sRNAs with characterized genes of the alkane sensing (ompS), chemotaxis (mcp, cheR, cheW2), transporting (ompT1, ompT2, ompT3) and hydroxylation (alkB1, alkB2, almA) were created based on the genome-wide targets prediction. Overall, the sRNAs landscape lays the ground for uncovering cryptic regulations in the critical marine bacterium, among which both core and species-specific sRNAs are implicated in the alkane adaptive metabolisms.

microbiology↗

bioRxiv2022

Accurate and efficient protein sequence designthrough learning concise local environment of residues

Protein sequence design has been widely applied in rational protein engineering and increasing the design accuracy and efficiency is highly desired. Here we present ProDESIGN-LE, an accurate and efficient design approach, which adopts a concise but informative representation of residues local environment and trains a transformer to select an appropriate residue at a position from its local environment. ProDESIGN-LE iteratively applies the transformer on the positions in the target structure, eventually acquiring a designed sequence with all residues fitting well with their local environments. ProDESIGN-LE designed sequences for 68 naturally occurring and 129 hallucinated proteins within 20 seconds per protein on average, and the predicted structures from the designed sequences perfectly resemble the target structures with state-of-the-art average TM-score exceeding 0.80. We further experimentally validated ProDESIGN-LE by designing five sequences for an enzyme, chloramphenicol O-acetyltransferase type III (CAT III), and recombinantly expressing the proteins in E. coli. Of these proteins, three exhibited excellent solubility, and one yielded monomeric species with circular dichroism spectra consistent with the natural CAT III protein.

bioinformatics↗

bioRxiv2022

DNA packaging via hierarchical chromatin structures revealed by live-cell 3D imaging

Single-molecule localization microscopy is a powerful superresolution imaging technique to study biological questions by visualizing subcellular fine structures with nanometer-scale precision. However, its application in live-cell imaging studies has been impeded by the paucity of self-blinking organic fluorophores that enable high spatiotemporal resolution and labeling/localization density at a moderate laser intensity. Herein, we report a self-blinking Si-rhodamine dye 6-HESiR with a suitably increased "ON" fraction and a fluorogenic self-blinking dsDNA probe 6-HoeHESiR as a powerful tool for 3D superresolution imaging of native chromatin in eukaryotes without the use of photoswitching buffer and high laser intensity. With the probe 6-HoeHESiR, 3D superresolution imaging of in vitro reconstituted nucleosomal arrays and chromatin fibers yielded results consistent with EM analysis. Similar euchromatin and heterochromatin structures were visualized in fixed and live cells with high spatiotemporal resolution and labeling density, providing the first live-cell evidence for a hierarchical model of chromatin organization. 3D imaging results obtained in the presence of selective inhibitors of histone deacetylases also corroborate chromatin fiber decompaction upon hyperacetylation of histones.

cell biology↗

bioRxiv2022

Disentanglement of Resting State Brain Networks for Localizing Epileptogenic Zone in Focal Epilepsy

Resting state electromagnetic recordings have been analyzed in epilepsy patients aiding presurgical evaluation. However, it has been rarely explored how pathological networks can be separated and thus used for epileptogenic focus localization purpose. We proposed here a resting state EEG/MEG analysis framework, to disentangle brain functional networks represented by electrophysiological oscillations. Firstly, by using an Embedded Hidden Markov Model (EHMM), we constructed a state space for resting state recordings consisting of brain states with different spatiotemporal patterns. After that, functional connectivity analysis along with graph theory were applied on the extracted brain states to quantify the network features of the extracted brain states, and we determine the source location of pathological states based on these features. The EHMM model was rigorously evaluated using computer simulations. Our simulation results revealed the proposed framework can extract brain states with high accuracy regarding both spatial and temporal profiles. We than validated the entire framework as compared with clinical ground truth in 10 patients with drug-resistant focal epilepsy who underwent MEG recordings. We segmented the resting state MEG recordings into a few brain states with diverse connectivity patterns and extracted pathological brain states by applying graph theory on the constructed functional networks. We showed reasonable localization results using the extracted pathological brain states in 6/10 patients, as compared to the invasive clinical findings. The framework can serve as an objective tool in extracting brain functional networks from noninvasive resting state electromagnetic recordings. It promises to aid presurgical evaluation guiding intracranial EEG electrodes implantation.

