Biology subjects

Yang, J.-R.

Publications and source records attributed to Yang, J.-R..

13 recordsLinked to original sources

bioRxiv2024

Peptide Information Compression Technology (PICT): A New Frontier in Therapeutic Peptide Discovery

Therapeutic peptides hold tremendous market potential, yet the discovery methods for active peptides lag considerably behind those for small molecules and biological macromolecule drugs. Due to their respective limitations, traditional peptide compound synthesis and display libraries fail to meet the growing demands of the peptide drug market. Here, we introduce a novel Peptide Information Compression Technology (PICT) and, based on this technology, a large-scale physical peptide library and its accompanying high-throughput screening (HTS) platform. By screening for inhibitors of TSLP/TSLPR/IL7R and antagonists of MC3R at both the molecular and cellular levels, we have identified active molecules in the single-digital micromolar and nanomolar ranges, respectively. This demonstrates the immense application value of Peptide Information Compression Technology in the efficient discovery of peptide drugs.

molecular biology↗

bioRxiv2024

VIACOT: a web server for interactive visualization and comparison of cell lineage trees

The cell lineage tree (CLT) records some or all cell division events during the development of multicellular organisms, as well as the functional characteristics of terminal cells, and is therefore commonly considered one of the most fundamental types of biological data. The combining of single-cell RNA sequencing with DNA barcoding has recently led to the rapid accumulation of CLT datasets. Unlike biological sequence data, web-based analysis and visualization tools for CLT data are currently lacking. In order to facilitate studies surrounding CLT, we built a webserver named VIACOT (Visualize Interactively And COmpare Trees). VIACOT is not only a comprehensive repository of published CLT datasets, but also a web tool that enables three preliminary analyses of preprocessed CLT datasets, including. (i) interactive visualization of CLT allowing fine-grain or coarse-grain exploration. (ii) calculations of correlations among single-cell metrics, such as gene expression levels, either using the original metrics or their phylogenetic independent contrasts. (iii) comparison among different CLTs to identify differences in cell fate. We anticipate that VIACOT will be a useful tool for exploration and biological interpretation of CLTs.

bioinformatics↗

bioRxiv2024

Stereotyped cell lineage trees support robust development

Multicellular organisms must have robust development to ensure physiological stability in the face of environmental changes or perturbations. While various mechanisms contributing to developmental robustness have been identified at the subcellular level, those at the intercellular and tissue level remain largely unknown. Our study explores this question using an in vitro directed differentiation model of human embryonic stem cells (hESCs) into lung progenitor cells. Integrated analysis of single-cell transcriptomes and high-density cell lineage trees (CLTs) of the same colonies allowed a fine-resolution recapitulation of known cell types, as well as their differentiation hierarchies and developmental trajectories. Most importantly, we observed stable cell type compositions among many sub-CLTs across biological replicates. Systematic comparison among CLTs by a novel computational framework for CLT alignment suggests that stereotypical development extends beyond stable cell type composition to a degree of significant resemblance in sub-CLT topology. The existence of such sub-CLTs resembling each other not only deepens our understanding of developmental robustness by demonstrating the existence of a stereotyped program, but also suggests a novel perspective for the function of specific cell types in the context of stereotyped sub-CLTs.

developmental biology↗

bioRxiv2024

Discovery of Waddington's developmental canals elucidates the embryogenesis stability in Caenorhabditis elegans

During embryogenesis, the cells in an embryo need to make numerous spatiotemporal decisions. However, there is inherent noise in each decision due to genetic or environmental fluctuations. How to suppress the noise accumulation to achieve stable embryonic end-products, a process known as Waddingtons developmental canalization, has been a major puzzle in biology since the 1940s. Previous studies have focused on the molecular noise within a cell instead of the cell noise within an embryo, thus providing indirect understandings (e,g., the well-known genetic capacitor Hsp90). In this study, we applied time-lapse microscopic imaging to capturing the spatiotemporal features of single cells, including cell position and cell cycle length, during the embryogenesis of approximately 2,100 Caenorhabditis elegans embryos exposed to various genetic or environmental perturbations. By treating the deviation of a cells spatiotemporal feature from the expected value as noise, we modeled the transmission of noise from each mother cell to their daughters. We discovered pervasive mother-daughter negative feedbacks, which collectively constitute continuous and comprehensive canals for suppressing noise accumulation along the developmental cell lineages, with the steepness (measuring noise suppression efficacy) and depth (measuring noise tolerance level) of the canals quantitatively defined. The learned quantitative rules enabled us to develop a cell-noise-based model that accurately predicts the nematode hatching phenotype, revealing how embryonic stochasticity could cause phenotypic disparity. With a high-dimensional mathematical tool we then proved the system stability of embryogenesis against the cell spatiotemporal noise. We also revealed several dozen canal-maintaining genes and proposed a novel association study framework that links embryonic cells rather than genetic variants with organismal traits. In sum, this study discovered and quantitatively characterized the developmental canals that directly stabilize embryogenesis in a metazoan, illuminating an 80-year-old puzzle and paving a way for studying the phenotypic plasticity and robustness of multicellular organisms from the perspective of embryogenesis.

