Biology subjects

Wei, C.

Publications and source records attributed to Wei, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery

Sorghum is a C4 crop well-known for its high efficiency of biomass accumulation and adaptation to drought and hot environments. This study reports the assembly of complete genome sequence of two sorghum genomes using a combination of ultra-long reads from Oxford Nanopore Technology, high-fidelity long reads from Pacbio and Hi-C reads. The accuracy and completeness of the T2T assemblies were comprehensively validated using a range of parameters, including coverage depth assessment, BUSCO, LTR assembly index, ect. Our T2T assembly of BTx623 identified 36.25 Mb of new sequence, in addition to dozens of misoritation and mispositioning of large DNA segments in the BTx623-v3. Correcting these assembly errors in the reference genome is critical for exploiting genetic information in these complex regions in sorghum. Comparison of the two T2T genomes shed new insights on variation of centromeres in sorghum. The two high-quality T2T genomes represent an important resource for sorghum improvement and gene discovery. They would serve as the new reference genomes to unlock the full potential of global sequence variation of this valuable crop.

genomics↗

bioRxiv2024

Uncovering disease-related multicellular pathway modules on large-scale single-cell transcriptomes with scPAFA

Pathway analysis is a crucial analytical phase in disease research on single-cell RNA sequencing (scRNA-seq) data, offering biological interpretations based on prior knowledge. However, currently available tools for generating cell-level pathway activity scores (PAS) exhibit computational inefficacy in large-scale scRNA-seq datasets. Besides, disease-related pathways are commonly identified by cross-condition comparisons in each cell type, neglecting the potential multicellular patterns. Here, we present single-cell pathway activity factor analysis (scPAFA), a Python library designed for large-scale single-cell dataset allowing rapid PAS computation and uncovering biologically interpretable disease-related multicellular pathway modules, which are low-dimensional representations of disease-related PAS variance in multiple cell types. Application on colorectal cancer (CRC) dataset with 371,223 cells and large-scale lupus atlas over 1.2 million cells demonstrated that scPAFA can achieve > 33-fold decreases in runtime of PAS computation and further identified reliable and interpretable multicellular pathway modules that capture the transcriptomic features of CRC tumor status and transcriptional abnormalities in lupus patients, respectively.

bioinformatics↗

bioRxiv2024

Genetic polymorphisms of Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3) gene in African American kidney transplant recipients are associated with post-transplant graft failure

BackgroundAfrican American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared to other racial and ethnic populations, highlighting the need to identify causative factors underlying this disparity. MethodWe analyzed RNA sequences of pretransplant whole blood from subjects followed in three kidney transplant cohorts to identify single nucleotide polymorphisms (SNPs) associated with death censored graft loss (DCGL). We employed a meta-analysis to uncover key transcriptional signatures and pathways associated with the identified SNPs and used single cell RNA to define cellular specificity. We characterized SNP functions using in vitro immunological and survival assays and tested for associations between the identified SNPs and other immune-related diseases using a [~]30,100 subject, electronic health record (EHR)-linked database. ResultsWe uncovered a cluster of four consecutive missense SNPs in the Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3, a negative immune response regulator) gene that strongly associated with DCGL. This LILRB3-4SNPs cluster encodes missense mutations at amino acids 617-618 proximal to a SHP-1/2 phosphatase-binding ITIM motif. LILRB3-4SNPs is specifically enriched within subjects of AA ancestry (8.6% prevalence vs 2.3% in Hispanic and 0.1% in European populations), is not linked to APOL1 G1/G2 alleles, and exhibited a strong association with DCGL. Analysis of PBMC and transplant biopsies from recipients with LILRB3-4SNPs showed evidence of enhanced adaptive immune responsiveness and ferroptosis-associated death in monocytes. Overexpression of the variant allele in THP-1 cells (macrophage line) induced augmented inflammation and ferroptosis, which were attenuated by a ferroptosis inhibitor, verifying a causal link. The LILRB3-4SNPs also associated with multiple systemic and organ-specific immune-related diseases in AAs, consistent with conferring a broadly relevant immune function. Conclusionthe LILRB3-4SNPs represent a functionally important, distinct genetic risk factor for kidney transplant outcome and development/severity of other immune-related diseases in patients of AA ancestry. Pharmacological targeting of ferroptosis should be tested to prevent or treat these disease processes in AA recipients carrying LILRB3-4SNPs.

