Publications by authors named "Huanming Yang"

426 Publications

Transcriptional Start Site Coverage Analysis in Plasma Cell-Free DNA Reveals Disease Severity and Tissue Specificity of COVID-19 Patients.

Front Genet 2021 28;12:663098. Epub 2021 May 28.

BGI-Shenzhen, Shenzhen, China.

Symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic to severe pneumonia and death. A deep understanding of the variation of biological characteristics in severe COVID-19 patients is crucial for the detection of individuals at high risk of critical condition for the clinical management of the disease. Herein, by profiling the gene expression spectrum deduced from DNA coverage in regions surrounding transcriptional start site in plasma cell-free DNA (cfDNA) of COVID-19 patients, we deciphered the altered biological processes in the severe cases and demonstrated the feasibility of cfDNA in measuring the COVID-19 progression. The up- and downregulated genes in the plasma of severe patient were found to be closely related to the biological processes and functions affected by COVID-19 progression. More importantly, with the analysis of transcriptome data of blood cells and lung cells from control group and cases with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, we revealed that the upregulated genes were predominantly involved in the viral and antiviral activity in blood cells, reflecting the intense viral replication and the active reaction of immune system in the severe patients. Pathway analysis of downregulated genes in plasma DNA and lung cells also demonstrated the diminished adenosine triphosphate synthesis function in lung cells, which was evidenced to correlate with the severe COVID-19 symptoms, such as a cytokine storm and acute respiratory distress. Overall, this study revealed tissue involvement, provided insights into the mechanism of COVID-19 progression, and highlighted the utility of cfDNA as a noninvasive biomarker for disease severity inspections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.663098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194351PMC
May 2021

Life History Recorded in the Vagino-cervical Microbiome Along with Multi-omics.

Genomics Proteomics Bioinformatics 2021 Jun 9. Epub 2021 Jun 9.

BGI-Shenzhen, Shenzhen 518083, China.

The vagina contains at least a billion microbial cells, dominated by lactobacilli. Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age, and cervical, fecal, and salivary samples from a second cohort of 632 women. Factors such as pregnancy, delivery histories, cesarean section, and breast-feeding were all more important than menstrual cycle in shaping the microbiome, and such information would be necessary before trying to interpret differences between vagino-cervical microbiome data. Greater proportion of Bifidobacterium breve was seen with older age at sexual debut. The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history. Potential markers for lack of menstrual regularity, heavy flow, dysmenorrhea, and contraceptives were also identified. Lactobacilli were rare during breast-feeding or post-menopause. Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome. Gut and salivary microbiome, plasma vitamins, metals, amino acids, and hormones showed associations with the vagino-cervical microbiome. Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gpb.2021.01.005DOI Listing
June 2021

Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning.

Nat Commun 2021 05 28;12(1):3238. Epub 2021 May 28.

Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, Qingdao, China.

The design of CRISPR gRNAs requires accurate on-target efficiency predictions, which demand high-quality gRNA activity data and efficient modeling. To advance, we here report on the generation of on-target gRNA activity data for 10,592 SpCas9 gRNAs. Integrating these with complementary published data, we train a deep learning model, CRISPRon, on 23,902 gRNAs. Compared to existing tools, CRISPRon exhibits significantly higher prediction performances on four test datasets not overlapping with training data used for the development of these tools. Furthermore, we present an interactive gRNA design webserver based on the CRISPRon standalone software, both available via https://rth.dk/resources/crispr/ . CRISPRon advances CRISPR applications by providing more accurate gRNA efficiency predictions than the existing tools.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163799PMC
May 2021

Evolutionary and biomedical insights from a marmoset diploid genome assembly.

Nature 2021 Jun 28;594(7862):227-233. Epub 2021 Apr 28.

Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

The accurate and complete assembly of both haplotype sequences of a diploid organism is essential to understanding the role of variation in genome functions, phenotypes and diseases. Here, using a trio-binning approach, we present a high-quality, diploid reference genome, with both haplotypes assembled independently at the chromosome level, for the common marmoset (Callithrix jacchus), an primate model system that is widely used in biomedical research. The full spectrum of heterozygosity between the two haplotypes involves 1.36% of the genome-much higher than the 0.13% indicated by the standard estimation based on single-nucleotide heterozygosity alone. The de novo mutation rate is 0.43 × 10 per site per generation, and the paternal inherited genome acquired twice as many mutations as the maternal. Our diploid assembly enabled us to discover a recent expansion of the sex-differentiation region and unique evolutionary changes in the marmoset Y chromosome. In addition, we identified many genes with signatures of positive selection that might have contributed to the evolution of Callithrix biological features. Brain-related genes were highly conserved between marmosets and humans, although several genes experienced lineage-specific copy number variations or diversifying selection, with implications for the use of marmosets as a model system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03535-xDOI Listing
June 2021

Characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients.

Cell Discov 2021 Apr 13;7(1):23. Epub 2021 Apr 13.

BGI-Shenzhen, Shenzhen, 518083, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-021-00257-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043102PMC
April 2021

Whole-genome resequencing of 445 Lactuca accessions reveals the domestication history of cultivated lettuce.

Nat Genet 2021 05 12;53(5):752-760. Epub 2021 Apr 12.

State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen, China.

Lettuce (Lactuca sativa) is an important vegetable crop worldwide. Cultivated lettuce is believed to be domesticated from L. serriola; however, its origins and domestication history remain to be elucidated. Here, we sequenced a total of 445 Lactuca accessions, including major lettuce crop types and wild relative species, and generated a comprehensive map of lettuce genome variations. In-depth analyses of population structure and demography revealed that lettuce was first domesticated near the Caucasus, which was marked by loss of seed shattering. We also identified the genetic architecture of other domestication traits and wild introgressions in major resistance clusters in the lettuce genome. This study provides valuable genomic resources for crop breeding and sheds light on the domestication history of cultivated lettuce.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00831-0DOI Listing
May 2021

stLFRsv: A Germline Structural Variant Analysis Pipeline Using Co-barcoded Reads.

Front Genet 2021 18;12:636239. Epub 2021 Mar 18.

BGI-Shenzhen, Shenzhen, China.

Co-barcoded reads originating from long DNA fragments (mean length >30 kbp) maintain both single base level accuracy and long-range genomic information. We propose a pipeline, stLFRsv, to detect structural variation using co-barcoded reads. stLFRsv identifies abnormal large gaps between co-barcoded reads to detect potential breakpoints and reconstruct complex structural variants (SVs). Haplotype phasing by co-barcoded reads increases the signal to noise ratio, and barcode sharing profiles are used to filter out false positives. We integrate the short read SV caller smoove for smaller variants with stLFRsv. The integrated pipeline was evaluated on the well-characterized genome HG002/NA24385, and 74.5% precision and a 22.4% recall rate were obtained for deletions. stLFRsv revealed some large variants not included in the benchmark set that were verified by long reads or assembly. For the HG001/NA12878 genome, stLFRsv also achieved the best performance for both resource usage and the detection of large variants. Our work indicates that co-barcoded read technology has the potential to improve genome completeness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.636239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012683PMC
March 2021

Single-cell transcriptome profiling reveals molecular heterogeneity in human umbilical cord tissue and culture-expanded mesenchymal stem cells.

FEBS J 2021 Mar 24. Epub 2021 Mar 24.

BGI-Shenzhen, China.

