Biology subjects

Yang, W.

Publications and source records attributed to Yang, W..

At least 253 records · Page 14Linked to original sources

bioRxiv2021

SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cells ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

genetics↗

bioRxiv2021

A Developmentally Prometastatic Niche to Hepatoblastoma in Neonatal Liver mediated by the Cxcl1/Cxcr2 Axis

Background and RationaleHepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development. MethodsHB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. ResultsWe found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers. ConclusionWe demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.

cancer biology↗

bioRxiv2021

Integrated analysis of single-cell and transcriptome based RNA-seq multilayer network and WGCNA for construction and validation of an immune cell-related prognostic model in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer (RCC). The increasing incidence and poor prognosis of ccRCC after tumour metastasis makes the study of its pathogenesis extremely important. Traditional studies mostly focus on the regulation of ccRCC by single gene, while ignoring the impact of tumour heterogeneity on disease progression. The purpose of this study is to construct a prognostic risk model for ccRCC by analysing the differential marker genes related to immune cells in the single-cell database for providing help in clinical diagnosis and targeted therapy. Single-cell data and ligand-receptor relationship pair data were downloaded from related publications, and ccRCC phenotype and expression profile data were downloaded from TCGA and CPTAC. The DEGs and marker genes of the immune cell were combined and then intersected with the ligand-receptor gene data, and the 981 ligand-receptor relationship pairs obtained were intersected with the target gene of the transcription factor afterwards; 7,987 immune cell multilayer network relationship pairs were finally observed. Then, the genes in the network and the genes in TCGA were intersected to obtain 966 genes for constructing a co-expression network. Subsequently, 53 genes in black and magenta modules related to prognosis were screened by WGCNA for subsequent analysis. Whereafter, using the data of TCGA, 28 genes with significant prognostic differences were screened out through univariate Cox regression analysis. After that, LASSO regression analysis of these genes was performed to obtain a prognostic risk scoring model containing 16 genes, and CPTAC data showed that the effectiveness of this model was good. The results of correlation analysis between the risk score and other clinical factors showed that age, grade, M, T, stage and risk score were all significantly different (p < 0.05), and the results of prognostic accuracy also reached the threshold of qualification. Combined with clinical information, univariate and multivariate Cox regression analyses verified that risk score was an independent prognostic factor (p < 0.05). A nomogram constructed based on a predictive model for predicting the overall survival was established, and internal validation performed well. Our findings suggest that the predictive model built based on the immune cells scRNA-seq will enable us to judge the prognosis of patients with ccRCC and provide more accurate directions for basic relevant research and clinical practice.

cancer biology↗

bioRxiv2021

Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. As the protective role of pre-existing cross-reactivity to homologous peptides is unclear, we aimed to identify SARS-CoV-2-specific minimal epitopes recognized by CD8 T-cells among 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identified nine conserved SARS-CoV-2-specific epitopes restricted by four of the most prevalent HLA class I alleles in the Norwegian study cohort, to which responding CD8 T cells were detected in 70-100% of convalescents expressing the relevant HLA allele. Only two of these were derived from the Spike protein, included in current vaccines. We found a strong correlation between immunoprevalence and immunodominance. Thus, the CD8 T-cell response to SARS-CoV-2 is more focused than previously believed. Using a new algorithm, we predict that a vaccine including these epitopes could induce a T-cell response in 83% of Caucasians.

immunology↗

bioRxiv2021

Development and verification of SSR markers from drought stress-responsive miRNAs in common wild rice

PREMISEDongxiang wild rice (Oryza rufipogon Griff., DXWR) is the northernmost common wild rice found in the world, which possesses abundant elite genetic resources. We developed a set of drought stress-responsive microRNA (miRNA)-based single sequence repeat (SSR) markers for DXWR, which will help breed drought stress-resistant rice varieties. METHODS AND RESULTSNinety-nine SSR markers were developed from the drought stress-responsive miRNAs of DXWR. The SSR loci were distributed in all 12 rice chromosomes and most were in chromosomes 2 and 6, with di- and trinucleotides being the most abundant repeat motifs. Nine out of ten synthesized SSR markers were displayed high levels of genetic diversity in the genomes of DXWR and 41 modern rice varieties worldwide. The number of alleles per locus ranged from 2 to 6, and the observed and expected heterozygosity ranged from 0.000 to 0.024 and 0.461 to 0.738, respectively. CONCLUSIONSThese SSR markers developed from drought stress-responsive miRNAs in DXWR could be additional tools for elite genes mapping and useful for drought stress-resistant rice breeding.

