Biology subjects

Wen, H.

Publications and source records attributed to Wen, H..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Effects of short-term salinity exposure on haemolymph osmolality, gill morphology and Na+/K+ - ATPase activity in Solenaia oleivora

In order to explore the physiological reaction to hyperosmotic environment, Solenaia oleivora were exposed to 2.23{per thousand} salinity. In 48h, the hemolymph osmolality kept increasing, and the hemolymph protein concentration increased in the first 6h and then decreased significantly, while the free amino acid content increased in the first 24h and then kept stable (P < 0.05). The activity of Na+/K+-ATPase at 0h was significantly higher than other times in most organs except intestine, which was highest at 3h (P < 0.05). The ions concentration were also influenced. The concentration of Na+ rose in haemolymph, axe foot and intestine, but decreased in gill and hepatopancreas. In hemolymph, gill, hepatopancreases and adductor muscle, the K+ concentration was the highest at 0h, while in axe foot and intestine, it showed a positive tendency. The concentration of Cl- in haemolymph, adductor muscle, intestine and axe foot were positively correlated with treatment time, while hepatopancreas showed opposite tendency. High salinity stress caused a difference in the gill histological structure, the gill structure shrunk, the gill lamellas space and shrinking degree showed an enlarging trend with salinity treatment time.

animal behavior and cognition↗

bioRxiv2021

RNANetMotif: identifying sequence-structure RNA network motifs in RNA-protein binding sites

RNA molecules can adopt stable secondary and tertiary structures, which is essential in mediating physical interactions with other partners such as RNA binding proteins (RBPs) and in carrying out their cellular functions. In vivo and in vitro experiments such as RNAcompete and eCLIP have revealed in vitro binding preferences of RBPs to RNA oligomers and in vivo binding sites in cells. Analysis of these binding data showed that the structure properties of the RNAs in these binding sites are important determinants of the binding events; however, it has been a challenge to incorporate the structure information into an interpretable model. Here we describe a new approach, RNANetMotif, which takes predicted secondary structure of thousands of RNA sequences bound by an RBP as input and uses a graph theory approach to recognize enriched subgraphs. These enriched subgraphs are in essence shared sequence-structure elements that are important in RBP-RNA binding. To validate our approach, we performed RNA structure modeling via discrete molecular dynamics folding simulations for selected 4 RBPs, and RNA-protein docking for LIN28. The simulation results, e.g., solvent accessibility and energetics, further support the biological relevance of the discovered network subgraphs. Author SummaryRNA binding proteins (RBPs) regulate every aspect of RNA biology, including splicing, translation, transportation, and degradation. High-throughput technologies such as eCLIP have identified thousands of binding sites for a given RBP throughout the genome. It has been shown by earlier studies that, in addition to nucleotide sequences, the structure and conformation of RNAs also play important role in RBP-RNA interactions. Analogous to protein-protein interactions or protein-DNA interactions, it is likely that there exist intrinsic sequence-structure motifs common to these RNAs that underlie their binding specificity to specific RBPs. It is known that RNAs form energetically favorable secondary structures, which can be represented as a graph, with nucleotides being nodes and backbone covalent bonds and base-pairing hydrogen bonds representing edges. We hypothesize that these graphs can be mined by graph theory approaches to identify sequence-structure motifs as enriched sub-graphs. In this article, we described the details of this approach, termed RNANetMotif and associated new concepts, namely EKS (Extended K-mer Subgraphs) and GraphK graph search algorithm. To test the utility of our approach, we conducted 3D structure modeling of selected RNA sequences through molecular dynamics (MD) folding simulation and evaluated the significance of the discovered RNA motifs by comparing their spatial exposure with other regions on the RNA. We believe that this approach has the novelty of treating the RNA sequence as a graph and RBP binding sites as enriched subgraph, which has broader applications beyond RBP-RNA interactions.

bioinformatics↗

bioRxiv2021

One viral sequence for each host? - The neglected within-host diversity as the main stage of SARS-CoV-2 evolution

The standard practice of presenting one viral sequence for each infected individual implicitly assumes low within-host genetic diversity. It places the emphasis on the viral evolution between, rather than within, hosts. To determine this diversity, we collect SARS-CoV-2 samples from the same patient multiple times. Our own data in conjunction with previous reports show that two viral samples collected from the same individual are often very different due to the substantial within-host diversity. Each sample captures only a small part of the total diversity that is transiently and locally released from infected cells. Hence, the global SARS-CoV-2 population is a meta-population consisting of the viruses in all the infected hosts, each of which harboring a genetically diverse sub-population. Advantageous mutations must be present first as the within-host diversity before they are revealed as between-host polymorphism. The early detection of such diversity in multiple hosts could be an alarm for potentially dangerous mutations. In conclusion, the main forces of viral evolution, i.e., mutation, drift, recombination and selection, all operate within hosts and should be studied accordingly. Several significant implications are discussed.