Human umbilical cord-derived mesenchymal stem/stromal cells (UMSCs) demonstrate great therapeutic potential in regenerative medicine. The use of UMSCs for clinical applications requires high quantity and good quality of cells usually by in vitro expansion. However, the heterogeneity and the characteristics of cultured UMSCs and the cognate human umbilical cord tissue at single-cell resolution remain poorly defined. In this study, we created a single-cell transcriptome profile of human umbilical cord tissue and the cognate culture-expanded UMSCs. Based on the inferred characteristics of cell clusters and trajectory analysis, we identified three subgroups in culture-expanded UMSCs and putative novel transcription factors (TFs) in regulating UMSC state transition. Further, putative ligand-receptor interaction analysis demonstrated that cellular interactions most frequently occurred in epithelial-like cells with other cell groups in umbilical cord tissue. Moreover, we dissected the transcriptomic differences of in vitro and in vivo subgroups and inferred the telomere-related molecules and pathways that might be activated in UMSCs for cell expansion in vitro. Our study provides a comprehensive and integrative study of the transcriptomics of human umbilical cord tissue and their cognate-cultured counterparts, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of UMSCs-based cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.15834DOI Listing
March 2021

Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals.

Aging Cell 2021 03 3;20(3):e13323. Epub 2021 Mar 3.

Center for the Study of Aging and Human Development, Medical School of Duke University, Durham, USA.

There is growing interest in studying the genetic contributions to longevity, but limited relevant genes have been identified. In this study, we performed a genetic association study of longevity in a total of 15,651 Chinese individuals. Novel longevity loci, BMPER (rs17169634; p = 7.91 × 10 ) and TMEM43/XPC (rs1043943; p = 3.59 × 10 ), were identified in a case-control analysis of 11,045 individuals. BRAF (rs1267601; p = 8.33 × 10 ) and BMPER (rs17169634; p = 1.45 × 10 ) were significantly associated with life expectancy in 12,664 individuals who had survival status records. Additional sex-stratified analyses identified sex-specific longevity genes. Notably, sex-differential associations were identified in two linkage disequilibrium blocks in the TOMM40/APOE region, indicating potential differences during meiosis between males and females. Moreover, polygenic risk scores and Mendelian randomization analyses revealed that longevity was genetically causally correlated with reduced risks of multiple diseases, such as type 2 diabetes, cardiovascular diseases, and arthritis. Finally, we incorporated genetic markers, disease status, and lifestyles to classify longevity or not-longevity groups and predict life span. Our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variance of life span) and presented a greater predictive efficiency in females than in males. Taken together, our findings not only shed light on the genetic contributions to longevity but also elucidate correlations between diseases and longevity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963337PMC
March 2021

Characterization of the human skin resistome and identification of two microbiota cutotypes.

Microbiome 2021 02 17;9(1):47. Epub 2021 Feb 17.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.

Background: The human skin microbiota is considered to be essential for skin homeostasis and barrier function. Comprehensive analyses of its function would substantially benefit from a catalog of reference genes derived from metagenomic sequencing. The existing catalog for the human skin microbiome is based on samples from limited individuals from a single cohort on reference genomes, which limits the coverage of global skin microbiome diversity.

Results: In the present study, we have used shotgun metagenomics to newly sequence 822 skin samples from Han Chinese, which were subsequently combined with 538 previously sequenced North American samples to construct an integrated Human Skin Microbial Gene Catalog (iHSMGC). The iHSMGC comprised 10,930,638 genes with the detection of 4,879,024 new genes. Characterization of the human skin resistome based on iHSMGC confirmed that skin commensals, such as Staphylococcus spp, are an important reservoir of antibiotic resistance genes (ARGs). Further analyses of skin microbial ARGs detected microbe-specific and skin site-specific ARG signatures. Of note, the abundance of ARGs was significantly higher in Chinese than Americans, while multidrug-resistant bacteria ("superbugs") existed on the skin of both Americans and Chinese. A detailed analysis of microbial signatures identified Moraxella osloensis as a species specific for Chinese skin. Importantly, Moraxella osloensis proved to be a signature species for one of two robust patterns of microbial networks present on Chinese skin, with Cutibacterium acnes indicating the second one. Each of such "cutotypes" was associated with distinct patterns of data-driven marker genes, functional modules, and host skin properties. The two cutotypes markedly differed in functional modules related to their metabolic characteristics, indicating that host-dependent trophic chains might underlie their development.