neuroscience↗

bioRxiv2021

MaveDB v2: a curated community database with over three million variant effects from multiplexed functional assays

A central problem in genomics is understanding the effect of individual DNA variants. Multiplexed Assays of Variant Effect (MAVEs) can help address this challenge by measuring all possible single nucleotide variant effects in a gene or regulatory sequence simultaneously. Here we describe MaveDB v2, which has become the database of record for MAVEs. MaveDB now contains a large fraction of published studies, comprising over two hundred datasets and three million variant effect measurements. We created tools and APIs to streamline data submission and access, transforming MaveDB into a hub for the analysis and dissemination of these impactful datasets.

genomics↗

bioRxiv2021

Imaging the Extent and Location of Spatiotemporally Distributed Epileptiform Sources from MEG Measurements

Non-invasive MEG/EEG source imaging provides valuable information about the epileptogenic brain areas which can be used to aid presurgical planning in focal epilepsy patients suffering from drug-resistant seizures. However, the source extent estimation for electrophysiological source imaging remains to be a challenge and is usually largely dependent on subjective choice. Our recently developed algorithm, fast spatiotemporal iteratively reweighted edge sparsity minimization (FAST-IRES) strategy, has been shown to objectively estimate extended sources from EEG recording, while it has not been applied to MEG recordings. In this work, through extensive numerical experiments and real data analysis in a group of focal drug-resistant epilepsy patients interictal spikes, we demonstrated the ability of FAST-IRES algorithm to image the location and extent of underlying epilepsy sources from MEG measurements. Our results indicate the merits of FAST-IRES in imaging the location and extent of epilepsy sources for pre-surgical evaluation from MEG measurements.

bioengineering↗

bioRxiv2021

An atlas of human viruses provides new insights into diversity and tissue tropism of human viruses

Viruses continue to threaten human health. Yet, the complete viral species carried by humans and their infection characteristics have not been fully revealed. This study curated an atlas of human viruses from public databases and literatures, and built the Human Virus Database (HVD) available at http://computationalbiology.cn/humanVirusBase/#/. The HVD contains 1,131 virus species of 54 viral families which were more than twice the number of the human-infecting virus species reported in previous studies. These viruses were identified in human samples including 68 human tissues, the excreta and body fluid. The viral diversity in humans was age-dependent with a peak in the infant and a valley in the teenager. The tissue range of viruses was found to be associated with several factors including the viral group (DNA, RNA or reverse-transcribing viruses), enveloped or not, viral genome length and GC content, viral receptors and the virus-interacting proteins. Finally, the tissue range of DNA viruses was predicted using a random-forest algorithm with a medium performance. Overall, the study not only provides a valuable resource for further studies of human viruses, but also deepens our understanding towards the diversity and tissue tropism of human viruses.

microbiology↗

bioRxiv2021

Increased neutralization of SARS-CoV-2 Delta variant by nanobody (Nb22) and the structural basis

