Biology subjects

Wu, X.

Publications and source records attributed to Wu, X..

At least 541 records · Page 30Linked to original sources

bioRxiv2020

COUP-TFI regulates diameter of the axon initial segment in the mammalian neocortex

The axon initial segment is a specialized structure that controls neuronal excitability by generating action potentials. Currently, AIS plasticity with regard to changes in length and location in response to neural activity has been extensively investigated, but how AIS diameter is regulated remains elusive. Here we report that COUP-TFI is an essential regulator of AIS diameter in both developing and adult mouse neocortex. Embryonic ablation of COUP-TFI prevented expansion of AIS diameter that occurs during postnatal development in layer II/III pyramidal cells of the mouse motor cortex, thereby leading to an impairment of action potential generation. Inactivation of COUP-TFI in adult neurons also led to reduced AIS diameter and impaired action potential generation. In contrast to different developmental stages, single-cell ablation and global ablation produced opposite effects on spontaneous network in COUP-TFI-deficient neurons. Further, mice exhibited less anxiety-like behaviors after postnatal inactivation of COUP-TFI induced by tamoxifen. Our results demonstrate that COUP-TFI is indispensable for both expansion and maintenance of AIS diameter and that a change in AIS diameter fine-tunes synaptic inputs through a metaplasticity mechanism in the adult neocortex.

neuroscience↗

bioRxiv2020

Attractive internuclear force drives the collective behavior of nuclear arrays in Drosophila embryos

The emerging collective behaviors during embryogenesis play an important role in precise and reproducible morphogenesis. An important question in the study of collective behavior is what rule underlies the emerging pattern. Here we use the Drosophila embryo as a test tube to study this question. We focus on the nuclear array without membrane separation on the embryo periphery from the nuclear cycle (NC) 11 to NC14. After live imaging with light sheet microscopy, we extract the nuclear trajectory, speed, and internuclear distance with an automatic nuclear tracing method. We find that the nuclear speed shows a period of standing waves along the anterior-posterior (AP) axis after each metaphase as the nuclei collectively migrate towards the embryo poles and partially move back. And the maximum nuclear speed dampens by 38% in the second half of the standing wave. Moreover, the nuclear density is 35% higher in the middle than the pole region of the embryo during the S phase of NC11-NC14. To find mechanical rules controlling the collective motion and packing patterns of the nuclear array, we use the deep neural network (DNN) to learn the force field from data. We find two potential strong nuclear-age-dependent force fields, i.e., the repulsive or attractive force field. Simulations with the particle-based model indicate that only if the net internuclear force is attractive and increases with distance, the pseudo-synchronous mitotic wave in a nuclear array with lower nuclear density in embryo poles can drive the collective motion with the damped standing wave of the nuclear speed, and the collective nuclear motion, in turn, maintains the non-uniform nuclear density.

developmental biology↗

bioRxiv2020

Momilactone B inhibits Arabidopsis growth and development via disruption of ABA and auxin signaling

In competition for limited resources, many plants release allelochemicals to inhibit the growth of neighboring plants. Momilactone B (MB) is a major allelochemical produced by rice (Oryza sativa), however its mode of action is currently unknown. We used Arabidopsis (Arabidopsis thaliana) as a model system to evaluate potential mechanisms underlying the inhibitory effects of MB on seed germination, seedling establishment and root growth through the use of confocal microscopy and the examination of transcriptional responses in MB-treated seedlings. In response to MB treatment, transcript levels for genes encoding several key ABA biosynthetic enzymes and signaling components, including the transcription factor ABA-INSENSITIVE 4 (ABI4), were dramatically increased. Additionally, ABA insensitive 4 (abi4) mutant seedlings exhibited reduced susceptibility to exogenously-provided MB. Although the transcript levels of DELLA genes, which negatively regulate GA signaling, were significantly increased upon MB exposure, exogenous GA application did not reverse the inhibitory effects of MB on Arabidopsis germination and seedling development. Moreover, a reduction in seedling root meristematic activity, associated with reduced expression of auxin biosynthetic genes and efflux transporters, and apparent lowered auxin content, was observed in MB-treated root tips. Exogenous auxin applications partially rescued the inhibitory effects of MB observed in root growth. Our results indicate that MB suppresses Arabidopsis seed germination and root growth primarily via disruption of ABA and auxin signaling. These findings underscore the crucial roles played by phytohormones in mediating responses to allelochemical exposure. One-sentence summaryMomilactone B, the key allelochemical of rice, inhibits Arabidopsis growth and development via disruption of ABA and auxin signaling, suggesting the crucial roles of phytohormones in plant allelopathy

plant biology↗

bioRxiv2020

The role of cation diffusion facilitator CDF-1 in lipid metabolism in Caenorhabditis elegans