evolutionary biology↗

bioRxiv2021

Microbial tryptophan catabolism affects the vector competence of Anopheles

The influence of microbiota on mosquito physiology and vector competence is becoming increasingly clear but our understanding of interactions between microbiota and mosquitoes still remains incomplete. Here we show that gut microbiota of Anopheles stephensi, a competent malaria vector, participates mosquito tryptophan metabolism. Elimination of microbiota by antibiotics treatment leads to the accumulation of tryptophan (Trp) and its metabolites, kynurenine (Kyn), 3-hydroxykynurenine (3-HK) and xanthurenic acid (XA). Of these, 3-HK impairs the structure of peritrophic matrix (PM), thereby promoting Plasmodium berghei infection. Among the major gut microbiota in An. stephensi, Pseudomonas alcaligenes plays a role in catabolizing 3-HK as revealed by whole genome sequencing and LC-MS metabolic analysis. The genome of P. alcaligenes encodes kynureninase (KynU) that is responsible for the conversion of 3-HK to 3-Hydroxyanthranilic acid (3-HAA). Mutation of this gene abrogates the ability of P. alcaligenes to metabolize 3-HK, which in turn abolishes its role on PM protection. Colonization of An. stephensi with KynU mutated P. alcaligenes fails to protect mosquitoes against parasite infection as effectively as those with wild type bacterium. In summary, we identify an unexpected function of gut microbiota in controlling mosquito tryptophan metabolism with the major consequences on vector competence.

microbiology↗

bioRxiv2021

Landscape of glioblastoma niches reveals the prognostic effects of tumor-infiltrating cells

A comprehensive characterization of non-tumor cells in the niches of primary glioblastoma is not fully established yet. This study aims to present an overview of tumor-infiltrating non-malignant cells in the complex microenvironment of glioblastoma with detailed characterizations of their prognostic effects. We curate 540 gene signatures covering a total of 64 non-tumor cell types. Cell type-specific expression patterns are interrogated by normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with a total number of 967 cases. The GBMs in each cohort are hierarchically clustered into negative or positive immune response classes with significantly different overall survival. Our results show that astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are risk factors, while CD8 T cells, CD8+ T cells, and plasma cells are protective factors. Moreover, we find that the immune system and organogenesis are uniformly enriched in negative immune response clusters, in contrast to the enrichment of nervous system in positive immune response clusters. Mesenchymal differentiation is also observed in the negative immune response clusters. High enrichment status of macrophages in negative immune response clusters are independently validated by analyzing scRNA-seq data from eight high-grade gliomas, revealing that negative immune response samples comprised 46.63% to 55.12% of macrophages, whereas positive immune response samples comprised only 1.70% to 8.12%, with IHC staining of samples from six short-term and six long-term survivors of GBMs confirming the results. Simple SummaryThe landscape of infiltrating non-tumor cells in glioblastoma niches remains unclear. In this study, we explore the enrichment status of a total of 64 non-tumor cell types predicted by applying 540 gene signatures curated from literature and normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with 967 cases. Based on non-tumor cell type-based enrichment status, GBMs in each cohort are classified into positive or negative immune response clusters, showing a statistically significant different overall survival. Astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are identified as risk factors, as well as protector factors of CD8 T cells, CD8+ T cells, and plasma cells. Our results also find that immune system- and organogenesis-related GO terms are uniformly enriched in negative immune response clusters, whereas positive immune response clusters are enriched with GO terms concerning the nervous system. The mesenchymal differentiation is observed in the negative immune response clusters. Particularly, the high presence of macrophages in the negative immune response clusters is further validated using scRNA-seq analysis and IHC staining of GBMs from independent cohorts.