Current COVID-19 vaccines need to take at least one month to complete inoculation and then become effective. Around 51% global population are still not fully vaccinated. Instantaneous protection is an unmet need among those who are not fully vaccinated. In addition, breakthrough infections caused by SARS-CoV-2 are widely reported. All these highlight the unmet needing for short-term instantaneous prophylaxis (STIP) in the communities where SARS-CoV-2 is circulating. Previously, we reported nanobodies isolated from an alpaca immunized with the spike protein, exhibiting ultrahigh potency against SARS-CoV-2 and its variants. Herein, we found that Nb22, among our previously reported nanobodies, exhibited ultrapotent neutralization against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM). Furthermore, the crystal structural analysis revealed that the binding of Nb22 to WH01 and Delta RBDs both effectively blocked the binding of RBD to hACE2. Additionally, intranasal Nb22 exhibited protection against SARS-CoV-2 Delta variant in the post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Of note, intranasal Nb22 also demonstrated high efficacy against SARS-CoV-2 Delta variant in STIP for seven days administered by single dose and exhibited long-lasting retention in the respiratory system for at least one month administered by four doses, providing a means of instantaneous short-term prophylaxis against SARS-CoV-2. Thus, ultrahigh potency, long-lasting retention in the respiratory system as well as stability at room-temperature make the intranasal or inhaled Nb22 to be a potential therapeutic or STIP agent against SARS-CoV-2. Brief summaryNb22 exhibits ultrahigh potency against Delta variant in vitro and is exploited by crystal structural analysis; furthermore, animal study demonstrates high effectiveness in the treatment and short-term instantaneous prophylaxis in hACE2 mice via intranasal administration. HighlightsO_LINb22 exhibits ultrapotent neutralization against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM). C_LIO_LIStructural analysis elucidates the ultrapotent neutralization of Nb22 against Delta variant. C_LIO_LINb22 demonstrates complete protection in the treatment of Delta variant infection in hACE2 transgenic mice. C_LIO_LIWe complete the proof of concept of STIP against SARS-CoV-2 using intranasal Nb22 with ultrahigh potency and long-lasting retention in respiratory system. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/459055v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@144516corg.highwire.dtl.DTLVardef@3dc17forg.highwire.dtl.DTLVardef@6a8962org.highwire.dtl.DTLVardef@619cd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

Connectome-based model predicts individual psychopathic traits in college students

BackgroundPsychopathic traits have been suggested to increase the risk of violations of socio-moral norms. Previous studies revealed that abnormal neural signatures are associated with elevated psychopathic traits; however, whether the intrinsic network architecture can predict psychopathic traits at the individual level remains unclear. MethodsThe present study utilized connectome-based predictive modeling (CPM) to investigate whether whole-brain resting-state functional connectivity (RSFC) can predict psychopathic traits in the general population. RS functional magnetic resonance imaging data were collected from 84 college students with varying psychopathic traits measured by the Levenson Self-Report Psychopathy Scale (LSRP). ResultsWe found that RSFC of the negative networks predicted individual differences in total LSRP and secondary psychopathy scores but not primary psychopathy score. Particularly, nodes with the most connections in the predictive connectome anchored in the prefrontal cortex (e.g., anterior prefrontal cortex and orbitofrontal cortex) and limbic system (e.g., anterior cingulate cortex and insula). In addition, the connections between the occipital network (OCCN) and cingulo-opercular network (CON) served as a significant predictive connectome for total LSRP and secondary psychopathy score. ConclusionCPM constituted by whole-brain RSFC significantly predicted psychopathic traits individually in the general population. The prefrontal cortex and limbic system at the anatomic level and the CON and OCCN at the functional network level plays a special role in the predictive model--reflecting atypical executive control and affective processing for individuals with elevated psychopathic traits. These findings may provide some implications for early detection and potential intervention of psychopathic tendency.

neuroscience↗

bioRxiv2021

Altered effective connectivity from the posterior insula to the amygdala mediates the relationship between psychopathic traits and concern with the Harm foundation

Psychopathic traits have been demonstrated to be associated with different types of morality; however, the neuropsychological mechanism underlying the relationship between psychopathic traits and morality remains unclear. Our study examined the effective connectivity (EC) of psychopathic traits-related brain regions and its association to concern with different moral foundations by combining behavioral measures with resting-state fMRI. We administered the Levenson Self-Report Psychopathy Scale (LSRP) and Moral Foundation Questionnaire (MFQ) to 78 college students after resting-state fMRI scanning. Our results showed that total and primary psychopathic traits score predicted concern with the Harm foundation. The EC from the posterior insula to the amygdala was negatively correlated with psychopathic traits and positively with concern with the Harm foundation. Altered posterior insula-amygdala EC partially mediated the relationship between psychopathic traits and concern with the Harm foundation. Our findings indicated that individuals with elevated psychopathic traits may have atypical processes in recognizing and integrating bodily state information into emotional responses, leading to less concern for harm-related morality. The study deepened our understanding of the neuropsychological mechanism underlying the relationship between psychopathic traits and morality and may have implications for the prevention of higher psychopathic traits individuals from committing serious transgressions.

