Biology subjects

Nie, S.

Publications and source records attributed to Nie, S..

At least 19 recordsLinked to original sources

bioRxiv2026

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.

genetics↗

bioRxiv2026

Relational biological structure improves fine-mapping of causal GWAS variants under weak signal

Linkage disequilibrium (LD) makes causal GWAS variants indistinguishable from correlated neighbours; resolving them is the fine-mapping problem, and the challenge is species-specific: humans face dense ancestry-imbalanced LD, yeast and Arabidopsis exceptionally long LD, and crop germplasm sparse and fragmented annotations that defeat human-biobank curation pipelines. Bayesian fine-mappers integrate annotations as flat per-variant priors, discarding the relational structure linking variants to tissue-specific eQTLs, pathways and protein-protein interactions. Hierarchical belief propagation (HBP) on a variant-gene-pathway factor graph matches Bayesian baselines at 5-40x speed; an annotation-adaptive complement, graph-augmented fine-mapping (GAFM), wins 27-2 against SuSiE at weak signal and recovers LDLR, APOE, LPL, GCKR and ANGPTL3 at single-variant resolution across four Pan-UK Biobank ancestries. On the 3,000 Rice Genomes grain weight + shape panel, mixture-prior posterior reweightings of GAFM/HBP and their ensemble (GAFM-MX, HBP-MX, ENS) reach 47.6% top-1-PIP exact-position recovery of 21 panel-matched stable QTNs -- the highest of any method, exceeding SuSiE (28.6%) and SBayesRC (14.3%) -- at 200-700x SuSiEs per-locus speed. Across 692 leads in four species, a non-uniform per-variant prior, not uniform high coverage, lets the graph break LD ties: adding a regulatory-element flag to an otherwise uniform human cache flips HBP narrower than GAFM from 0% to 88% on 321 Pan-UKB leads. These results recast multi-omics fine-mapping as a non-uniform-prior-curation problem rather than a uniform-coverage problem, and reframe post-GWAS analysis as message passing over biological structure rather than weighted regression on flattened annotations.

genomics↗

bioRxiv2026

HYPER-Net: Physics-Conditioned Self-Supervised Reconstruction for Fourier Light-Field Microscopy

The rapid convergence of optical innovation and machine intelligence is reshaping biological imaging by enabling platforms that jointly advance image formation and computational reconstruction for highspeed, high-resolution volumetric microscopy. However, broadly accessible three-dimensional imaging at high spatiotemporal resolution remains limited by the reliance of existing supervised methods on large modality-matched training datasets, the computational burden of conventional iterative reconstruction, and sensitivity to optical mismatch arising from small deviations in the spatial-angular point spread functions. Here, we introduce HYPER-Net, a physics-conditioned self-supervised framework for Fourier light-field microscopy that integrates scan-free volumetric acquisition with fast, robust three-dimensional reconstruction. HYPER-Net incorporates experiment-specific point-spread functions into the learning process in two complementary roles: as the forward operator that enforces measurement consistency and as a conditioning signal that adaptively modulates intermediate feature representations. This design reduces reliance on paired experimental ground-truth volumes, improves robustness to system variation, and enables generalizable reconstruction across diverse biological contexts. Using human colon organoids, embryonic Xenopus laevis hearts, hiPSC-derived cardiac spheroids, and freely moving Caenorhabditis elegans, we demonstrate high-fidelity volumetric imaging of tissue morphology, cardiac function, calcium-contraction coupling, and locomotion-associated neural and muscular dynamics. These results position HYPER-Net as a versatile framework for rapid volumetric imaging and quantitative analysis of dynamic biological systems across basic research and biomedical applications.

bioengineering↗

bioRxiv2026

GraphMana: graph-native data management for population genomics projects

Population genomics projects rely on fragmented file-based workflows that lose provenance and require full reprocessing when samples are added. Graph-Mana stores variant data in a graph database as packed genotype arrays with pre-computed population statistics, enabling incremental sample addition, provenance tracking, cohort management, and export to 17 formats. Two access paths serve different needs: a FAST PATH reading population-level arrays in O(K) time and a FULL PATH unpacking per-sample genotypes in O(N) time. On human 1000 Genomes data (3,202 samples, 70.7M variants), Graph-Mana completed a 46-operation lifecycle in 98 minutes from a single persistent database.