cancer biology↗

bioRxiv2021

PepNN: a deep attention model for the identification of peptide binding sites

Protein-peptide interactions play a fundamental role in facilitating many cellular processes, but remain underexplored experimentally and difficult to model computationally. Here, we present PepNN-Struct and PepNN-Seq, structure and sequence-based approaches for the prediction of peptide binding sites on a protein given the sequence of a peptide ligand. A main difficulty for the prediction of peptide-protein interactions is the flexibility of peptides and their tendency to undergo conformational changes upon binding. To account for this behaviour, we developed a novel reciprocal attention module that simultaneously updates the encodings of peptide and protein residues and explicitly enforces the symmetry in the updates, allowing for information flow and reflecting the biochemical reality of conformational changes in the peptide. PepNN additionally makes use of modern graph neural network layers that are effective at learning representations of molecular structure. Finally, to compensate for the scarcity of peptide-protein complex structural information, we make use of available protein-protein complex and protein sequence information through a series of transfer learning steps. PepNN-Struct achieves state-of-the-art performance on the task of identifying peptide binding sites, with a ROC AUC of 0.893 and an MCC of 0.483 on an independent test set. Beyond prediction of binding sites on proteins with a known peptide ligand, we also show that the developed models make reasonable peptide-agnostic predictions, allowing for the identification of novel peptide binding proteins.

bioinformatics↗

bioRxiv2020

neoDL: A novel neoantigen intrinsic feature-based deep learning model identifies IDH wild-type glioblastomas with the longest survival

BackgroundIDH wild-type glioblastoma (GBM) is the most aggressive tumor in the central nervous system in spite of extensive therapies. Neoantigen based personalized immune therapies achieve promising results in melanoma and lung cancer, but few neoantigen based models perform well in IDH wild-type GBM. Unlike the neoantigen load and occurrence that are well studied and often found useless, the association between neoantigen intrinsic features and prognosis remain unclear in IDH wild-type GBM. ResultsWe presented a novel neoantigen intrinsic feature-based deep learning model (neoDL) to stratify IDH wild-type GBMs into subgroups with different survivals. We first calculated a total of 2928 intrinsic features for each neoantigen and filtered out those not associated with survival, followed by applying neoDL in the TCGA data cohort. Leave one out cross validation (LOOCV) in the TCGA demonstrated that neoDL successfully classified IDH wild-type GBMs into different prognostic subgroups, which was further validated in an independent data cohorts from Asian population. Long-term survival IDH wild-type GBMs identified by neoDL were found characterized by 12 protective neoantigen intrinsic features and enriched in development and cell cycle. ConclusionsOur results provide a novel model, neoDL, that can be therapeutically exploited to identify IDH wild-type GBM with good prognosis who will most likely benefit from neoantigen based personalized immunetherapy.

bioinformatics↗

bioRxiv2020

Identification of four linear B-cell epitopes on the SARS-CoV-2 spike protein able to elicit neutralizing antibodies

SARS-CoV-2 unprecedentedly threatens the public health at worldwide level. There is an urgent need to develop an effective vaccine within a highly accelerated time. Here, we present the most comprehensive S-protein-based linear B-cell epitope candidate list by combining epitopes predicted by eight widely-used immune-informatics methods with the epitopes curated from literature published between Feb 6, 2020 and July 10, 2020. We find four top prioritized linear B-cell epitopes in the hotspot regions of S protein can specifically bind with serum antibodies from horse, mouse, and monkey inoculated with different SARS-CoV-2 vaccine candidates or a patient recovering from COVID-19. The four linear B-cell epitopes can induce neutralizing antibodies against both pseudo and live SARS-CoV-2 virus in immunized wild-type BALB/c mice. This study suggests that the four linear B-cell epitopes are potentially important candidates for serological assay or vaccine development.

microbiology↗

bioRxiv2020

Many are called but few are chosen - Multiple clonal origins greatly elevate the functional heterogeneity of tumors

Each tumor is usually accepted to be of a single origin from a progenitor cell. The shared evolutionary paths impose a limit on the nature of genetic diversity of the tumor. However, there are also numerous stem cell niches with independent proliferation potentials. To reconcile the contrasting perspectives, we propose a model whereby each tumor is of multiple clonal origins but the most proliferative one would eclipse other minor clones. The detection of the minor clones would entail an extreme scheme of large-number but small-volume sampling. In two cases of colon tumors so sampled, one indeed has 13 independent clones of disparate sizes and even the smaller clones have tens of thousands of cells dispersed non-locally. The other, much larger, tumor has only one prevailing clone that engulfs two tiny patches of minor clones. In both cases, the expanding clone spawns a hierarchy of subclones that resemble vassal states on its wake of expansion. The timing of metastasis can also be mapped to the precise stage of the clonal expansion. In conclusion, multiple independent clones, likely common but difficult to detect, can greatly elevate the non-neutral diversity within a tumor. This much-elevated diversity has many theoretical and clinical implications.