neuroscience↗

bioRxiv2021

OsciDrop: A versatile on-demand droplet generator

Droplet microfluidics is a powerful tool in many biological and clinical applications. Microfluidic chips, such as flow-focusing droplet generators, have been extensively used to high-throughput encapsulate reactions with single-cell and single-molecular resolutions. However, microfabrication is expensive and precision-demanding, preventing it from widespread use in biomedical laboratories and clinical facilities. Herein, we present a versatile chip-free droplet generator, OsciDrop, for generating size-tunable droplets on demand, with high uniformity. OsciDrop segments the fluid flowing out of the orifice of a micropipette tip into droplets by oscillating the tip under the surface of a continuous oil phase. We investigated the factors influencing droplet generation by examining several control parameters. Results show that flow rate, oscillating amplitude, and frequency are key parameters to generate monodisperse droplets on demand. And OsciDrop is able to generate droplets in a flexible and repeatable manner. Importantly, using an optimal asymmetrical oscillation waveform, OsciDrop can controllably generate monodisperse droplets spanning a wide volume range (200 pL - 2 L). To demonstrate the ability of OsciDrop for chip-free droplet assays, a digital loop-mediated isothermal amplification (dLAMP) was performed to absolutely quantify African swine fever virus (ASFV). The OsciDrop method opens up a feasible and versatile avenue to perform droplet-based assays, exhibiting full accessibility for chip-free droplet microfluidics.

bioengineering↗

bioRxiv2021

Genetic code degeneracy is established by the decoding center of the ribosome

The degeneracy of the genetic code confers a wide array of properties to coding sequences. Yet, its origin is still unclear. A structural analysis has shown that the stability of the Watson-Crick base pair at the second position of the anticodon-codon interaction is a critical parameter controlling the extent of non-specific pairings accepted at the third position by the ribosome, a flexibility at the root of degeneracy. Based on recent cryo-EM analyses, the present work shows that residue A1493 of the decoding center provides a significant contribution to the stability of this base pair, revealing that the ribosome is directly involved in the establishment of degeneracy. Building on existing evolutionary models, we show the evidence that the early appearance of A1493 and A1492 established the basis of degeneracy when an elementary kinetic scheme of translation was prevailing. Logical considerations on the expansion of this kinetic scheme indicate that the acquisition of the peptidyl transferase center was the next major evolutionary step, while the induced-fit mechanism, that enables a sharp selection of the tRNAs, necessarily arose later when G530 was acquired by the decoding center.

molecular biology↗

bioRxiv2021

Multi-animal pose estimation and tracking with DeepLabCut

Estimating the pose of multiple animals is a challenging computer vision problem: frequent interactions cause occlusions and complicate the association of detected keypoints to the correct individuals, as well as having extremely similar looking animals that interact more closely than in typical multi-human scenarios. To take up this challenge, we build on DeepLabCut, a popular open source pose estimation toolbox, and provide high-performance animal assembly and tracking--features required for robust multi-animal scenarios. Furthermore, we integrate the ability to predict an animals identity directly to assist tracking (in case of occlusions). We illustrate the power of this framework with four datasets varying in complexity, which we release to serve as a benchmark for future algorithm development.

animal behavior and cognition↗

bioRxiv2021

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. AKT is a relevant target for inhibition, in addition to KIT, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated significant synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to cell cycle arrest and cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.

cancer biology↗

bioRxiv2020

Enhanced virus detection and metagenomic sequencing in patients with meningitis and encephalitis

Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific diagnostic tests, sometimes over days to weeks. Metagenomic next-generation sequencing (mNGS) is a high-throughput platform that profiles all nucleic acid in a sample. We prospectively enrolled 68 patients from New England with known or suspected CNS infection and performed mNGS from both RNA and DNA to identify potential pathogens. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects. This included some pathogens traditionally diagnosed by serology or not typically identified in CSF, including three transmitted by Ixodes scapularis ticks (Powassan virus, Borrelia burgdorferi, Anaplasma phagocytophilum). Among 24 subjects with no clinical diagnosis, we detected enterovirus in two subjects and Epstein Barr virus in one subject. We also evaluated two methods to enhance detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed detection of varicella zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with similar efficacy to pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis. ImportanceMeningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures. Despite intensive diagnostic efforts, 40-60% of people with meningitis or encephalitis have no clear cause of their CNS disease identified. As diagnostic uncertainty often leads to costly inappropriate therapies, the need for novel pathogen detection methods is paramount. Metagenomic next-generation sequencing (mNGS) offers the unique opportunity to circumvent these challenges using unbiased laboratory and computational methods. Here, we performed comprehensive mNGS from 68 patients with suspected CNS infection, and define enhanced methods to improve the detection of CNS pathogens, including those not traditionally identified in the CNS by nucleic acid detection. Overall, our work helps elucidate how mNGS can become a mainstay in the diagnostic toolkit for CNS infections.