genetics↗

bioRxiv2023

PNLDC1 catalysis and postnatal germline function are required for piRNA trimming, LINE1 silencing, and spermatogenesis in mice

PIWI-interacting RNAs (piRNAs) play critical and conserved roles in transposon silencing and gene regulation in the animal germline. Two distinct piRNA populations are present during mouse spermatogenesis: pre-pachytene piRNAs in fetal/neonatal testes and pachytene piRNAs in adult testes. PNLDC1 is required for both pre-pachytene piRNA and pachytene piRNA 3 end maturation in multiple species. However, whether PNLDC1 is the bona fide piRNA trimmer and the physiological role of 3 trimming of two distinct piRNA populations in spermatogenesis remain unclear. Here, by inactivating Pnldc1 exonuclease activity in vitro and in mice, we reveal that PNLDC1 trimmer activity is required for both pre-pachytene piRNA and pachytene piRNA 3 end trimming and male fertility. Furthermore, conditional inactivation of Pnldc1 in postnatal germ cells causes LINE1 transposon de-repression and spermatogenic arrest in mice. This indicates that pachytene piRNA trimming, but not pre-pachytene piRNA trimming, is essential for mouse germ cell development and transposon silencing. Our findings highlight the potential of inhibiting germline piRNA trimmer activity as a potential means for male contraception.

developmental biology↗

bioRxiv2023

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

bioRxiv2023

SWI/SNF chromatin remodeling determines brassinosteroid-induced transcriptional activation

The brassinosteroid (BR) hormone is a central modulator of plant growth, development, and responses to stresses by activating or repressing the expression of thousands of genes through the transcription factor BRASSINAZOLE-RESISTANT 1 (BZR1) and its homologues. However, the molecular mechanism that determines the transcriptional activation versus repression activity of BZR1 remains largely unclear. Here, we show that BZR1-responsive transcriptional activation at thousands of loci requires the Switch defective/sucrose non-fermentable (SWI/SNF)-complexes-mediated chromatin accessibility regulation. BR-activated BZR1 controls the activation or repression of thousands of BZR1 target genes through reprograming genome-wide chromatin accessibility landscape in Arabidopsis thaliana. BZR1 physically interacts with the BRAHMA (BRM)-Associated SWI/SNF complexes (BAS), co-localizes with BRM on the genome, and enhances BRM occupancy at sites of increased accessibility by BR. Loss of BRM abrogates the capacity of BZR1 to increase but not decrease chromatin accessibility, blocks BR-induced hypocotyl elongation, and diminishes BZR1-mediated transcriptional activation rather than repression. Together, our work reveals that the BAS chromatin remodeling complex is a critical epigenetic regulatory partner in dictating BZR1-mediated transcriptional activation ability, thus providing a long sought mechanistic explanation for how BR signaling activates gene transcription in shaping diverse developmental programs. TeaserBZR1-responsive transcriptional activation activity at thousands of loci requires the SWI/SNF-complexes-mediated chromatin accessibility regulation.

plant biology↗

bioRxiv2023

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [≥] 7 (37/398, 9.3%) and 1-year survival model score [≥] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗

bioRxiv2023

WEGS: a cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome

0Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a novel, cost-effective method, which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.

genomics↗

bioRxiv2023

Dynamics and Plasticity of Immune Cells within Tumor Microenvironment

The tumor microenvironment harbors a complex ecosystem of immune cells, the heterogeneity of which has been extensively characterized, yet the developmental trajectories and plasticity of these populations remain poorly understood. Here, by integrating mitochondrial DNA mutations and chromosomal single-nucleotide polymorphisms inferred from single-cell RNA sequencing data, we established a robust lineage tracing framework to precisely reconstruct phylogenetic relationships among immune cells at single-cell resolution across multiple human cancers. This approach enabled us to systematically map the dynamics within the tumor immune landscape, revealing extensive plasticity including transitions between immune cell subtypes, transdifferentiation across lineages, and dedifferentiation toward progenitor states--all occurring with cancer-type specificity. Tumor microenvironment extrinsic factors were identified as key drivers of this plasticity, directing both the acquisition of transitional states and the orientation of fate changes. Mechanistically, these plasticity events were governed by profound epigenetic reprogramming, with global remodeling of chromatin accessibility and DNA methylation patterns underlying identity shifts. Our study provides a comprehensive atlas of immune cell plasticity in human tumors, establishes the molecular principles governing these dynamic processes, and reveals new opportunities for therapeutic intervention through manipulation of immune cell state or fate decisions.