Zinc is one of the most important trace elements that plays a vital role in many biological processes, and aberrant zinc metabolism has been implicated in lipid-related metabolic diseases. Previously, we showed that zinc antagonizes iron to regulate sterol regulatory element-binding proteins and stearoyl-CoA desaturase (SREBP-SCD) pathway in lipid metabolism in model organism Caenorhabditis elegans. Here, we further identified another cation diffusion facilitator CDF-1 in addition to SUR-7 in response to zinc to regulate lipid metabolism. Inactivation of SBP-1, the only homolog of SREBPs, leads to increased zinc level but decreased lipid accumulation reversely. However, either cdf-1(n2527) or sur-7(tm6523) mutation could successfully restore the altered fatty acid profile, fat content and zinc level of sbp-1(ep79) mutant. Furthermore, we found that CDF-1/SUR-7 may function bypass SBP-1 to directly affect the conversion activity of SCD in the biosynthesis of unsaturated fatty acids and lipid accumulation. Collectively, these results consistently support the link between zinc homeostasis and lipid metabolism via SREBP-SCD axis by cation diffusion facilitators CDF-1 and SUR-7.

zoology↗

bioRxiv2020

Higher-order sensorimotor circuit of the brain' global network supports human consciousness

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brains global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brains global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

neuroscience↗

bioRxiv2020

Early Emergence and Long-Term Persistence of HIV-Infected T Cell Clones in Children

Little is known about the emergence and persistence of HIV-infected T cell clones in perinatally-infected children. We analyzed peripheral blood mononuclear cells for clonal expansion in 11 children who initiated antiretroviral therapy (ART) between 1.8-17.4 months of age and with viremia suppressed for 6-9 years. We obtained 8,662 HIV-1 integration sites from pre-ART and 1,861 sites on ART. Expanded clones of infected cells were detected pre-ART in 10/11 children. In 8 children, infected cell clones detected pre-ART persisted for 6-9 years on ART. A comparison of integration sites in the samples obtained on ART with healthy donor PBMC infected ex-vivo showed selection for cells with proviruses integrated in BACH2 and STAT5B. Our analyses indicate that, despite marked differences in T cell composition and dynamics between children and adults, HIV-infected cell clones are established early in children, persist for up to 9 years on ART, and can be driven by proviral integration in proto-oncogenes.

microbiology↗

bioRxiv2020

Evaluation of Nanopore sequencing technology to differentiate Salmonella serotypes and serotype variants with the same or closely related antigenic formulae

Our previous study demonstrated that whole genome sequencing (WGS) data generated by Oxford Nanopore Technologies (ONT) can be used for rapid and accurate prediction of Salmnonella serotypes. However, one limitation is that established methods for WGS-based serotype prediction cannot differentiate certain serotypes and serotype variants with the same or closely related antigenic formulae. This study aimed to evaluate Nanopore sequencing and corresponding data analysis for differentiation of these serotypes and serotype variants, thus overcoming this limitation. Five workflows that combined different flow cells, library construction methods and basecaller models were evaluated and compared. The workflow that consisted of the R9 flow cell, rapid sequencing library construction kit and guppy basecaller with base modified model performed best for Single Nucleotide Polymorphism (SNP) analysis. With this workflow, as high as 99.98% matched the identity of the assembled genomes and only less than five high quality SNPs (hqSNPs) between ONT and Illumina sequencing data were achieved. SNP typing allowed differentiation of Choleraesuissensu stricto, Choleraesuis var. Kunzendorf, Choleraesuis var. Decatur, Paratyphi C, and Typhisuis that share the same antigenic formula 6,7:c:1,5. Prophage prediction further distinguished Orion var. 15+ and Orion var. 15+, 34+. Our study improves the readiness of ONT as a Salmonella subtyping and source tracking tool for food industry applications. HighlightsO_LISalmonella serotypes or serotype variants with the same antigenic formula were differentiated by SNP typing. C_LIO_LINanopore sequencing followed by phage prediction identified the Salmonella serotype variants caused by phage conversion. C_LIO_LIThe latest ONT technology is capable of high fidelity SNP typing of Salmonella. C_LI

microbiology↗

bioRxiv2020

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

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

cancer biology↗

bioRxiv2020

NOise Reduction with DIstribution Corrected (NORDIC) PCA in dMRI with complex-valued parameter-free locally low-rank processing