bioinformatics↗

bioRxiv2026

GraphPop: graph-native computation decouples population genomics complexity from sample count

Matrix-based population genomics tools scale as O(V x N ), re-reading the full genotype matrix for every analysis. Here we present GraphPop, a graph database engine that reduces summary statistic complexity to O(V x K) where K is population count--independent of sample count--by computing on pre-aggregated allele-count arrays stored as graph node properties. The same architecture enables annotation-conditioned queries via edge traversal, persistent analytical records, and multi-statistic composition. Applied to rice 3K (29.6M SNPs, 3,024 accessions) and human 1000 Genomes (3,202 samples, 22 autosomes), GraphPop reveals that all 12 rice subpopulations show{pi} N /{pi}S > 1.0, uncovers opposite consequence-level Fst regimes between species, and identifies KCNE1 as a candidate pre-Out-of-Africa sweep via convergence of five stored statistics. GraphPop achieves 146-327x query-time speedup for pre-aggregated statistics and 63-179x for bit-packed haplotype computation (iHS, XP-EHH, nSL), at constant[~] 160 MB procedure working memory. This complexity reduction makes systematic, annotation-integrated population genomics practical at scale.

bioinformatics↗

bioRxiv2026

Volumetric Scattering Microscopy

Optical scattering in biological tissues fundamentally limits fluorescence imaging by disrupting spatial and angular information, thereby restricting volumetric visualization. Although hardware-intensive and computational approaches have advanced scattering microscopy, practical three-dimensional imaging through tissue remains constrained by instrumental complexity and axial ambiguity. Here, we present volumetric scattering microscopy (VSM), a scan-free, optical-computational framework for three-dimensional fluorescence imaging in scattering biological media. VSM captures angularly resolved speckle-encoded fluorescence using an aperture-segmented Fourier light-field configuration and reconstructs volumetric structure through adaptive feature-based descattering and joint sub-pupil alignment. This hybrid strategy preserves angular information embedded in scattered light without wavefront measurement or mechanical scanning, while maintaining the simplicity of a standard epi-fluorescence architecture. We demonstrate high-fidelity volumetric reconstruction across phantoms, engineered cellular systems, ex vivo tissues with volumetric muscle loss, and intact Xenopus embryos, achieving preserved spatial resolution, enhanced optical sectioning, and quantitative accuracy under strong scattering conditions. VSM supports large-field, robust volumetric imaging in both layered and fully embedded scattering environments. By transforming scattered light into a structured encoding resource, VSM establishes a scalable pathway toward routine three-dimensional fluorescence imaging in complex biological systems.

bioengineering↗

bioRxiv2026

Doxycycline inhibits both apicoplast and mitochondrial translation in apicomplexan parasites

Doxycycline is a tetracycline-class antibiotic used for malarial prophylaxis and as an occasional partner drug in malaria treatment. Doxycyclines antimalarial mechanism of action is attributed to inhibiting the prokaryotic 70S ribosomes of the apicoplast, a non-photosynthetic plastid present in most apicomplexan species including Plasmodium and Toxoplasma. At lower concentrations (<5 M) doxycycline exhibits a delayed death phenotype, typical of inhibitors of apicoplast housekeeping processes. Unlike other delayed death drugs (e.g. clindamycin), doxycycline has rapid schizonticidal activity at higher concentrations (>10 M) via an unknown and apicoplast-independent mechanism. In other eukaryotes, and plausibly in Plasmodium and Toxoplasma, doxycycline inhibits mitochondrial 70S ribosomes. Here we use a mass spectrometry approach to assess steady state and turnover for apicoplast DNA encoded proteins in Plasmodium falciparum. We directly show that these proteins decrease in both abundance and synthesis following treatment with doxycycline and clindamycin. High concentrations of doxycycline, but not clindamycin, also reduced the abundance of a mitochondrial-encoded protein. Proteins encoded by the mitochondrial genome are required for the formation of complexes III and IV in the electron transport chain. We show a reduction in abundance and activity of complex IV following doxycycline treatment in Toxoplasma gondii. High doxycycline concentrations also disrupt oxidative phosphorylation in both P. falciparum and T. gondii, likely as a consequence of impaired complex III and IV formation. For the first time we directly measure apicoplast translation inhibition and characterise doxycycline as a mitochondrial translation inhibitor of P. falciparum and T. gondii.