cell biology↗

bioRxiv2023

Marmoset Brain Mapping V5: an Anatomical and Connectivity Atlas of the Cerebellum

The cerebellum is a key region of the brain for motor control and cognitive functioning, and it is involved bidirectional communication with the cerebral cortex. As one of the smallest non-human primates, the common marmoset provides many advantages in the study of the anatomy and the functions of cerebello-cerebral circuits. However, the cerebellum of the marmoset is far from being well described in published resources. In this study, we present a comprehensive atlas of the marmoset cerebellum in three parts: 1) fine-detailed anatomical atlases and surface-analyzing tools of the cerebellar cortex, based on ultra-high resolution ex-vivo MRI; 2) functional-connectivity gradients of the cerebellar cortex, based on awake resting-state fMRI; and 3) structural-connectivity based mapping of the cerebellar nuclei, based on high-resolution diffusion tractography. The atlas shows the anatomical details of the marmoset cerebellum; reveals distinct gradient patterns of the intra-cerebellar and the cerebello-cerebral functional connectivity; and maps the topological relationship of the cerebellar nuclei in cerebello-cerebral circuits. As version 5 of the Marmoset Brain Mapping project, the atlas describes the anatomical and connectivity details of the marmoset cerebellum and is publicly available via marmosetbrainmapping.org.

neuroscience↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

CRISPR-Cas phage defense systems and prophages in Candidatus Accumulibacter

Candidatus Accumulibacter is a key genus of polyphosphate-accumulating organisms (PAOs) found in laboratory- and full-scale wastewater treatment systems, mediating enhanced biological phosphorus removal (EBPR). However, little is known about their ability to resist phage infection. We conducted a systematic analysis of the occurrence and characteristics of clustered regularly interspaced short palindromic repeats and associated proteins (CRISPR-Cas) systems and prophages in diverse Ca. Accumulibacter taxa (43 in total, including 10 newly recovered genomes). Fourty complete CRISPR loci were identified in 28 genomes, falling into 6 subtypes. The occurrence and distribution of CRISPR-Cas systems did not follow a vertical evolutionary relationship. Phylogenetic analyses of the cas genes and direct repeats (DRs) suggested that the CRISPR-Cas systems were likely acquired via horizontal gene transfer, with acquisition rates higher than those of speciation, rendering different Ca. Accumulibacter distinct adaptivity to phage predations. 2448 spacers were identified, 67 of them matched to known phages. Major differences were observed among the numbers of spacers for different Ca. Accumulibacter, showing unique phages that could be resisted by different members. A comparison of the spacers in genomes having the same cas gene but from distinct geographical locations indicated that habitat isolation may have resulted in the acquisition of different spacers by different Ca. Accumulibacter. Metagenomic analysis allowed the identification of 26 viral contigs (18 are Caudovirales members) in 6 metagenomic datasets from three lab-scale enrichment reactors, matching to 73 spacers in 10 Ca. Accumulibacter genomes in these reactors, showing the specific immunity of these Ca. Accumulibacter. Metatranscriptomic analyses showed the activity of the CRISPR-Cas system under both anaerobic and aerobic conditions. Extra efforts were made to identify prophages in Ca. Accumulibacter genomes. In total, 133 prophage regions were identified. Twenty-seven of them were classified as potentially active prophages. Three prophages (all are Caudovirales members, in DS2011, SCELSE-7IIH and SCELSE-5IIH, respectively) are readily activable. Differences in the occurrence of CRISPR-Cas systems and prophages in Ca. Accumulibacter will lead to their distinct responses under phage predation. This study represents the first systematic analysis of CRISPR-Cas systems and prophages with combined experimental and bioinformatic methods in the Ca. Accumulibacter lineage, providing new perspectives on the potential impacts of phages on Ca. Accumulibacter and EBPR systems.

bioinformatics↗

bioRxiv2022

Innate immune sensing of self-derived double-stranded RNA by RIG-I-MAVS-TNF-α regulates the survival and senescence fate of SARS-2-S syncytia

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without denovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy. Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNF-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

cell biology↗

bioRxiv2022

Correlation analysis between drug resistance and virulence genes of carbapenem-resistant Acinetobacter baumannii In Western Guilin