developmental biology↗

bioRxiv2023

Genome-wide impact of codon usage bias on translation optimization in Drosophila melanogaster

Accuracy and efficiency are fundamental characteristics of the translational process. Codon usage bias is widespread across species. Despite the long-standing association between codon optimization and improved translation, our understanding of the evolutionary basis and functional effects of codon optimization is limited. Drosophila has been widely used to study codon usage bias, but genome-scale experimental data on codon optimization and translation are scarce. We examined high-resolution mass spectrometry datasets from D. melanogaster development and employed different strategies to reduce bias when comparing translation error rates. We demonstrated that optimal codons have lower translation errors than nonoptimal codons after accounting for these biases. Our findings also shed light on codon-anticodon mismatches in translation errors. Through genomic-scale analysis of ribosome profiling data, we showed that optimal codons are translated more rapidly than nonoptimal codons in D. melanogaster. While we did not find conclusive evidence that natural selection favored synonymous mutations during the long-term evolution of the D. melanogaster lineage after its divergence from D. simulans, we did find that positive selection drives codon optimization-related mutations in the D. melanogaster population. This study expands our understanding of the functional consequences of codon optimization, and serves as a foundation for future investigations into the molecular mechanisms governing gene expression evolution at the translation level.

genetics↗

bioRxiv2022

The fitness landscape of the mobilized colistin resistance gene mcr-1

The emergence and global discovery of the mobilized colistin resistance gene, mcr-1, limits the clinical effectiveness of colistin as last-resort antibiotic against multiple-drug resistant bacteria. Although MCR-1 exhibits low levels of colistin resistance in E. coli, it is currently unknown whether mcr-1 may potentially evolve a high level of colistin resistance in the future. Here, we generated mcr-1 mutant library that included 27,965 variants, covering 94.44% of the single-nucleotide mutations. We quantified the relative growth of these variant strains under colistin exposure. Notably, most mutations in the catalytic domain, but not in the transmembrane domain, reduce colistin resistance. The structural basis for the mutational effects revealed that the transmembrane domain may contribute to MCR-1 evolution. Altogether, our data shed light on the prediction of MCR-1 evolution, which could be useful for designing novel treatment strategies.

evolutionary biology↗

bioRxiv2020

The Evolution of Sex Chromosome Dosage Compensation in Animals

The evolution of sex chromosomes in the XY or ZW systems shall lead to gene expression dosage problems, as in at least one of the sexes, the sex-linked gene dose has been reduced by half. It has been proposed, most notably by Susumu Ohno for mammals, that the transcriptional output of the whole sex chromosome should be doubled for a complete dosage compensation. However, due to the variability of the existing methods to determine the transcriptional differences between Sex chromosomes and Autosomes (S:A ratios) in different studies, whether clade-specific results are comparable and whether there is a more general model to explain dosage compensation states remain unanswered. In this study, we collected more than 500 public RNA-seq datasets from multiple tissues and species in major clades (including mammals, birds, fishes, insects, and worms) and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species. We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes. We found that in mammals and birds, the S:A ratio is approximately 0.5, while in insects, fishes and flatworms, the S:A ratio is approximately 1. Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the sex chromosome is significantly correlated with the S:A ratio. In addition, the degree of degradation of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage-compensation mechanism. Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that the dosage sensitivity states of sex chromosomes is a major factor underlying different evolutionary strategies of dosage compensation.

evolutionary biology↗

bioRxiv2020

Sequence variation among SARS-CoV-2 isolates in Taiwan

Taiwan experienced two waves of imported cases of coronavirus disease 2019 (COVID-19), first from China in January to late February, followed by those from other countries starting in early March. Additionally, several cases could not be traced to any imported cases and were suspected as sporadic local transmission. Twelve full viral genomes were determined in this study by Illumina sequencing either from virus isolates or directly from specimens, among which 5 originated from clustered infections. Phylogenetic tree analysis revealed that these sequences were in different clades, indicating that no major strain has been circulating in Taiwan. A deletion in open reading frame 8 was found in one isolate. Only a 4-nucleotide difference was observed among the 5 genomes from clustered infections.