Conclusions: The development of the iHSMGC will facilitate further studies on the human skin microbiome. In the present study, it was used to further characterize the human skin resistome. It also allowed to discover the existence of two cutotypes on the human skin. The latter finding will contribute to a better understanding of the interpersonal complexity of the skin microbiome. Video abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40168-020-00995-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890624PMC
February 2021

A genome-wide association study for gut metagenome in Chinese adults illuminates complex diseases.

Cell Discov 2021 Feb 9;7(1). Epub 2021 Feb 9.

BGI-Shenzhen, Shenzhen,, Guangdong 518083, China.

The gut microbiome has been established as a key environmental factor to health. Genetic influences on the gut microbiome have been reported, yet, doubts remain as to the significance of genetic associations. Here, we provide shotgun data for whole genome and whole metagenome from a Chinese cohort, identifying no <20% genetic contribution to the gut microbiota. Using common variants-, rare variants-, and copy number variations-based association analyses, we identified abundant signals associated with the gut microbiome especially in metabolic, neurological, and immunological functions. The controversial concept of enterotypes may have a genetic attribute, with the top two loci explaining 11% of the Prevotella-Bacteroides variances. Stratification according to gender led to the identification of differential associations in males and females. Our two-stage metagenome genome-wide association studies on a total of 1295 individuals unequivocally illustrates that neither microbiome nor GWAS studies could overlook one another in our quest for a better understanding of human health and diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-020-00239-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873036PMC
February 2021

Tracing the genetic footprints of vertebrate landing in non-teleost ray-finned fishes.

Cell 2021 Mar 4;184(5):1377-1391.e14. Epub 2021 Feb 4.

BGI-Shenzhen, Shenzhen 518083, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, 32 Jiaochang Donglu, Kunming 650223, China; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Villum Center for Biodiversity Genomics, Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Rich fossil evidence suggests that many traits and functions related to terrestrial evolution were present long before the ancestor of lobe- and ray-finned fishes. Here, we present genome sequences of the bichir, paddlefish, bowfin, and alligator gar, covering all major early divergent lineages of ray-finned fishes. Our analyses show that these species exhibit many mosaic genomic features of lobe- and ray-finned fishes. In particular, many regulatory elements for limb development are present in these fishes, supporting the hypothesis that the relevant ancestral regulation networks emerged before the origin of tetrapods. Transcriptome analyses confirm the homology between the lung and swim bladder and reveal the presence of functional lung-related genes in early ray-finned fishes. Furthermore, we functionally validate the essential role of a jawed vertebrate highly conserved element for cardiovascular development. Our results imply the ancestors of jawed vertebrates already had the potential gene networks for cardio-respiratory systems supporting air breathing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.01.046DOI Listing
March 2021

Accurate Haplotype-Resolved Assembly Reveals The Origin Of Structural Variants For Human Trios.

Bioinformatics 2021 Feb 4. Epub 2021 Feb 4.

BGI-QingDao, Qingdao, 266555, China.

Motivation: Achieving a near complete understanding of how the genome of an individual affects the phenotypes of that individual requires deciphering the order of variations along homologous chromosomes in species with diploid genomes. However, true diploid assembly of long-range haplotypes remains challenging.

Results: To address this, we have developed Haplotype-resolved Assembly for Synthetic long reads using a Trio-binning strategy, or HAST, which uses parental information to classify reads into maternal or paternal. Once sorted, these reads are used to independently de novo assemble the parent-specific haplotypes. We applied HAST to co-barcoded second-generation sequencing data from an Asian individual, resulting in a haplotype assembly covering 94.7% of the reference genome with a scaffold N50 longer than 11 Mb. The high haplotyping precision (∼99.7%) and recall (∼95.9%) represents a substantial improvement over the commonly used tool for assembling co-barcoded reads (Supernova), and is comparable to a trio-binning-based third generation long-read based assembly method (TrioCanu) but with a significantly higher single-base accuracy (up to 99.99997% (Q65)). This makes HAST a superior tool for accurate haplotyping and future haplotype-based studies.