microbiology↗

bioRxiv2026

Z-RNA-ZBP1 axis drives Tau-mediated neurodegeneration

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

neuroscience↗

bioRxiv2026

Morphological innovation without gene co-option: the Drosophila sex comb evolved via changes in developmental tempo and energy metabolism

The individualization of serially repeated homologs is one route through which novel traits are thought to evolve. Under this model, a repeated character--like a limb, digit, or sensory bristle--is individualized from its homologs by changes in the regulatory apparatus ( character identity network, ChIN) that specifies its development. Individualization then enables downstream gene networks that build the repeated character to diverge from one another in different parts of the body, ultimately allowing new phenotypic endpoints to be reached. Despite this models intuitive appeal, the genetic mechanisms through which new ChINs rewire trait-building gene networks remain largely uncharacterized. A promising system in which to study this process is the Drosophila sex comb. Found in a sublineage of Drosophila species, the sex comb is a recently evolved, male-specific innovation that evolved from a more evolutionarily ancient precursor--the mechanosensory (MS) bristle--following the gain of a novel ChIN centered on the sex determination gene dsx and HOX gene Scr. Here, we use time-series single-cell RNA-seq to show that rather than co-opting new genes, this new ChIN orchestrates quantitative and heterochronic changes in the ancestral MS bristle transcriptome. These changes affect gene modules that control energy metabolism, endoreplication, and actin dynamics. The net effect of these changes is an organ-specific shift in developmental rate, leading to accelerated growth in sex comb teeth. Collectively, our work suggests that morphological innovation can proceed without the co-option of new genes into downstream trait-building networks and instead through metabolically driven differences in developmental rate between serial homologs.

evolutionary biology↗

bioRxiv2025

A SUMO-interacting motif in the guanine nucleotide exchange factor EPAC1 is required for subcellular targeting and function

Exchange protein directly activated by cAMP (EPAC1), a multifunctional intracellular cAMP receptor, dynamically localizes to various cellular loci, engaging with diverse molecular partners to maintain cellular homeostasis. The study investigates the role of the SUMO interacting motif (SIM) in the subcellular targeting and cellular functions of EPAC1. It reveals that the SIM is a critical structural element for EPAC1s association with RanBP2/Nup358, a nucleoporin of the cytoplasmic filament component of the nuclear pore complex (NPC). Mutational disruption of EPAC1 SIM interferes with EPAC1s ability to activate its canonical effectors, small GTPases, Rap1 and Rap2, and non-canonical functions, such as the formation of nuclear condensates and cellular SUMOylation. Because SIM is also directly involved in cAMP binding, RanBP2s association with EPAC1 with the SIM attenuates EPAC1s cAMP binding affinity to generate an EPAC1 signaling microdomain with reduced cAMP sensitivity around the NPC. The coupling between EPAC1s scaffold association and cAMP binding enables EPAC1 to tune its sensitivity to stress stimuli spatially depending on the cellular locations. These findings provide novel structural insights into EPAC1 signaling, highlighting the importance of SIM in EPAC1s cellular functions and potential novel strategies for therapeutically targeting EPAC1.

cell biology↗

bioRxiv2025

VZV gE Promotes STING Degradation via Midnolin-Proteasome Pathway to Inhibit cGAS-STING Signaling