cancer biology↗

bioRxiv2020

Deletion of the voltage-gated calcium channel, CaV1.3, causes deficits in motor performance and associative learning

L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltage-gated calcium channel isoforms in the brain is CaV1.3. Mice lacking CaV1.3 are reported to have impairments in fear conditioning and depressive-like behaviors, which have been linked to CaV1.3 function in the hippocampus and amygdala. Genetic variation in CaV1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning, and social function. Here, we explored whether CaV1.3 plays a role in these behaviors. We found that CaV1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in CaV1.3 knockout mice on assays of anxiety-like, depression-like, or social preference behaviors. Our results suggest an important role for CaV1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.

neuroscience↗

bioRxiv2020

Sex, fitness decline and recombination - Muller's ratchet vs. Ohta's ratchet

It is generally accepted that the absence of recombination reduces the efficacy of natural selection for, or against, mutations. A special case is Mullers Ratchet (MR) whereby non-recombining genomes experience irreversible fitness decline due to the accumulation of deleterious mutations. MR has been a main hypothesis for sexual reproduction as well as many other biological phenomena. We now ask whether the fitness decline can indeed be stopped if an asexual population turns sexual to become recombining. The possible fitness decline under recombination is referred to as Ohtas Ratchet (OR). In comparison, MR is more effective in driving fitness reduction than OR, but only in a restricted parameter space of mutation rate, population size and selection. Outside of this space, the two ratchets are equally effective or, alternatively, neither is sufficiently powerful. Furthermore, beneficial mutations can affect the population fitness, which may diverge between the two ratchets, but only in a small parameter space. Since recombination plays a limited role in driving fitness decline, the operation of MR could be far less common in nature than believed. A companion report (see Supplement) surveying the biological phenomena attributed to MR indeed suggests the alternative explanations to be generally more compelling.

evolutionary biology↗

bioRxiv2020

Primary and secondary motoneurons use different calcium channel types to control escape and swimming behaviors in zebrafish

The escape response and rhythmic swimming in zebrafish are distinct behaviors mediated by two functionally distinct motoneuron (Mn) types. The primary (1{degrees}Mn) type depresses, has a large quantal content (Qc), and a high release probability (Pr). Conversely, the secondary (2{degrees}Mn) type facilitates and has low and variable Qc and Pr. This functional duality matches well the distinct associated behaviors, with the 1{degrees}Mn providing the strong, singular C-bend initiating escape and the 2{degrees}Mn confers weaker, rhythmic contractions. Contributing to these functional distinctions is our identification of P/Q type calcium channels mediating transmitter release in 1{degrees}Mns and N type channels in 2{degrees}Mns. Remarkably, despite these functional and behavioral distinctions, all ~15 individual synapses on each muscle cell are shared by a 1{degrees}Mn bouton and at least one 2{degrees}Mn bouton. This novel blueprint of synaptic sharing provides an efficient way of controlling two different behaviors at the level of a single postsynaptic cell.

neuroscience↗

bioRxiv2020

Cross-subunit Interactions that Stabilize Open States Mediate Gating in NMDA Receptors

NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are of current interest. Very likely, the earliest steps in the activation reaction include glutamate binding to and compression of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical coupling with transmembrane helices. Here, we used double-mutant cycle analyses to demonstrate that a direct chemical interaction between GluN1-I642 (on M3) and GluN2A-L550 (on L1-M1) stabilizes receptors after they have opened, and therefore represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence predicts deficits in charge transfer by GluN1-I642L, a pathogenic human variant. SIGNIFICANCE STATEMENTNMDA receptors are glutamatergic channels whose activations control the strength of excitatory synapses in the central nervous system. Agonist binding initiates a complex activation reaction that consists of a stepwise sequence of reversible isomerizations. In addition to previously identified steps in this series, which include agonist-induced closure of the ligand-binding lobes, and the subsequent mechanical pulling by the ligand-binding domain on the gate-forming transmembrane helix, we identify a new cross-subunit interaction, which stabilizes open receptors and slows the rate of the current decay. Naturally occurring NMDA receptor variants lacking this interaction are pathogenic.

biophysics↗

bioRxiv2019

Changes in spinal cord hemodynamic reflect modulation of spinal network with different parameters of epidural stimulation