BackgoundIn order to detect the resistance of Acinetobacter baumannii to {beta}-lactam antibiotics in western Guilin, analyze the reasons for its resistance, and provide laboratory basis for clinical treatment; method for the {beta}-lactamase gene of Acinetobacter baumannii, and to explore the relationship between the presence of the {beta}-lactamase gene of Acinetobacter baumannii and multidrug resistance. MethodsFrom November 2020 to June 2022, 78 non-repeated Acinetobacter baumannii strains from the Second Affiliated Hospital of Guilin Medical University were collected, and their resistance to carbapenem antibiotics was analyzed. PCR was used to detect resistance-related genes (blaOXA-23, blaOXA-51, blaOXA-58, blaOXA-24, blaIMP and blaSIM) and virulence genes (cusE, abaI and bfmS). To analyze the relationship between drug resistance and virulence genes of Acinetobacter baumannii. ResultsMost of the 165 non-enterobacteriaceae bacteria we collected from the hospital were Acinetobacter baumannii and Pseudomonas aeruginosa, and most of the specimen types were from sputum and secretions, and most of them were from respiratory and critical care diseases area and intensive care unit, among them, there are 78 strains of Acinetobacter baumannii studied this time. After screening, 78 Acinetobacter baumannii strains were resistant to Cefazolin, Ampicillin, Amoxicillin/Clavulanate, Aztreonam, Chloramphenicol, Tetracycline, Cefotaxime, Ampicillin/Sulbactam, Piperacillin, Gentamicin, Ciprofloxacin, Levofloxacin, Moxifloxacin, Cefepime, Ceftazidime, Piperacillin/Tazobactam, Compound Sulfonamide, Meropenem, Imipenem, Amikacin, Polymyxin, resistance rates were 98.72%, 98.72%, 96.16%, 96.15%, 96.15%, 66.67%, 60.26%, 58.98%, 58.97%, 57.69%, 57.69%, 57.69%, 57.69%, 57.69%, 56.41%, 55.13%, 53.85%, 52.56%, 52.56%, 50%, 0%. Among them, 17 strains with drug resistance gene blaOXA-51 were detected,accounting for 21.79%; drug gene blaOXA-23, blaOXA-24, blaIMP, blaOXA-58, blaSIM gene were not detected; 17 strains with virulence gene bfmS was detected, accounting for 21.79%; abaI, csuE virulence gene was not detected. ConclusionAcinetobacter baumannii in the hospital is highly resistant to carbapenems, mainly carrying blaOXA-51 resistance genes. Drug resistance is closely related to the virulence gene bfmS.

microbiology↗

bioRxiv2022

High-throughput TCRB enrichment sequencing of human cord blood exhibited a distinct fetal T cell repertoire in the third trimester of pregnancy

Study questionWhat are the molecular characteristics during the maturation process of the human fetal immune system in the third trimester of pregnancy? Summary answerBoth the diversity and length of complementarity determining region 3 (CDR3s) in the fetal TCRB repertoire were less than those of adult CDR3s, and the fetal CDR3 length increased with gestation weeks in late pregnancy. What is known alreadyThe adaptive immune system recognizes various pathogens based on a large repertoire of T-cell receptors (TCR repertoire), but the maturation dynamics of the fetal TCR repertoire in the third trimester are largely unknown. The CDR3is the most diversified segment in the T-cell receptor {beta} chain (TCRB) that binds and recognizes the antigen. Study design, size, and durationThis was a basic research to assess the composing characteristics of TCRBs in core blood and the dynamic pattern with fetal development in the third trimester of pregnancy. Participants/materials, setting methodsHigh-throughput TCRB-enrichment sequencing was utilized to characterize the TCRB repertoire of cord blood at 24~38 weeks of gestational age (WGA) with nonpreterm fetuses and to investigate their difference compared with that of adult peripheral blood. Main results and the role of chanceCompared to the adult control, the fetal TCRB repertoire had a 4.8-fold lower number of unique CDR3s, a comparable Shannon diversity index (p=0.7387), a lower mean top clone rate (p < 0.001) and a constrictive top 1000 unique clone rates. Although all kinds of TCRBV and TCRBJ genes present in adult CDR3s were identified in fetuses, nearly half of these fragments showed a significant difference in usage. Moreover, the fetal TCRB repertoire held a shorter CDR3 length, and the CDR3 length showed a progressive increase with fetal development. Jensen-Shannon (JS) divergences of TCRBV and TCRBJ gene usage in dizygotic twins were much lower than those in unrelated pairs. In the parental-fetal pair, JS divergence of TCRBV gene usage was not obviously different, while that of TCRBJ gene usage was only slightly lower. Limitations, reasons for cautionThe sample size is limited due to the limited accessibility to cord blood in late pregnancy with healthy nonpreterm fetuses. Wider implications of the findingsOur findings reveal the unique properties of fetal TCRB repertoires in the third trimester, fill the gap in our understanding of the maturation process of prenatal fatal immunity, and deepen our understanding of the immunologically relevant problems in neonates. Study funding/competing interest(s)This work was supported by the National Natural Science Foundation of China (82171661) and Tianjin Municipal Science and Technology Special Funds for Enterprise Development (NO. 14ZXLJSY00320). The authors declare that they have no competing interests.