Varicella-zoster virus (VZV) infects 85 million individuals annually and it is known for its intricate interplay with host cellular mechanisms, significantly impacting antiviral immune responses. Previous studies have highlighted the critical role of VZV glycoprotein E (gE) in virus-host interactions, but the precise mechanisms remain to be elucidated. Our results demonstrate that VZV gE interacts with STING, specifically through the gE (350-480aa) and STING (151-160aa) regions. This interaction predominantly involves incompletely glycosylated gE. Functional assays revealed that gE inhibits the cGAS-STING signaling pathway. gE enhances VZV proliferation and promotes STING degradation via the proteasome pathway, without affecting STING ubiquitination. We identified Midnolin as a mediator in this degradation process, with gE facilitating the interaction between STING and Midnolin. In vivo, gE expression in mice led to diminished antiviral responses upon HSV-1 infection, highlighting gEs role in modulating immune signaling. Our findings provide significant insights into VZVs evasion of host immune responses. By promoting STING degradation through an unconventional Midnolin-proteasome pathway, VZV gE effectively suppresses antiviral signaling, facilitating enhanced viral proliferation. The findings contribute significantly to the understanding of VZV pathogenesis and provide new therapeutic strategies against VZV.

microbiology↗

bioRxiv2023

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

bioRxiv2023

Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan peoples major composition and accelerated the Tibetan Plateaus permanent occupation. Second, rice farmers dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.

genetics↗

bioRxiv2023

Malaria resistance-related biological adaptation and complex evolutionary footprints of Tai-Kadai people inferred from 796 genomes

Pathogen-host adaptative interaction and complex population demographical processes, including admixture, drift and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia keep unknown as the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide-SNP variations from 796 Tai-Kadai (TK) genomes, including Bouyei first reported here, to explore the genetic history, population structure and biological adaptative features of TK-speaking people from Southern China and Southeast Asia. We found geography-related population substructure among TK-speaking people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the Northern TK-speaking people from Guizhou harboured one TK-dominant ancestry maximised in Bouyei people, and the Southern one from Thailand obtained more influences from Southeast Asians and indigenous people. We reconstructed the fitted admixture models and demographic graphs, which showed that TK-speaking people received gene flow from ancient rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and Northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

genetics↗

bioRxiv2023

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people inferred from 500 whole genome data from 39 populations

Tibeto-Burman (TB) people have tried to adapt to the hypoxic, cold and high-UV high-altitude Tibetan Plateau and complex disease exposure in the lowland wet and hot rainforest since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB people and their interaction mechanism remained unknown. We generated a whole-genome-based meta-database of 500 individuals from 39 TB populations from East Asia and Southeast Asia and presented a comprehensive landscape of genetic diversity, admixture history and differentiated adaptative features of geographically different TB people. We identified geography/language-related genetic differentiation among Tibetan Plateau, Tibetan-Yi-Corridor (TYC) and Southeast Asian TB people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between TYC people and ancient YR people supported the Northern origin hypothesis of TB people. We reported population substructure-related differentiated biological adaptative signatures between highland Tibetans and lowland TB people and between geographically different Lolo speakers. Highland adaptative EPAS1 and EGLN variants riched in Tibetans but lacked in TYC people whose adaptation is associated with the physical features and skin pigmentation (EDAR and SLC24A5), hepatic alcohol metabolism (ALDH9A1), regulation of cell-cell adhesion of muscle cells (CTNNA3) and immune/fat metabolism-related adaptative signature. TB-related genomic resources provided new insights into the genetic basis of phenotype differences and better reference for the anthropologically-informed sampling design in biomedical and genomic cohort research.

genetics↗

bioRxiv2023

Virally induced lipid droplets are a platform for innate immune signalling complexes