plant biology↗

bioRxiv2021

Single-cell RNA transcriptome analysis reveals CXCL16/CXCR6 as maintenance factors for CNS tissue resident T cells that drive synapse elimination during viral recovery

BackgroundEmerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. MethodsHere, we examined the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation, genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. ResultsProfiling of host transcriptome at 25 days post-infection revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 is required not only for the maintenance of WNV-specific, CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. ConclusionsWe provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 during recovery may reduce CNS CD8+ TRM cells.

immunology↗

bioRxiv2021

IMCellXMBD: A statistical approach for robust cell identification and quantification from imaging mass cytometry images

Imaging Mass Cytometry (IMC) has become a useful tool in biomedical research due to its capability to measure over 100 markers simultaneously. Unfortunately, some protein channels in IMC images can be very noisy, which may significantly affect the phenotyping results without proper data processing. We developed IMCellXMBD1, a highly effective and generalizable cell identification and quantification method for IMC images. IMCell performs denoising by subtracting an estimated background noise value from pixel values for each individual protein channel, identifies positive cells from negative cells by comparing the distribution between segmented cells and decoy cells, and normalize the protein expression levels of the identified positive cells for downstream data analysis. Experimental results demonstrate that our method significantly improves the reliability of cell phenotyping which is essential for using IMC in biomedical studies.

bioinformatics↗

bioRxiv2021

Robust de novo design of protein binding proteins from target structural information alone

The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge. We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes and interactions, and then intensifies the search in the most promising regions. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of four of the binder-target complexes, and all four are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

synthetic biology↗

bioRxiv2021

Renal Interstitial Cells Promote Nephron Regeneration by Secreting Prostaglandin E2

In organ regeneration, progrnitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation and differentiation. However, what kind of cells provide a native microenvironment for renal progenitor cells has not been clarified. Here, single-cell sequencing of zebrafish kidney revealed that fabp10 was a marker of renal interstitial cells (RICs), and the Tg(fabp10a:GFP) transgenic line can specifically label RICs in zebrafish kidney. The formation of RICs and nephrons are closely accompanied during nephron regeneration. RICs form a network to wrap the renal progenitor cell aggregates. RICs in close contact with cell aggregates express cyclooxygenase 2 and secrete prostaglandin 2 (PGE2). Inhibiting PGE2 production prevented nephrogenesis by reducing the proliferation and differentiation of progenitor cell aggregates. PGE2 promoted maturation of the nephron by activating the WNT signaling pathway in progenitor cell aggregates in cooperation with Wnt4a. These findings suggest that RICs provide a necessary microenvironment for rapid nephrogenesis during nephron regeneration.

developmental biology↗

bioRxiv2021

Genome-wide development of lncRNA-derived-SSR markers for Dongxiang wild rice (Oryza rufipogon Griff.)

Dongxiang wild rice (Oryza rufipogon Griff., DXWR) is the northernmost distributed common wild rice found in the world. It contains a large number of agronomically valuable genes, which makes it a natural gene pool for rice breeding. Molecular markers, especially simple repeat sequence (SSR) markers, play important roles in crop breeding. Although a large number of SSR markers have been developed, most of them are derived from the genome coding sequences, rarely from non-coding sequences. Meanwhile, long non-coding RNAs (lncRNAs), which are derived from the transcription of non-coding sequences, play vital roles in plant growth, development and stress responses. In this study, 1878 SSR loci were detected from the lncRNA sequences of DXWR, and 1258 lncRNA-derived-SSR markers were developed on the genome-wide scale. To verify the validity and applicability of these markers, 72 pairs of primers were randomly selected to test 44 rice materials. The results showed that 42 (58.33%) pairs of primers have abundant polymorphism among these rice materials; the polymorphism information content (PIC) values ranged from 0.04 to 0.87 with an average of 0.50; the genetic diversity index of SSR loci varied from 0.04 to 0.88 with an average of 0.56; and the number of alleles per marker ranged from 2 to 11 with an average of 4.36. Thus, we concluded that these lncRNA-derived-SSR markers are a very useful source for future basic and applied research, including genetic diversity analysis, QTL mapping, and molecular breeding programs, to make good use of the elite lncRNA genes from DXWR.

plant biology↗

bioRxiv2021

Exploring ensemble structures of Alzheimer's amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift

Aggregation of intrinsically disordered amyloid {beta} (A{beta}) is a hallmark of Alzheimers disease. Although complex aggregation mechanisms have been increasingly revealed, structural ensembles of A{beta} monomers with heterogeneous and transient properties still hamper detailed experimental accesses to early events of amyloidogenesis. We herein developed a new mathematical tool based on multiple linear regression to obtain the reasonable ensemble structures of A{beta} monomer by using the solution nuclear magnetic resonance (NMR) and molecular dynamics simulation data. Our approach provided the best-fit ensemble to two-dimensional NMR chemical shifts, also consistent with circular dichroism and dynamic light scattering analyses. The major monomeric structures of A{beta} including {beta}-sheets in both terminal and central hydrophobic core regions and the minor partially-helical structures suggested initial structure-based explanation on possible mechanisms of early molecular association and nucleation for amyloid generation. A wide-spectrum application of the current approach was also indicated by showing a successful utilization for ensemble structures of folded proteins. We propose that multiple linear regression in combination to experimental results will be highly promising for studies on protein misfolding diseases and functions by providing a convincing template structure. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/457317v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b4e6eeorg.highwire.dtl.DTLVardef@1a533eeorg.highwire.dtl.DTLVardef@f48eb3org.highwire.dtl.DTLVardef@1c4bf9a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

The relationship between benthic nutrient fluxes and bacterial community in Aquaculture tail-water treatment systems

Constructed-wetlands, Biofilms, and sedimentation are potential aquaculture tail-water treatments however their roles on the distribution of benthic microbial community and the way they affect the interaction between microbial community and inorganic nutrient fluxes have not been fully explored. This study applied 16S rRNA high-throughput sequencing technology to investigate the microbial community distribution and their link with nutrient fluxes in an aquaculture tail-water bioremediation system. Results showed that bacterial community compositions were significantly different in constructed-wetland and biofilm treatments (p<0.05) relative to sedimentation. The composition of the 16S rRNA genes among all the treatments was enriched with Proteobacteria, Bacteroidetes, Firmicutes, and Flavobacteria. NMDS analysis showed that the bacterial composition in constructed-wetland and biofilm samples clustered separately compared to those in sedimentation. The Functional-Annotation-of-Prokaryotic-Taxa analysis indicated that the proportions of sediment-microbial-functional groups (aerobic-chemoheterophy, chemoheterotrophy, and nitrate-ammonification combined) in the constructed-wetland treatment were 47%, 32% in biofilm and 13% in sedimentation system. Benthic-nutrient fluxes for phosphate, ammonium, nitrite, nitrate and sediment oxygen consumption differed markedly among the treatments (p<0.05). Canonical correspondence analysis indicated constructed-wetland had the strongest association between biogeochemical contents and the bacterial community relative to other treatments. This study suggests that the microbial community distributions and their interactions nutrient fluxes were most improved in the constructed-wetland followed by the area under biofilm and sedimentation treatment.

ecology↗

bioRxiv2021

Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report here structure, function and antigenicity of its full-length spike (S) trimer in comparison with those of other variants, including Gamma, Kappa, and previously characterized Alpha and Beta. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2 and its pseudotyped viruses infect target cells substantially faster than all other variants tested, possibly accounting for its heightened transmissibility. Mutations of each variant rearrange the antigenic surface of the N-terminal domain of the S protein in a unique way, but only cause local changes in the receptor-binding domain, consistent with greater resistance particular to neutralizing antibodies. These results advance our molecular understanding of distinct properties of these viruses and may guide intervention strategies.

biochemistry↗

bioRxiv2021

Cell type determination for cardiac differentiation occurs soon after seeding of human induced pluripotent stem cells

Cardiac directed differentiation of human induced pluripotent stem cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types even when using very well-characterized protocols. We wondered whether differentiated cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation. By associating individual differentiated cells that share a common hiPS cell precursor, we were able to test whether expression variability in differentiated cells was pre-determined from the hiPS cell state. Although within a single experiment, differentiated cells that share an hiPS cell progenitor were more transcriptionally similar to each other than to other cells in the differentiated population, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurred during differentiation in a manner that suggested that all cells were equally likely to survive or die, suggesting that there was no intrinsic selection bias for cells descended from particular hiPS cell progenitors. These results led us to wonder about how cells grow out spatially during the directed differentiation process. Labeling cells by their expression of a few canonical cell type marker genes, we showed that cells expressing the same marker tended to occur in patches observable by visual inspection, suggesting that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions. Altogether, our results show that while there is substantial heterogeneity in the initial hiPS cell population, that heterogeneity is not responsible for heterogeneous outcomes, and that the window during which cell type specification occurs is likely to begin shortly after the seeding of hiPS cells for differentiation.

