Biology subjects

Lin, Q.

Publications and source records attributed to Lin, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

RhoA effectors ROCK and SLK/LOK oppositely regulate VE-cadherin mobility at endothelial junctions

Cellular contractile forces regulate VE-cadherin dynamics, adhesion, and endothelial junction integrity. RhoA controls these forces through two parallel effector kinases: ROCK, which activates non-muscle myosin II motors, and SLK/LOK, which promote actin-membrane attachment through phosphorylation of ezrin, radixin, moesin proteins (ERM). How these two RhoA effector pathways differentially affect VE-cadherin dynamics at junctions is not known. Using single-molecule tracking of Halo-tagged VE-cadherin, we obtained a detailed characterization of VE-cadherin diffusive behavior inside and outside junctional regions in cultured human umbilical vein endothelial cells (HUVEC). VE-cadherin was substantially less mobile and more confined within junctions than in non-junctional membrane. Inhibiting ROCK with Y-27632 increased VE-cadherin mobility both inside and outside junctions, consistent with RhoA/ROCK-driven contractility restraining cadherin diffusion globally. Unexpectedly, inhibiting SLK/LOK produced the opposite effect, selectively reducing VE-cadherin mobility within junctions with no comparable change outside them. This effect was accompanied by an increase in reticular junctions, suggesting that SLK/LOK inhibition alters VE-cadherin mobility indirectly, through a change in junctional architecture, rather than through a direct effect of actin-membrane coupling on VE-cadherin itself. These findings identify SLK/LOK as a regulator of VE-cadherin dynamics acting in parallel to ROCK downstream of RhoA and point to junctional architecture as a previously unappreciated determinant of VE-cadherin mobility at endothelial cell-cell contacts.

biophysics↗

bioRxiv2026

Dynamic merging of enhancer- and promoter-associated assemblies is coupled to transcriptional bursting

Classical models attribute distal enhancer function to chromatin looping, whereas emerging models propose that spatially organized assemblies of transcriptional regulators also facilitate enhancer-promoter communication. To investigate how these processes relate to transcription, we developed an endogenous-tagging-based four-color live-cell imaging platform and an integrated quantitative analysis pipeline in mouse embryonic stem cells (mESCs), enabling simultaneous visualization of regulatory assembly dynamics, chromatin organization and transcriptional bursting at the endogenous Sox2 locus. We find that the pluripotency transcription factor OCT4 and the coactivator BRD4 form numerous spatially distinct but dynamically interacting assemblies. At non-bursting Sox2 alleles, the promoter and the distal Sox2 enhancer SCR occupy distinct assembly environments, with stronger BRD4 association at the SCR than at the promoter. At bursting Sox2 alleles, transcription is coupled to transient merging and partial overlap of enhancer- and promoter-associated assemblies, with the SCR, promoter and nascent RNA frequently sharing OCT4/BRD4-enriched assembly environments across a broad range of SCR-promoter distances. Pharmacological perturbation of bromodomain-dependent BRD4 function preferentially suppresses long-duration, high-amplitude bursts. Together, our findings support a model in which transcriptional bursting is coupled to the dynamic reorganization and merging of enhancer- and promoter-associated regulatory assemblies, linking chromatin-looping and assembly-based views of enhancer-promoter communication.

molecular biology↗

bioRxiv2026

N-terminal Trimming Supports Proteostasis Under Secretory Protein Mislocalization Stress

Secretory proteins that fail to enter the endoplasmic reticulum (ER) are mislocalized to the cytosol, where they threaten cellular proteostasis. How cells manage these mislocalized proteins remains poorly understood. Here, we show that inefficient Sec61 translocon activity induces a transcriptional stress response, which is enhanced by blocking NRF-1-dependent adaptation of proteasomal capacity. To maintain proteasomal capacity, thermodynamically stable mislocalized proteins persist in the cytosol of HepG2 and HEK293T cells, while mislocalized proteins that are inherently more aggregation-prone are preferentially ubiquitinated and degraded. This triaging process is accomplished through N-terminal trimming of the signal sequence of thermodynamically stable proteins, which simultaneously reduces their aggregation and prevents proteasomal degradation. These findings reveal a stability-dependent cytosolic triaging mechanism that matches substrate burden to proteasome capacity when ER import is challenged.