Diffusion-weighted magnetic resonance imaging (dMRI) has found great utility for a wide range of neuroscientific and clinical applications. However, high-resolution dMRI, which is required for improved delineation of fine brain structures and connectomics, is hampered by its low signal-to-noise ratio (SNR). Since dMRI relies on the acquisition of multiple different diffusion weighted images of the same anatomy, it is well-suited for denoising methods that utilize correlations across the image series to improve the apparent SNR and the subsequent data analysis. In this work, we introduce and quantitatively evaluate a comprehensive framework, NOise Reduction with Distribution Corrected (NORDIC) PCA method for processing dMRI. NORDIC uses low-rank modeling of g-factor-corrected complex dMRI reconstruction and non-asymptotic random matrix distributions to remove signal components which cannot be distinguished from thermal noise. The utility of the proposed framework for denoising dMRI is demonstrated on both simulations and experimental data obtained at 3 Tesla with different resolutions using human connectome project style acquisitions. The proposed framework leads to substantially enhanced quantitative performance for estimating diffusion tractography related measures and for resolving crossing fibers as compared to a conventional/state-of-the-art dMRI denoising method. HighlightsO_LIWe propose a framework, NORDIC, for denoising complex valued dMRI data using Gaussian statistics C_LIO_LIThe effectiveness of the proposed denoising method is distinguished by the ability to remove only signal which cannot be distinguished from thermal noise C_LIO_LIThe proposed method outperforms a state-of-art method for denoising dMRI in terms of fiber orientation dispersion C_LIO_LIQuantitative evaluation of NORDIC across different resolutions and SNR using human connectome type acquisitions and analysis shows up to 6 fold improvement in apparent SNR for 0.9mm whole brain dMRI at 3T. C_LI

neuroscience↗

bioRxiv2020

Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to construct pluripotency gene regulatory network

The pluripotency gene regulatory network of porcine-induced pluripotent stem cells (piPSCs), especially in epigenetics, remains elusive. To determine this biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs. SummaryErasure of H3K9 methylation in porcine pluripotent stem cells depends on the complex of transcription factors OCT4/SOX2 and histone demethylase KDM3A/KDM3B.

cell biology↗

bioRxiv2020

Human ORC/MCM density is low in active genes and correlates with replication time but does not solely define replication initiation zones

Eukaryotic DNA replication initiates during S phase from origins that have been licensed in the preceding G1 phase. Here, we compare ChIP-seq profiles of the licensing factors Orc2, Orc3, Mcm3, and Mcm7 with gene expression, replication timing and fork directionality profiles obtained by RNA-seq, Repli-seq and OK-seq. ORC and MCM are strongly and homogeneously depleted from transcribed genes, enriched at gene promoters, and more abundant in early-than in late-replicating domains. Surprisingly, after controlling these variables, no difference in ORC/MCM density is detected between initiation zones, termination zones, unidirectionally replicating and randomly replicating regions. Therefore, ORC/MCM density correlates with replication timing but does not solely regulate the probability of replication initiation. Interestingly, H4K20me3, a histone modification proposed to facilitate late origin licensing, was enriched in late replicating initiation zones and gene deserts of stochastic replication fork direction. We discuss potential mechanisms that specify when and where replication initiates in human cells.

cell biology↗

bioRxiv2020

IGF targeting perturbs global replication through ribonucleotide reductase dysfunction

IGF receptor (IGF-1R) inhibition delays repair of radiation-induced DNA double-strand breaks (DSBs), prompting us to investigate whether IGF-1R influences endogenous DNA damage. We demonstrate that IGF-1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. We detect delayed replication fork progression in IGF-inhibited or IGF-1R depleted cancer cells, with activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflects unanticipated regulation of global replication by IGF-1, mediated via AKT, MEK/ERK and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. IGF-1R inhibition or depletion downregulate RRM2, compromising RNR function and dNTP supply. The resulting delay in fork progression and hallmarks of replication stress are rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF-1 regulates replication. Following targeted compound screens, we identify synergy between IGF inhibition and ATM loss, with evidence that IGF inhibition compromises growth of ATM null cells and xenografts. This synthetic lethal effect reflects conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. These data implicate IGF-1R in alleviating replication stress, and the identified reciprocal IGF:ATM co-dependence provides an approach to exploit this effect in ATM-deficient cancers.