genomics↗

bioRxiv2021

Metabolic reprogramming of cytotoxic T lymphocytes by high glucose enhances pancreatic beta cell apoptosis via TRAIL

Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL-mediated antigen-independent killing remains elusive. Here, we report that TNF-related apoptosis inducing ligand (TRAIL) is substantially up- regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. The PI3K- Akt-NF{kappa}B axis and non-mitochondrial reactive oxygen species are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect 1.4E7 cells from TRAIL-mediated apoptosis. Notably, in patients with diabetes, correlation between Vitamin D concentrations in plasma and glucose levels is linked to HG-enhanced TRAIL expression on CTLs. Microarray data reveal that OXCT2, an important enzyme in ketone body catabolism, is a promising target in response to vitamin D. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients.

immunology↗

bioRxiv2021

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

neuroscience↗

bioRxiv2021

The northern gene flow into southeastern East Asians inferred from genome-wide array genotyping

The population history of Southeast China remains poorly understood due to the sparse sampling of present-day populations and far less modeling with ancient genomic data. We here newly reported genome-wide genotyping data from 207 present-day Han Chinese and Hmong-Mien-speaking She people from Fujian and Taiwan, southeast China. We co-analyzed with 66 early-Neolithic to Iron-Age ancient Fujian and Taiwan individuals obtained from literature to explore the genetic continuity and admixture based on the genetic variations of high-resolution time transect. We found the genetic differentiation between northern and southern East Asians defined by a north-south East Asian genetic cline and the studied southern East Asians were clustered in the southern end of this cline. We also found that southeastern coastal continental modern East Asians harbored the genetic differentiation with other southern Tai-Kadai, Hmong-Mien, Austronesian and Austroasiatic speakers, as well as geographically close Neolithic-to-Iron Age populations, but relatedly close to post-Neolithic Yellow River ancients, which suggested the influence of southward gene flow on the modern southern coastal gene pool. Besides, we also identified one new Hmong-Mien genetic cline in East Asia with the coastal Fujian She localizing at the intersection position between Hmong-Mien and Han clines in the principal component analysis. She people show stronger genetic affinity with southern East Asian indigenous populations with the main ancestry deriving from Hanben-related populations. The southeastern Han Chinese could be modeled with the primary ancestry deriving from the group related to the Yellow River Basin millet farmers and the remaining from groups related to southeastern ancient indigenous rice farmers, which was consistent with the northern China origin of modern southeastern Han Chinese and in line with the historically and archaeologically attested southward migrations of Han people and their ancestors. Interestingly, f4-statistics and three-way admixture model results showed both coastal ancient sources related to Austronesian speakers and inland ancient sources related to Austroasiatic speakers complexed the modern observed fine-scale genetic structure here. Our estimated north-south admixture time ranges based on the decay of the linkage disequilibrium spanned from the Bronze age to historic periods, suggesting the recent large-scale population migrations and subsequent admixture participated in the formation of modern Han in Southeast Asia.

genetics↗

bioRxiv2021

ADAR mediated A-to-I RNA editing affects SARS-CoV-2 characteristics and fuels its evolution

Upon SARS-CoV-2 infection, viral intermediates activate the Type I interferon (IFN) response through MDA5-mediated sensing and accordingly induce ADAR1 p150 expression, which might lead to A-to-I RNA editing of SARS-CoV-2. Here, we developed an RNA virus-specific editing identification pipeline, surveyed 7622 RNA-seq data from diverse types of samples infected with SARS-CoV-2, and constructed an atlas of A-to-I RNA editing sites in SARS-CoV-2. We found that A-to-I editing was dynamically regulated, and on average, approximately 91 editing events were deposited at viral dsRNA intermediates per sample. Moreover, editing hotspots were observed, including recoding sites in the spike gene that affect viral infectivity and antigenicity. Finally, we provided evidence that RNA editing accelerated SARS-CoV-2 evolution in humans. Collectively, our data suggest that SARS-CoV-2 hijacks components of the host antiviral machinery to edit its genome and fuel its evolution.

microbiology↗