cell biology↗

bioRxiv2026

Charting sex divergence in the human brain across the lifespan

Biological sex fundamentally shapes human brain organization, but sex-specific normative neuroanatomical trajectories across the lifespan remain largely uncharted. Here, we constructed independent, sex-specific lifespan brain charts using structural neuroimaging data from 59,915 healthy individuals (29,760 males and 30,155 females) ranging in age from 266 postconception days to 100 years. By examining 296 structural phenotypes across global, cortical, and subcortical measures, these models revealed widespread sex differences in maturational timing, with males reaching peak milestones later than females. These trajectories demonstrate that sex differences evolve dynamically, with phenotype-specific windows of emergence and maximal separation. Compared with conventional sex-pooled references, sex-specific models achieved superior predictive accuracy and reduced misestimation of individual deviations in healthy populations. Across five neuropsychiatric conditions, sex-specific models improved the detection of extreme deviations and revealed both shared and sex-dependent patterns of disorder-related neuroanatomical abnormalities. These sex-specific charts establish tailored normative references for assessing brain development, ageing, and disease.

neuroscience↗

bioRxiv2026

Widespread structural variations at human chromosome ends

The highly repetitive regions of the human genome were long underrepresented from reference assemblies, limiting study of their biological function. Long-read sequencing and improved assembly algorithms have since resolved many of these regions, from centromeres to ribosomal DNA arrays, revealing structural variation increasingly linked to human disease. However, the subtelomeres, the repeat-rich regions adjacent to the telomeres at each chromosome end, have remained poorly characterized. Here we present a collection of complete subtelomeric sequences spanning all non-acrocentric chromosome arms, derived from 860 haploid assemblies across six ancestry groups. We find that while subtelomeres are mosaics of blocks shared between chromosome arms, individual arms diverge extensively, such that most non-acrocentric autosomal arms (54%, 21 of 39) carry multiple haplotypes differing by up to 100-200 kb. These blocks are broadly conserved across the great apes. In humans, their diversity is associated with chromosome arm rather than ancestry, suggesting that cross-arm paralogy block duplications predate human population divergence, although some haplotypes show ancestry-specific enrichment. Remarkably, these divergent haplotypes differ in gene content, driving gene copy-number variation between individuals among olfactory receptors and other genes. This study also revealed rare subtelomeric recombination. We further show that our subtelomere data set enables the accurate measurement of telomere length at individual chromosome ends from long-read data. Together, these assemblies reveal an unappreciated scale of variation at human chromosome ends and provide a resource for studying the roles of this variation in disease, telomere biology and genome evolution across diverse populations.

genomics↗

bioRxiv2026

The Wobble Uridine tRNA Writer MnmA Shapes Codon-Dependent Stress Response Systems