genetics↗

bioRxiv2019

Computational comparison of developmental cell lineage trees by alignments

The developmental cell lineage tree, which records every cell division event and the terminal developmental state of each single cell, is one of the most important traits of multicellular organisms, as well as key to many significant unresolved questions in biology. Recent technological breakthroughs are paving the way for direct determination of cell lineage trees, yet a general framework for the computational analysis of lineage trees, in particular an algorithm to compare two lineage trees, is still lacking. Based on previous findings that the same developmental program can be invoked by different cells on the lineage tree to produce highly similar subtrees, we designed Developmental Cell Lineage Tree Alignment (DELTA), an algorithm that exhaustively searches for lineage trees with phenotypic resemblance in lineal organization of terminal cells, meanwhile resolving detailed correspondence between individual cells. Using simulated and nematode lineage trees, we demonstrated DELTAs capability of revealing similarities of developmental programs by lineal resemblances. Moreover, DELTA successfully identifies gene deletion-triggered homeotic cell fate transformations, reveals functional relationship between mutants by quantifying their lineal similarities, and finds the evolutionary correspondence between cell types defined non-uniformly for different species. DELTA establishes novel foundation for comparative study of lineage trees, much like sequence alignment algorithm for biological sequences, and along with the increase of lineage tree data, will likely bring unique insights for the myriads of important questions surrounding cell lineage trees.

bioinformatics↗

bioRxiv2018

Specificity of RNA folding and its association with evolutionarily adaptive mRNA secondary structure

Secondary structure is a fundamental feature for both noncoding and messenger RNA. However, our understandings about the secondary structure of mRNA, especially for the coding regions, remain elusive, likely due to translation and the lack of RNA binding proteins that sustain the consensus structure, such as those bind to noncoding RNA. Indeed, mRNA has recently been found to bear pervasive alternative structures, whose overall evolutionary and functional significance remained untested. We hereby approached this problem by estimating folding specificity, the probability that a fragment of RNA folds back to the same partner once re-folded. We showed that folding specificity for mRNA is lower than noncoding RNA, and displays moderate evolutionary conservation between orthologs and between paralogs. More importantly, we found that specific rather than alternative folding is more likely evolutionarily adaptive, since it is more frequently associated with functionally important genes or sites within a gene. Additional analysis in combination with ribosome density suggests the capability of modulating ribosome movement as one potential functional advantage provided by specific folding. Our findings revealed a novel facet of RNA structome with important functional and evolutionary implications, and points to a potential way of disentangling mRNA secondary structures maintained by natural selection from molecular noise.

evolutionary biology↗

bioRxiv2018

Dosage sensitivity of X-linked genes in human embryonic single cells

Fifty years ago, Susumu Ohno proposed that the expression levels of X-linked genes have doubled as dosage compensation for autosomal genes due to degeneration of Y-linked homologs during evolution of mammalian sex chromosomes. Recent studies have nevertheless shown that the X to autosome expression ratio equals ~1 in haploid human parthenogenetic embryonic stem (pES) cells and ~0.5 in diploid pES cells, thus refuting Ohnos hypothesis. Here, by reanalyzing a RNA-seq-based single-cell transcriptome dataset of human embryos (Petropoulos, et al. 2016), we found that from the 8-cell stage until the time-point just prior to implantation, the expression levels of X-linked genes are not two-fold upregulated in male cells and gradually decrease from two-fold in female cells. This observation suggests that the expression levels of X-linked genes are imbalanced, with autosomal genes starting from the early 8-cell stage, and that the dosage conversion is fast, such that the X:AA expression ratio reaches ~0.5 in no more than a week. Additional analyses of gene expression noise further suggest that the dosage sensitivity of X-linked genes is weaker than that of autosomal genes in differentiated female cells, which contradicts a key assumption of Ohnos hypothesis. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes. Our results collectively suggest an alternative to Ohnos hypothesis that X-linked genes are less likely to be dosage sensitive than autosomal genes.

genomics↗

bioRxiv2016

Intra- and inter-specific variations of gene expression levels in yeast are largely neutral

It is commonly, although not universally, accepted that most intra- and inter-specific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only [~]0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra- and inter-specific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution.

evolutionary biology↗

bioRxiv2016

Deciphering the genic basis of environmental adaptations by simultaneous forward and reverse genetics in Saccharomyces cerevisiae

The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding the genetic basis of natural phenotypic variation is limited by the inefficiency of association mapping owing to strong and complex population structure. To facilitate association mapping, we analyzed 190 high-quality genomes of diverse strains, including 85 newly sequenced ones, to uncover yeasts population structure that varies substantially among genomic regions. We identified 181 yeast genes that are absent from the reference genome and demonstrated their expression and role in important functions such as drug resistance. We then simultaneously measured the growth rates of over 4500 lab strains each deficient of a nonessential gene and 81 natural strains across multiple environments using unique DNA barcode present in each strain. We combined the genome-wide reverse genetic information with genome-wide association analysis to determine potential genomic regions of importance to environmental adaptations, and for a subset experimentally validated their role by reciprocal hemizygosity tests. The resources provided permit efficient and reliable association mapping in yeast and significantly enhances its value as a model for understanding the genetic mechanisms of phenotypic polymorphism and evolution.

genomics↗