cancer biology↗

bioRxiv2020

Vorinostat corrects cognitive and non-cognitive symptoms in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is caused by mutations in the FMR1 (fragile X mental retardation 1) gene. It is a significant form of heritable intellectual disability with comorbidity of other symptoms such as autism. Due to the lack of efficacious medication, repurposing the existing FDA-approved drugs may offer an opportunity to advance clinical intervention for FXS. Analysis of the whole-genome transcription signatures predicts new therapeutic action of vorinostat to correct pathological alterations associated with FXS. We further find that the administration of vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout (KO) mice. For the non-cognitive behavioral symptoms, vorinostat corrects the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampens hyperactivity in the center area of the arena. Surprisingly, vorinostat does not affect the abnormally elevated protein synthesis in Fmr1 KO neurons, suggesting different outcomes from correcting behavioral symptoms and specific aspects of cellular pathology. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS and advocate efficacy testing with human patients.

neuroscience↗

bioRxiv2020

Similarities and dissimilarities between psychiatric cluster disorders

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets as well as challenges associated with data normalization. However, publicly available databases offer a unique opportunity to expand such investigations both in terms of the number and types of diseases. Here, we used DisGeNET, a database of over 24,000 gene-disease associations to investigate the similarities and dissimilarities associated with enrichment of pathways, cell-types, drug targets, and human chromosomes within an unbiased cluster of psychiatric disorders. We show that cognition and neurotransmission related pathways are involved across all disorders, whereas those associated with immune system and signal-response coupling (cell-surface receptors, signal-transduction, gene-expression, and metabolic process) are associated with few disorders of the cluster. The drug-target based enrichment confirms the involvement of neurotransmission related changes across these disorders. At cell-type level, dendrite targeting interneurons, across all layers, are most involved across all disorders. Finally, using a clustering-based similarity index, we showed that the similarity between the disorders are influenced most at chromosomal level and to some extent at cellular level. Collectively, the results provide a comprehensive comparison of many psychiatric diseases in an unbiased manner and expand our understanding of the cellular and molecular pathologies associated with similar and comorbid psychiatric disorders.

bioinformatics↗

bioRxiv2020

Intrinsic neural timescales related to sensory processing: Evidence from abnormal behavioural states

The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioural states. We address these questions by investigating the brains intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anaesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activitys intrinsic neural timescale is related to specifically sensory rather than motor information processing in the healthy brain. HighlightsO_LIEEG resting-state shows a hierarchy of intrinsic neural timescales. C_LIO_LISensory deficits as in disorders of consciousness lead to prolonged intrinsic neuraltimescales. C_LIO_LIClinical conditions with motor deficits do not show changes in intrinsic neural timescales.20 C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/229161v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1893c45org.highwire.dtl.DTLVardef@d4176dorg.highwire.dtl.DTLVardef@4dfaa8org.highwire.dtl.DTLVardef@183621e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

ESRP1-Mediated Alternative Splicing During Oocyte Development is Required for Mouse Fertility

Alternative splicing (AS) contributes to gene diversification in cells, but the importance of AS during germline development remains largely undefined. Here, we interrupted pre-mRNA splicing events controlled by epithelial splicing regulatory protein 1 (ESRP1) and found that it induced female infertility in mice. Germline-specific knockout of Esrp1 perturbed spindle organization, chromosome alignment, and metaphase-to-anaphase transformation in oocytes. The first polar body extrusion (PBE) was blocked during oocyte meiosis and was found to be due to abnormal activation of spindle assembly checkpoint (SAC) and insufficiency of anaphase-promoting complex/cyclosome (APC/C) in Esrp1-knockout oocytes. Esrp1-knockout in oocytes hampered follicular development and ovulation; eventually, premature ovarian failure (POF) occurred in six-month-old Esrp1-knockout mouse. Using single-cell RNA sequencing analysis, 528 aberrant AS events of maternal mRNA transcripts were revealed and were preferentially associated with microtubule cytoskeletal organization in Esrp1-knockout oocytes. Notably, we found that loss of ESRP1 disturbed a comprehensive set of gene-splicing sites--including those within Trb53bp1, Rac1, Bora, Kif2c, Kif23, Ndel1, Kif3a, Cenpa, and Lsm14b--that ultimately caused abnormal spindle organization. Taken together, our findings provide the first report elucidating the AS program of maternal mRNA transcripts, mediated by the splicing factor, ESRP1, that is required for oocyte meiosis and female fertility in mice.