Escherichia coli uses wobble uridine (U34) modifications to tune codon decoding, but how individual tRNA writer enzymes shape gene expression remains unclear. Here, we identify MnmA, the U34 thiolation enzyme for tRNALys, tRNAGln, and tRNAGlu, as a central regulator linking codon-directed translation to regulon control and stress response. Loss of MnmA depleted s2U-dependent wobble modifications, preventing geranyl-(ges2U) and seleno-(se2U)-based modifications, causing growth defects, reduced catalase activity, and multi-level gene expression dysregulation. The {Delta}mnmA cells showed broad adaptive transcriptional reprogramming associated with RpoS- and OxyR-regulated pathways, which was accompanied by compromised protein output. Endogenous and tagged-protein analyses revealed specific impairment of transcriptional regulators, adaptive and detoxification proteins, including RpoS, OxyR, FliA, KatE, and KatG. Polysome profiling and polysome-associated RNA sequencing showed that MnmA deficiency globally reduces translational capacity and uncouples mRNA abundance from translational efficiency, which is exacerbated during oxidative stress. We developed genome-wide codon-usage mapping analytics to identify five codon-defined gene clusters, with specific clusters enriched for Lys, Gln, and Glu codons disproportionately affected by MnmA loss. Together, these findings support that wobble uridine thiolation and downstream modifications pair with corresponding codon architecture to coordinate the translation of regulon controllers and stress-response networks linked to bacterial fitness. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/745044v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a4058borg.highwire.dtl.DTLVardef@167f4cdorg.highwire.dtl.DTLVardef@1f8c7a8org.highwire.dtl.DTLVardef@1fc0767_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Introns encode a vast class of Kink-loop RNAs that autoregulate pre-mRNA splicing

Introns occupy nearly one-third of the human genome, yet whether they encode widespread regulatory functions remains unclear. Here, we identify a vast new class of intron-derived Kink-loop RNAs (klRNAs) that autoregulate host pre-mRNA splicing. We developed orthogonal sequencing methods to systematically uncover approximately 15,200 and 3,500 previously unannotated klRNAs in humans and mice, respectively. Bound by the conserved RNA-binding protein 15.5K, klRNAs are compact orphan RNAs characterized by stereotypically positioned terminal C/D motifs that form K-loop structures. Depletion of 15.5K broadly disrupts klRNA biogenesis. Functional and genetic perturbations establish that klRNAs suppress host intron excision through a K-loop-dependent mechanism. Together, our findings establish klRNA-mediated autoregulation as a widespread principle governing intron fate and reveal a previously unrecognized regulatory layer encoded within mammalian introns.

molecular biology↗

bioRxiv2026

Nutrient flux governs osteogenic fate commitment through the SLC3A1-cystine Axis

Skeletal and mesenchymal cells have limited bone-forming potential due to their rarity, tendency for senescence and/or unstable osteogenic lineage commitment. We previously identified an osteopotent CXCR4 stem cell population with unclear mechanism for its differentiation potential. Here, we found that the cystine transporter SLC3A1 was selectively enriched in CXCR4+ stem cells, uncovering a role for amino acid transport in regulating osteogenic fate commitment. Enforced SLC3A1 expression reprogrammed mesenchymal cells toward a stable osteogenic state while suppressing adipogenic differentiation. Mechanistically, SLC3A1-mediated cystine flux established a glutathione-dependent metabolic program that preserved mitochondrial fitness and restrained stem cell senescence. SLC3A1 also stabilized IGF-1 through suppression of ZMYND8-mediated ubiquitination, uncovering ZMYND8 as a previously unrecognized E3 ligase regulating osteogenic commitment. Cystine supplementation phenocopied the effects of SLC3A1 activation, promoting osteogenic differentiation and skeletal regeneration without genetic manipulation. In vivo, cystine administration accelerated bone regeneration and attenuated ovariectomy-induced bone loss, while analyses of a human osteoporosis cohort, osteoporotic specimens, and single-cell transcriptomic datasets revealed coordinated suppression of the SLC3A1-cystine-IGF-1 pathway in osteoporotic mesenchymal cells. Taken together, these findings establish SLC3A1-mediated cystine transport as a programmable metabolic determinant of osteogenic fate commitment and identify cystine metabolism as a therapeutically targetable axis for skeletal regeneration and osteoporosis.

cell biology↗

bioRxiv2026

GALE-dependent glycoproteome remodelling is a determinant of oncogenic RAS transformation