Availability: The code of the analysis is available at https://github.com/BGI-Qingdao/HAST.

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btab068DOI Listing
February 2021

Genome diversity in Ukraine.

Gigascience 2021 Jan;10(1)

Department of Medicine, Uzhhorod National University, Uzhhorod 88000, Ukraine.

Background: The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage.

Results: The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population.

Conclusions: Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gigascience/giaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804371PMC
January 2021

Platypus and echidna genomes reveal mammalian biology and evolution.

Nature 2021 Apr 6;592(7856):756-762. Epub 2021 Jan 6.

Tree of Life Programme, Wellcome Sanger Institute, Cambridge, UK.

Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-03039-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081666PMC
April 2021

Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma.

Cell 2021 Jan 23;184(2):404-421.e16. Epub 2020 Dec 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute Rockville, MD 20850, USA.

Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8 T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8 T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8 T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.11.041DOI Listing
January 2021

A Chromosome-Level Genome Assembly of the Anglerfish .

Front Genet 2020 27;11:581161. Epub 2020 Nov 27.

Key Lab of Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, China.

Anglerfishes are a highly diverse group of species with unique characteristics. Here, we report the first chromosome-level genome of a species in the order Lophiiformes, the yellow goosefish (), obtained by whole genome shotgun sequencing and high-throughput chromatin conformation capture. Approximately 97.20% of the assembly spanning 709.23 Mb could be anchored to 23 chromosomes with a contig N50 of 164.91 kb. The BUSCO value was 95.4%, suggesting that the quality of the assembly was high. A comparative gene family analysis identified expanded and contracted gene families, and these may be associated with adaptation to the benthic environment and the lack of scales in the species. A majority of positively selected genes were related to metabolic processes, suggesting that digestive and metabolic system evolution expanded the diversity of yellow goosefish prey. Our study provides a valuable genetic resource for understanding the mechanisms underlying the unique features of the yellow goosefish and for investigating anglerfish evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.581161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729161PMC
November 2020

Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility.

Cell Discov 2020 Nov 10;6(1):83. Epub 2020 Nov 10.

The Third People's Hospital of Shenzhen, National Clinical Research Center for Infectious Disease, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518112, China.

The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People's Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189-UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-020-00231-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653987PMC
November 2020

The White-Spotted Bamboo Shark Genome Reveals Chromosome Rearrangements and Fast-Evolving Immune Genes of Cartilaginous Fish.

iScience 2020 Nov 2;23(11):101754. Epub 2020 Nov 2.

Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia.

Chondrichthyan (cartilaginous fish) occupies a key phylogenetic position and is important for investigating evolutionary processes of vertebrates. However, limited whole genomes impede our in-depth knowledge of important issues such as chromosome evolution and immunity. Here, we report the chromosome-level genome of white-spotted bamboo shark. Combing it with other shark genomes, we reconstructed 16 ancestral chromosomes of bamboo shark and illustrate a dynamic chromosome rearrangement process. We found that genes on 13 fast-evolving chromosomes can be enriched in immune-related pathways. And two chromosomes contain important genes that can be used to develop single-chain antibodies, which were shown to have high affinity to human disease markers by using enzyme-linked immunosorbent assay. We also found three bone formation-related genes were lost due to chromosome rearrangements. Our study highlights the importance of chromosome rearrangements, providing resources for understanding of cartilaginous fish diversification and potential application of single-chain antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677710PMC
November 2020

D283 Med, a Cell Line Derived from Peritoneal Metastatic Medulloblastoma: A Good Choice for Missing Protein Discovery.

J Proteome Res 2020 12 19;19(12):4857-4866. Epub 2020 Nov 19.

BGI-Shenzhen, Beishan Industrial Zone 11th Building, Yantian District, Shenzhen, Guangdong 518083, China.