genetics↗

bioRxiv2022

DBP2Vec: Predicting DNA-binding proteins directly using pre-trained protein language model

DNA-binding proteins (DBPs) play a crucial role in numbers of biological processes and have received wide attention in recent years. Meanwhile, the rapid development of sequencing technologies lead to the explosive growth of new protein sequences, it is highly desired to develop a fast and accurate method for DNA-binding proteins prediction. Experimental methods such as chromatin immunoprecipitation on microarray (ChIP-chip) and X-ray crystallography are highly accurate but expensive and time-consuming. To address this issue, many computational methods have been proposed, they usually exploit multiple information about protein sequence, e.g., sequence composition information, physicochemical properties, evolutionary information, structural information, etc. Despite the effectiveness of these approaches, they heavily depend on prior biological knowledge and undergo a very complex process of feature extraction. In view of these shortcomings, here, we present a novel method, named DBP2Vec, to predict DNA-binding proteins directly from pre-trained protein language model (e.g., ESM-1b) which effectively encode biological properties without any prior knowledge by virtue of deep representation learning (e.g., BERT) on large protein sequences databases (e.g., UniParc). Tests on two DBPs benchmark datasets (e.g., PDB296, UniSwiss-Tst) demonstrate that our proposed method significantly outperforms existing state-of-the-art methods. The source code and the datasets used in the paper are publicly available at: https://github.com/hgcwei/DBP2Vec.

bioinformatics↗

bioRxiv2022

Widespread of horizontal gene transfer regions in eukaryotes

Horizontal gene transfer (HGT) is the transfer of genetic material between distantly related organisms. While most genes in prokaryotes can be horizontally transferred, HGT events in eukaryotes are considered as rare, particularly in mammals. Here we reported the identification of HGT regions (HGTs), which are genomic sequence fragments indicating the occurrence of HGT events, in human, mouse, cow, lizard, frog, zebrafish, fruit fly, nematode, Arabidopsis and yeast. By comparing the genomes of these 10 representative eukaryotes with 1,496 eukaryotic genomes, 16,098 bacteria and 11,695 viruses, we found between 10 and 243 non-redundant HGTs per species, and most of these HGTs were previously unknown. These HGTs have transformed their host genomes with various numbers of copies and have impacted hundreds, even thousands of genes. We listed several examples of HGTs and proposed some possible routes that HGT events occurred. Further analysis showed that the majority of the 1,496 eukaryotes with full length genome sequences also contain HGTs. Our findings reveal that HGT is widespread in eukaryotic genomes, and HGT is a ubiquitous driver of genome evolution for eukaryotes.

genomics↗

bioRxiv2022

CPPVec: an accurate coding potential predictor based on adistributed representation of protein sequence

Long non-coding RNAs (lncRNAs) play a crucial role in numbers of biological processes and have received wide attention during the past years. Meanwhile, the rapid development of high-throughput transcriptome sequencing technologies (RNA-seq) lead to a large amount of RNA data, it is urgent to develop a fast and accurate coding potential predictor. Many computational methods have been proposed to alleviate this issue, they usually exploit information on open reading frame (ORF), k-mer, evolutionary signatures, or known protein databases. Despite the effectiveness, these methods still have much room to improve. Indeed, none of these methods exploit the context information of sequence, simple measures that are calculated with the continuous nucleotides are not enough to reflect global sequence order information. In view of this shortcoming, here, we present a novel alignment-free method, CPPVec, which exploits the global sequence order information of transcript for coding potential prediction for the first time, it can be easily implemented by distributed representation (e.g., doc2vec) of protein sequence translated from the longest ORF. Tests on human, mouse, zebrafish, fruit fly and Saccharomyces cerevisiae datasets demonstrate that CPPVec is an accurate coding potential predictor and significantly outperforms existing state-of-the-art methods.

bioinformatics↗