In this study functional ultrasound (fUS) imaging has been implemented to explore the local hemodynamic response induced by electrical epidural stimulation and to study real-time in vivo functional changes of the spinal cord, taking advantage of the superior spatiotemporal resolution provided by fUS. By quantifying the hemodynamic and electromyographic response features, we tested the hypothesis that the transient hemodynamic response of the spinal cord to electrical epidural stimulation could reflect modulation of the spinal circuitry and accordingly respond to the changes in parameters of electrical stimulation. The results of this study for the first time demonstrate that the hemodynamic response to electrical stimulation could reflect functional organization of the spinal cord. Response in the dorsal areas to epidural stimulation was significantly higher and faster compared to the response in ventral spinal cord. Positive relation between the hemodynamic and the EMG responses was observed at the lower frequencies of epidural stimulation (20 and 40 Hz), which according to our previous findings can facilitate spinal circuitry after spinal cord injury, compared to higher frequencies (200 and 500 Hz). These findings suggest that different mechanisms could be involved in spinal cord hemodynamic changes during different parameters of electrical stimulation and for the first time provide the evidence that functional organization of the spinal cord circuitry could be related to specific organization of spinal cord vasculature and hemodynamic.\n\nSignificance StatementElectrical epidural stimulation (EES) has been successfully applied to control chronic refractory pain and was evolved to alleviate motor impairment after spinal cord injury, in Parkinsons disease, and other neurological conditions. The mechanisms underlying the EES remain unclear, and current methods for monitoring EES are limited in sensitivity and spatiotemporal resolutions to evaluate functional changes in response to EES. We tested the hypothesis that the transient hemodynamic response of the spinal cord to EES could reflect modulation of the spinal cord circuitry and accordingly respond to the changes in parameters of EES. The proposed methodology opens a new direction for quantitative evaluation of the spinal cord hemodynamic in understanding the mechanisms of spinal cord functional organization and effect of neuromodulation.

neuroscience↗

bioRxiv2019

Investigating dual Ca2+ modulation of the ryanodine receptor 1 by molecular dynamics simulation

The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles. A deep understanding of the complex Ca2+-activation/inhibition mechanism of RyRs requires detailed structural and dynamic information for RyRs in different functional states (e.g., with Ca2+ bound to activating or inhibitory sites). Recently, high-resolution structures of the RyR isoform 1 (RyR1) were solved by cryo-electron microscopy, revealing the location of a Ca2+ binding site for activation. Toward elucidating the Ca2+-modulation mechanism of RyR1, we performed extensive molecular dynamics simulation of the core RyR1 structure in the presence and absence of bound and solvent Ca2+ (total simulation time is > 5 microseconds). In the presence of solvent Ca2+, Ca2+ binding to the activating site enhanced dynamics of RyR1 with higher inter-subunit flexibility, asymmetric inter-subunit motions, outward domain motions and partial pore dilation, which may prime RyR1 for subsequent channel opening. In contrast, the solvent Ca2+ alone reduced dynamics of RyR1 and led to inward domain motions and pore contraction, which may cause inhibition. Combining our simulation with the map of disease mutation sites in RyR1, we constructed a wiring diagram of key domains coupled via specific hydrogen bonds involving the mutation sites, some of which were modulated by Ca2+ binding. The rich structural and dynamic information gained from this study will guide future mutational and functional studies of RyR1 activation and inhibition by Ca2+.\n\nStatement of SignificanceThe ryanodine receptors (RyR) are key players in calcium signaling, and make prominent targets for drug design owning to their association with many diseases of cardiac and skeletal muscles. However, the molecular mechanism of their activation and inhibition by Ca2+ remains elusive for the lack of high-resolution structural and dynamic information. Recent solutions of RyR1 structures by cryo-EM have paved the way for structure-based investigation of this important receptor by atomistic molecular simulation. This study presented, to our knowledge, the most extensive MD simulation of RyR1 core structure. Our simulation has offered new insights to the dual modulation mechanism of Ca2+, in which Ca2+ binding to the activating site primes RyR1 activation by elevating its dynamics while solvent Ca2+ inhibits RyR1 by reducing its dynamics. Additionally, our simulation has yielded a new wiring diagram of the allosterically coupled RyR1 domains informed by disease mutations.

biophysics↗

bioRxiv2019

Mutations beget more mutations - The baseline mutation rate and runaway accumulation