Since the Chromosome-Centric Human Proteome Project (C-HPP) was launched in 2010, many techniques have been adopted for the discovery of missing proteins (MPs). Because of these efforts, only 1481 MPs remained as of July 2020; however, by relying only on technique optimization, researchers have reached a bottleneck in MP discovery. Protein expression is tissue- or cell-type-dependent. The tissues of the human testis and brain have been reported to harbor a large number of tissue-specific genes and proteins; however, few studies have been performed on human brain tissue or cells to identify MPs. Herein a metastatic cell line derived from brain cancer, D283 Med, was used to search for MPs. With a traditional and simple shotgun workflow to separate the peptides into 20 fractions, 12 MPs containing at least two unique non-nested peptides (amino acid length ≥9) were identified in this cell line with a protein false discovery rate of <1%. Following the same experimental protocol, only one MP was found in a nonmetastatic brain cancer cell line, U-118 MG. Furthermore, 12 MPs were verified as having two non-nested unique peptides by matching them with corresponding chemically synthesized peptides through parallel reaction monitoring. These results clearly demonstrate that the appropriate selection of experimental materials, either tissues or cell lines, is imperative for MP discovery. The data obtained in this study are available via ProteomeXchange (PXD021482) and PeptideAtlas (PASS01627).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.0c00743DOI Listing
December 2020

Dense sampling of bird diversity increases power of comparative genomics.

Nature 2020 11 11;587(7833):252-257. Epub 2020 Nov 11.

Centre for Zoo and Wild Animal Health, Copenhagen Zoo, Frederiksberg, Denmark.

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity. Sparse taxon sampling has previously been proposed to confound phylogenetic inference, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2873-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759463PMC
November 2020

Genomic and transcriptomic analysis unveils population evolution and development of pesticide resistance in fall armyworm Spodoptera frugiperda.

Protein Cell 2020 Oct 27. Epub 2020 Oct 27.

Department of Biochemistry, Genetics and Microbiology, Forestry and Agricultural Biotechnology Institute, University of Pretoria, Pretoria, South Africa.

The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China. Because of its rapid spread and great risks in China, understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies. Here, we assembled a chromosome-level genome of a male FAW (SFynMstLFR) and compared re-sequencing results of the populations from America, Africa, and China. Strain identification of 163 individuals collected from America, Africa and China showed that both C and R strains were found in the American populations, while only C strain was found in the Chinese and African populations. Moreover, population genomics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations. Taken together, FAWs invaded into China were most likely originated from Africa. Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW, of which 283 genes are specific to FAW. Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles, and several detoxification genes such as AOX, UGT and GST specially responded to the pesticides. These findings will be useful in developing effective strategies for management of FAW in China and other invaded areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13238-020-00795-7DOI Listing
October 2020

An Indo-Pacific Humpback Dolphin Genome Reveals Insights into Chromosome Evolution and the Demography of a Vulnerable Species.

iScience 2020 Oct 3;23(10):101640. Epub 2020 Oct 3.

BGI-Shenzhen, Shenzhen, Guangdong 518083, China.

The Indo-Pacific humpback dolphin () is a small inshore species of odontocete cetacean listed as Vulnerable on the IUCN Red List. Here, we report on the evolution of . chromosomes from its cetruminant ancestor and elucidate the evolutionary history and population genetics of two neighboring . populations. We found that breakpoints in ancestral chromosomes leading to . could have affected the function of genes related to kidney filtration, body development, and immunity. Resequencing of individuals from two neighboring populations in the northwestern South China Sea, Leizhou Bay and Sanniang Bay, revealed genetic differentiation, low diversity, and small contemporary effective population sizes. Demographic analyses showed a marked decrease in the population size of the two investigated populations over the last ~4,000 years, possibly related to climatic oscillations. This study implies a high risk of extinction and strong conservation requirement for the Indo-Pacific humpback dolphin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569330PMC
October 2020

The Chromosome Level Genome and Genome-wide Association Study for the Agronomic Traits of .

iScience 2020 Sep 8;23(9):101538. Epub 2020 Sep 8.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.