neuroscience↗

bioRxiv2020

Auxin guides germ cell specification in Arabidopsis anthers

Germ cells (GCs) transmit genetic information from one generation to the next. Unlike animal GCs, plant GCs are induced post-embryonically, forming locally from somatic cells. This induction is coordinated with organogenesis and might be guided by positional cues. In angiosperms, male GCs initiate from the internal layers at the four corners of the anther primordia and are gradually enclosed by parietal cell (PC) layers, leading to a concentric GC-PC pattern.1,2 However, the underlying mechanism of GC initiation and GC-PC pattern formation is unclear. Auxin affects pattern formation3 and anther development.4-11 However, whether GC formation involves auxin remains unknown. We report that the auxin distribution in pre-meiotic anthers parallels GC initiation, forming a centripetal gradient between the outer primordial cells and the inner GCs. The auxin biosynthesis genes TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1 (TAA1) and TRYPTOPHAN AMINOTRANSFERASE RELATED 2 (TAR2)5,12 are responsible for this patterning and essential for GC specification. SPOROCYTELESS/NOZZLE (SPL/NZZ, a determinant for GC specification)13-15 mediates the effect of auxin on GC specification, modulates auxin homeostasis, and maintains centripetal auxin patterning. Our results reveal that auxin is a key factor guiding GC specification in Arabidopsis anthers.

plant biology↗

bioRxiv2020

An agent-based model of adaptation of holobionts with different microbial symbiont transmission modes

The hologenome theory suggests that holobionts (host plus symbiont) with hosts that are only able to adapt slowly may be able to persist in deteriorating environmental conditions via rapid adaptation of their microbial symbionts. The effectiveness of such symbiont adaptation may vary depending on whether symbionts are passed directly to offspring (vertical transmission) or acquired from the environment (horizontal transmission). However, it has been suggested that holobionts with horizontal transmission cannot pass down their symbionts faithfully, preventing adaptation at the holobiont level because of host-symbiont disassociation between generations. Here we used an agent-based model to investigate whether holobionts with horizontal microbial symbiont transmission can adapt to increasing stress solely through symbiont adaptation and compared their adaptation to holobionts with vertical transmission. We found that holobionts with either transmission mode were able to adapt to increasing abiotic stress solely via symbiont adaptation. Moreover, those with horizontal transmission were more competitive than those with vertical transmission when hosts were able to selectively associate with the most suitable symbionts. However, those with horizontal transmission were less competitive than those with vertical transmission when symbiont establishment was random. Our results support the hologenome theory and demonstrate that holobionts with horizontal microbial symbiont transmission could adapt to increasing abiotic stress via their symbionts. We also showed that whether holobionts with horizontal or vertical symbiont transmission are favored in increasingly stressful conditions depends on the ability of hosts to recognize and foster microbial symbionts that confer stress tolerance. IMPORTANCESymbiotic organisms such as reef building corals are sensitive to environmental perturbations due to anthropogenic disturbances or climate change, and it is critical to understand whether they are able to adapt to previously unfavorable conditions. To date, studies have focused on the impacts of existing microbial symbiont variation on holobiont stress tolerance but here we use agent-based models to explore holobiont adaptation via symbiont adaptation. We studied both deterministic and stochastic processes in holobiont adaptation by investigating the following four factors: holobiont transmission modes, a hosts ability to recognize tolerance-conferring symbionts, a symbionts mutational variance, and rate of stress increase. Our simulation provides a comprehensive understanding of holobiont adaptation under stress, which not only has implications for future endangered symbiotic species management, but also provides fresh insight into species evolution as proposed by the hologenome theory.

evolutionary biology↗