Oncogenic transformation is accompanied by extensive remodelling of the cellular glycosylation landscape, yet the mechanisms linking oncogenic signalling to glycoproteome reprogramming remain poorly defined. We used site-resolved intact glycoproteomics to systematically map oncogenic RAS-dependent changes across the N- and O-linked glycoproteome. Integrating multiomics profiling with functional approaches, we identify UDP-glucose 4-epimerase (GALE) as a transcriptional target of oncogenic RAS that is induced through MAPK signalling and MYC-dependent transcription. GALE depletion selectively disrupted RAS-dependent glycoproteome remodelling, preferentially impairing sialylation of N-linked glycans and O-linked GalNAc-type glycosylation. Functionally, these glycosylation defects were accompanied by suppressed anchorage-independent growth and reduced in vivo tumorigenicity of KRAS-mutant cells, establishing GALE-dependent nucleotide-sugar interconversion as a requirement for malignant growth. Clinically, GALE expression was elevated in pancreatic ductal adenocarcinoma, wherein KRAS mutations are highly prevalent, and across a broad spectrum of human cancers. Collectively, our findings define a regulatory axis that connects oncogenic signalling to nucleotide-sugar precursor availability and diversification of the cellular glycan repertoire, revealing GALE as a metabolic dependency in RAS-driven cancer.

Cancer Biology↗

bioRxiv2026

Assessing and Optimizing Low-Frequency Somatic Mutation Detection: A Multi-Platform High-Throughput Sequencing Perspective

The availability of multiple commercial short-read sequencing platforms necessitates systematic cross-platform performance comparisons, particularly for challenging applications such as low-frequency somatic mutation detection. Here, a large-scale targeted sequencing dataset from five Genome in a Bottle (GIAB) human genomic DNA reference standards, HG001 to HG005, alongside Twist Biosciences cfDNA reference standards featuring 1% variant allele frequency (VAF), was generated by six platforms (NovaSeq 6000, NovaSeq X, FASTASeq 300, GenoLab M, SURFSeq 5000, and MGISEQ-T7). To build a realistic benchmark while keeping authentic sequencing backgrounds, we developed PosMix, a simulating tool that generates position-specific VAFs. To overcome the limitations of conventional variant callers (high recall with poor precision for VarScan2, higher precision with lower recall for Strelka2/Mutect2), we developed SomaticXGB, a machine learning-based caller. In this study, SURFSeq 5000 consistently exhibited the lowest error rates and achieved superior accuracy for VAFs as low as 0.5%, outperforming all other sequencing platforms. On the other hand, SomaticXGB attained F1 scores of approximately 0.92 on simulated datasets with VAFs ranging from 0.5% to 1.5% and 0.89 on Twist 1% standards, substantially outperforming conventional methods. This work delivers a valuable rich multi-platform data resource, offering a standardized pipeline for performance benchmarking and a machine learning-based strategy for optimized somatic mutation detection.

bioinformatics↗

bioRxiv2026

CMS: Achieving Uniform and High-Quality Sequencing across Challenging Non-canonical Genomic Regions

High-throughput sequencing is essential in modern biological research, yet low-complexity sequences remain challenging as they form structurally complex, non-canonical (non-B) DNA conformations that impede sequencing enzyme read-through. This leads to a long-standing trade-off: maximizing coverage introduces false positives (FP), while stringent filtering causes coverage loss and false negatives (FN). To address this, we developed CMS (Cross Mountains and Seas) on GeneMind sequencing platforms by optimizing its chemistry and enzymatic systems to traverse these secondary structures with high fidelity. Benchmarking across whole-genome (WGS) and whole-exome (WES) sequencing demonstrates that CMS addresses the trade-off by simultaneously enhancing both coverage uniformity and accuracy, notably achieving an approximately 100-fold reduction in low-coverage bins for WGS and a 70% reduction in FN insertions/deletions (INDELs) within complex non-B regions. Specifically, a synthetic G-quadruplex (G4) motif sequencing experiment demonstrates that CMS maintains a 1:1 strand ratio, effectively handling G4-induced biases where benchmarked platforms exhibit extensive depletion. These findings establish CMS as a reliable technology for the precise characterization of structural-challenging but functional-essential genome regions.