The Chinese ginseng is a domesticated herb with significant medicinal and economic value. Here we report a chromosome-level genome assembly with a high (∼79%) repetitive sequence content. The juxtaposition with the widely distributed, closely related Korean ginseng () genome revealed contraction of plant defense genes (in particular -genes) in the genome. We also investigated the reasons for the larger genome size of species, revealing contributions from two -specific whole-genome duplication events and transposable element expansion. Transcriptome data and comparative genome analysis revealed the candidate genes involved in the ginsenoside synthesis pathway. We also performed a genome-wide association study on 240 cultivated individuals and identified the associated genes with dry root weight (63 genes) and stem thickness (168 genes). The genome represents a critical step toward harnessing the full potential of an economically important and enigmatic plant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509215PMC
September 2020

Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).

Nat Commun 2020 10 6;11(1):5015. Epub 2020 Oct 6.

Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, Liaoning Province, China.

Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18414-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538905PMC
October 2020

Lineage-specific evolution of mangrove plastid genomes.

Plant Genome 2020 07 21;13(2):e20019. Epub 2020 Apr 21.

BGI-QingDao, BGI-Shenzhen, Qingdao, 266555, China.

Mangroves is an umbrella term for plants located across the tropics and sub-tropics that live in the coastal region, between the sea and the land. All mangroves evolved from terrestrial plants, providing the opportunity to assess convergence, as well as the lineage-specific features, at the genetic level. In this study, we compared chloroplast genomes from 21 mangrove species, covering main phylogenetic clades. We demonstrate that chloroplast gene order, content, and genome size is largely conserved in mangroves. The exceptions are loss of the photosystem I gene psaZ in Acanthus ilicifolius and inversion of the ribosomal protein gene rpl23 in Avicennia germinans. The repeat content of mangrove chloroplast varied between species, but was conserved within species of the same order. Sequence diversity analysis revealed that the IR (invert repeat) region was highly conserved compared to the SC (single-copy) region in most phylogenetic clades, except clade core leptosporangiates (ferns). The ribosomal protein gene rps7 was under positive selection in Kandelia obovato, Rhizophora stylosa, Bruguiera sexangular and Rhizophora mangle, a monophyletic branch of clade fabids, while no evidence of positive selection was found in other mangrove lineages. Taken together, our data suggests that convergent evolutionary dynamics leaves no significant signal on the plastid genome of mangroves. The complete chloroplast genomes provided in this study shed light on the evolution of these important plastids and provides a valuable resource for further research efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/tpg2.20019DOI Listing
July 2020

Lipidomic Biomarkers of Extracellular Vesicles for the Prediction of Preterm Birth in the Early Second Trimester.

J Proteome Res 2020 10 22;19(10):4104-4113. Epub 2020 Sep 22.

BGI-Shenzhen, Shenzhen 518083, China.

Preterm birth is the leading cause of infant death worldwide and results in a high societal economic burden associated with newborn care. Recent studies have shown that extracellular vesicles (EVs) play an important role in fetal development during pregnancy. Lipids in EVs related to preterm birth remain undefined. Here, we fully investigated differences in lipids in plasma, microvesicles (MVs), and exosomes (Exos) between 27 preterm and 66 full-term pregnant women in the early second trimester (12-24 weeks) using an untargeted lipidomics approach. Independent of other characteristics of samples, we detected 97, 58, and 10 differential features (retention time (RT) and /) with identification in plasma, MVs, and Exos, respectively. A panel of five lipids from MVs has an area under the receiver operating characteristic curve (AUC) of 0.87 for the prediction of preterm birth. One lipid of the panel (PS (34:0)) was validated in an additional 83 plasma samples (41 preterm and 42 full-term deliveries) by the pseudotargeted lipidomics method (AUC = 0.71). Our results provide useful information about the early prediction of preterm birth, as well as a better understanding of the underlying mechanisms and intervention of preterm birth. The MS data have been deposited in the CNSA (https://db.cngb.org/cnsa/) of CNGBdb with accession code CNP0001076.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.0c00525DOI Listing
October 2020