Lipid droplets (LDs) are upregulated by host cells in the face of pathogen infection, however, the reason for this phenomenon remains largely unknown. Here, we demonstrate that virally induced LDs house a distinct and dynamic proteome containing key antiviral signalling pathway members, including the essential pattern recognition receptor; RIG-I, key adaptor proteins; STAT1 and STAT2 and prominent interferon inducible proteins; viperin and MX1. Changes in the LD proteome were underpinned by specific key changes in the lipidome of virally driven LDs, particularity in the phospholipid membrane. Following virus infection, key antiviral proteins formed complex protein-protein interactions on the LD surface, positioning this organelle as a key antiviral signalling platform for the first time. It is clear that dynamic regulation of both the proteome and the lipidome of LDs occurs rapidly following viral infection towards the initiation of a successful innate immune response.

immunology↗

bioRxiv2023

Spatiotemporal coordination of Rac1 and Cdc42 at the whole cell level during cell ruffling

Rho-GTPases are central regulators within a complex signaling network that controls the cytoskeletal organization and cell movement. This network includes multiple GTPases, such as the most studied Rac1, Cdc42, and RhoA, and their numerous effectors that provide mutual regulation and feedback loops. Here we investigate the temporal and spatial relationship between Rac1 and Cdc42 during membrane ruffling using a simulation model which couples GTPase signaling with cell morphodynamics to capture the GTPase behavior observed with FRET-based biosensors. We show that membrane velocity is regulated by the kinetic rate of GTPase activation rather than the concentration of active GTPase. Our model captures both uniform and polarized ruffling. We also show that cell-type specific time delays between Rac1 and Cdc42 activation can be reproduced with a single signaling motif, in which the delay is controlled by feedback from Cdc42 to Rac1. The resolution of our simulation output matches those of the time-lapsed recordings of cell dynamics and GTPase activity. This approach allows us to validate simulation results with quantitative precision using the same pipeline for the analysis of simulated and experimental data.

cell biology↗

bioRxiv2023

Whole-genome sequencing of ethnolinguistic diverse northwestern Chinese Hexi Corridor people from the 10K_CPGDP project suggested the differentiated East-West genetic admixture along the Silk Road and their biological adaptations

The ancient Silk Road served as the main connection between East and West Eurasia for several centuries. At any rate, the genetic exchange between populations along the ancient Silk Road was likely to leave traces on the contemporary gene pool of local people in Northwest China, which was the passage of the Northern Silk Road. However, genetic sources from northwestern China are under-represented in the current population-scale genomic database. To characterize the genetic architecture and adaptative history of the Northern Silk Road ethnic populations, we performed whole-genome sequencing on 126 individuals from six ethnolinguistic groups (Tibeto-Burman (TB)-speaking Tibetan, Mongolic (MG)-speaking Dongxiang/Tu/eastern Yugur, and Turkic (TK)-speaking Salar/western Yugur) living in Gansu and Qinghai in the 10K Chinese people Genomic Diversity Project (10K_CPGDP). We observed ethnicity-related differentiated population structures among these geographically close Northwest Chinese populations, that is, Salar and Tu people showed a close affinity with southwestern TB groups, and other studied populations shared more alleles with MG and Tungusic groups. Overall, the patterns of genetic clustering were not consistent with linguistic classifications. We estimated that Dongxiang, Tibetan, and Yugur people inherited more than 10% West Eurasian ancestry, much higher than that of Salar and Tu people (<7%). Hence, the difference in the proportion of West Eurasian ancestry has primarily contributed to the genetic divergence of geographically close Northwest Chinese populations. The signatures of natural selection were identified in genes associated with cardiovascular system diseases or lipid metabolism related to triglyceride levels (e.g., PRIM2, PDE4DIP, NOTCH2, DDAH1, GALNT2, and MLIP) and developmental and neurogenetic diseases (e.g., NBPFs 8/9/20/25P, etc.). Moreover, the EPAS1 gene, a transcription factor regulating hypoxia response, showed relatively high PBS values in our studied groups. The sex-biased admixture history, in which the West Eurasian ancestry was introduced primarily by males, was identified in Dongxiang, Tibetan, and Yugur populations. We determined that the eastern-western admixture occurred [~]783-1131 years ago, coinciding with the intensive economic and cultural exchanges during the historic Trans-Eurasian cultural exchange era.

genomics↗