There is a sizable literature on mutation rate evolution (Drake 1991; Makova and Li 2002; Lynch 2011; Scally and Durbin 2012; Sung, et al. 2012) but few studies incorporate the recent genomic data from somatic tissues that suggest the operation of mutators. These data show that the mutation burden among cancer samples may vary by several orders of magnitude (Kandoth, et al. 2013; Lawrence, et al. 2013). We now propose a runaway model, applicable to both the germline and the soma, whereby the accumulation of mutator mutations forms a positive-feedback loop. In this loop, any mutator mutation would increase the probability of acquiring the next mutator, thus triggering a runaway escalation in mutation rate. The process can be initiated more readily if there are many weak, rather than a few strong, mutators. Interestingly, even a small increase in the mutation rate at birth could trigger the runaway process, resulting in unfit progeny in slowly reproducing species. In such species, the need to minimize the risk of this uncontrolled accumulation would entail a mutation rate that may seem unnecessarily low. In comparison, species that starts and ends reproduction much sooner do not face the risk and may set the baseline mutation rate higher. The mutation rate would evolve as the generation time changes, therefore explaining many puzzling evolutionary phenomena (Elango, et al. 2006; Thomas, et al. 2010; Langergraber, et al. 2012; Thomas, et al. 2018; Besenbacher, et al. 2019).

evolutionary biology↗

bioRxiv2019

Integrative methylome and transcriptome analysis of Japanese flounder (Paralichthys olivaceus) skeletal muscle during development

DNA methylation is an important epigenetic modification in vertebrate and is essential for epigenetic gene regulation in skeletal muscle development. We showed the genome-wide DNA methylation profile in skeletal muscle tissue of larval 7dph (JP1), juvenile 90dph (JP2), adult female 24 months (JP3) and adult male 24 months (JP4) Japanese flounder. The distribution and levels of methylated DNA within genomic features (1stexons, gene body, introns, TSS200, TSS1500 and intergenic) show different developmental landscapes. We also successfully identified differentially methylated regions (DMRs) and different methylated genes (DMGs) through a comparative analysis, indicating that DMR in gene body, intron and intergenic regions were more compared to other regions of all DNA elements. A gene ontology analysis indicated that the DMGs were mainly related to regulation of skeletal muscle fiber development process, Axon guidance, Adherens junction, and some ATPase activity. Methylome and transcriptome clearly revealed a exhibit a negative correlation. And integration analysis revealed a total of 425, 398 and 429 negatively correlated genes with methylation in the JP2_VS_JP1, JP3_VS_JP1 and JP4_VS_JP1 comparison groups, respectively. And these genes were functionally associated with pathways including Adherens junction, Axon guidance, Focal adhesion, cell junctions, Actin cytoskeleton and Wnt signaling pathways. In addition, we validated the MethylRAD results by bisulfite sequencing PCR (BSP) in some of the differentially methylated skeletal muscle growth-related genes (Myod1, Six1 and Ctnnb1). In this study, we have generated the genome-wide profile of methylome and transcriptome in Japanese flounder for the first time, and our results bring new insights into the epigenetic regulation of developmental processes in Japanese flounder. This study contributes to the knowledge on epigenetics in vertebrates.\n\nAuthor summaryEpigenetic mechanisms like DNA methylation have recently reported as vital regulators of some species skeletal muscle development through the control of genes related to growth. To date, although genome-wide DNA methylation profiles of many organisms have been reported and the Japanese flounder reference genome and whole transcriptome data are publically available, the methylation pattern of Japanese flounder skeletal muscle tissue remains minimally studied and the global DNA methylation data are yet to be known. Here we investigated the genome-wide DNA methylation patterns in Japanese flounder, throughout its development. These findings help to enrich research in molecular and developmental biology in vertebrates.

epidemiology↗

bioRxiv2019

Molecular evolution in large steps - Codon substitutions under positive selection

Molecular evolution is believed to proceed in small steps. The step size can be defined by a distance reflecting physico-chemical disparities between amino acid (AA) pairs that can be exchanged by single 1 bp mutations. We show that AA substitution rates are strongly and negatively correlated with this distance but only when positive selection is relatively weak. We use the McDonald and Kreitman (MK) test to separate the influences of positive and negative selection. While negative selection is indeed stronger on AA substitutions generating larger changes in chemical properties of amino acids, positive selection operates by different rules. For 65 of the 75 possible pairs, positive selection is comparable in strength regardless of AA distance. However, the 10 pairs under the strongest positive selection all exhibit large leaps in chemical properties. Five of the 10 pairs are shared between hominoids and Drosophila, thus hinting at a common but modest biochemical basis of adaptation across taxa. The hypothesis that adaptive changes often take large functional steps will need to be extensively tested. If validated, molecular models will need to better integrate positive and negative selection in the search for adaptive signal.

evolutionary biology↗