developmental biology↗

bioRxiv2020

Ecogenomics of groundwater viruses suggests niche differentiation linked to specific environmental tolerance

Viruses are ubiquitous microbiome components, shaping ecosystems via strain-specific predation, horizontal gene transfer and redistribution of nutrients through host lysis. Viral impacts are important in groundwater ecosystems, where microbes drive many nutrient fluxes and metabolic processes, however little is known about the diversity of viruses in these environments. We analyzed four groundwater plasmidomes and identified 200 viral sequences, which clustered into 41 ~ genus-level viral clusters (equivalent to viral genera) including 9 known and 32 putative new genera. We use publicly available bacterial whole genome sequences (WGS) and WGS from 261 bacterial isolates from this groundwater environment to identify potential viral hosts. We linked 76 of the 200 viral sequences to a range of bacterial phyla, the majority associated with Proteobacteria, followed by Firmicutes, Bacteroidetes and Actinobacteria. The publicly available microbial genome sequences enabled mapping bacterial hosts to a breadth of viral sequences. The WGS of groundwater isolates increased depth of host prediction by allowing identification of hosts at the strain level. The latter included 4 viruses that were almost entirely (>99% query coverage, >99% identity) identified as integrated in the genomes of specific Pseudomonas, Acidovorax and Castellaniella strains, resulting in very high-confidence host assignments. Lastly, 21 of these viruses encoded putative auxiliary metabolite genes for metal and antibiotic resistance, which might drive their infection cycles and/or provide selective advantage to infected hosts. Exploring the groundwater virome provides a necessary foundation for integration of viruses into ecosystem models where they act as key players in microbial adaption to environmental stress. ImportanceTo our knowledge, this is the first study to identify the bacteriophage distribution in a groundwater ecosystem shedding light on their prevalence and distribution across metal-contaminated and background sites. Our study is uniquely based on selective sequencing of solely the extrachromosomal elements of a microbiome followed by analysis for viral signatures, thus establishing a more focused approach for phage identifications. Using this method, we detect several novel phage genera along with those previously established. Our approach of using the whole genome sequences of hundreds of bacterial isolates from the same site enabled us to make host assignments with high confidence, several at strain levels. Certain phage-encoded genes suggest they provide an environment-specific selective advantage to their bacterial hosts. Our study lays the foundation for future research on directed phage isolations using specific bacterial host strains to further characterize groundwater phages, their lifecycles, and its effects on groundwater microbiome and biogeochemistry.

microbiology↗

bioRxiv2020

Fine-scale Population Structure and Demographic History of Han Chinese Inferred from Haplotype Network of 111,000 Genomes

ABSTRACTHan Chinese is the most populated ethnic group across the globe with a comprehensive substructure that resembles its cultural diversification. Studies have constructed the genetic polymorphism spectrum of Han Chinese, whereas high-resolution investigations are still missing to unveil its fine-scale substructure and trace the genetic imprints for its demographic history. Here we construct a haplotype network consisted of 111,000 genome-wide genotyped Han Chinese individuals from direct-to-consumer genetic testing and over 1.3 billion identity-by-descent (IBD) links. We observed a clear separation of the northern and southern Han Chinese and captured 5 subclusters and 17 sub-subclusters in haplotype network hierarchical clustering, corresponding to geography (especially mountain ranges), immigration waves, and clans with cultural-linguistic segregation. We inferred differentiated split histories and founder effects for population clans Cantonese, Hakka, and Minnan-Chaoshanese in southern China, and also unveiled more recent demographic events within the past few centuries, such as Zou Xikou and Chuang Guandong. The composition shifts of the native and current residents of four major metropolitans (Beijing, Shanghai, Guangzhou, and Shenzhen) imply a rapidly vanished genetic barrier between subpopulations. Our study yields a fine-scale population structure of Han Chinese and provides profound insights into the nation’s genetic and cultural-linguistic multiformity.Competing Interest StatementThe authors AL, KK, ST, XW, LW, TL, HW, JD, QZ, XY, and GC work for WeGene (Shenzhen Zaozhidao Technology Co. Ltd. or Shenzhen WeGene Clinical Laboratory).View Full Text

genomics↗