genomics↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

CEACAM5/6+ Tumor Cells and IL-1β+ Macrophages Drive Resistance to Chemo-immunotherapy in Gastric Cancer

Chemo-immunotherapy is a first-line treatment for advanced gastric cancer, yet response rates remain limited and resistance mechanisms are poorly defined. Here we generate a single-cell atlas of 542,121 cells from 35 patients treated with anti-PD-1 plus chemotherapy, profiling pre- and post-treatment tumors linked to clinical response. Integrating spatial transcriptomics, immunohistochemistry, and bulk RNA sequencing, we identify two temporally distinct resistance programs. Intrinsic resistance in pre-treatment non-responders is marked by enrichment of CEACAM5/6 tumor cells that form immune-excluded spatial niches characterized by macrophage recruitment and CD8 T-cell exhaustion. Acquired resistance in post-treatment non-responders is driven by expansion of IL-1{beta} macrophages, which induces coordinated NF-{kappa}B activation across tumor and stromal compartments, promoting PD-L1 upregulation, epithelial-mesenchymal transition, and chronic inflammation. These findings delineate an evolutionary trajectory of resistance and nominate CEACAM5/6 and IL-1{beta} as predictive biomarkers and therapeutic targets to improve anti-PD-1-based combination strategies.

cancer biology↗

bioRxiv2026

Deciphering epileptogenic and activity-dependent gene programs in the human brain

Neuronal activity is fundamental to brain function, yet chronically elevated activity underlies neurological disorders such as drug-resistant epilepsy (DRE). In animal models, activity induces defined transcriptional programs within activated neurons; however, the nature, cellular specificity, and pathological relevance of such programs in the human brain remain poorly understood. Here, we apply single-nucleus and spatial transcriptomics to epileptogenic, non-epileptogenic, and intraoperatively stimulated non-epileptogenic cortical tissue obtained from individuals with DRE. Across 26 cell types profiled, glutamatergic neurons projecting from cortical layers 2/3, 5, and 6 to intratelencephalic targets exhibit pronounced sensitivity to the epileptogenic microenvironment, inducing shared immediate-early genes alongside cell-type-specific programs linked to synaptic remodeling and cellular stress. Approximately one-third of transcripts enriched in the epileptogenic microenvironment were also induced by acute stimulation, suggesting that a fraction of epilepsy-associated gene expression reflects conserved responses to heightened activity rather than disease-specific programs. While transcripts induced by both epileptogenic and acute activity converged upon immediate-early genes and heat-shock proteins, only acute stimulation triggered a rapid, multicellular induction of transcripts involved in mitochondrial ATP synthesis. This divergence suggests that neurons within epileptogenic cortex may be unable to mount appropriate metabolic adaptations to sustained energetic demands. In parallel, both microglia and circulating CD14+ monocytes exhibit signs of immune activation in epilepsy, suggesting myeloid-driven inflammatory rewiring that extends beyond the brain. Together, these findings illuminate human activity-dependent gene programs and reveal signatures of neuronal vulnerability and inflammation in DRE.

neuroscience↗

bioRxiv2026

Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders

Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)--in which pathogenic infection during pregnancy increases ASD risk in offspring--disproportionately affects males. However, the basis for this male-specific vulnerability, and the mechanisms by which inflammatory signals cross the maternal-fetal interface to affect the male embryo, remain largely unknown. Using the poly(I:C) mouse model of neurodevelopmental disorders, we characterize fetal, placental, and amniotic changes occurring within twenty-four hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities--ranging from decreased fetal weight to altered sensory organ development--while 70% develop normally. These abnormalities occur exclusively in a subset of males, never in females. Single-nucleus transcriptomics revealed robust induction of pro-inflammatory gene programs in the placentas of affected males across a broad range of cell types, and most prominently in spongiotrophoblasts--fetally derived cells that partly form the maternal-fetal border. These cells simultaneously down-regulate extracellular matrix and hormone biosynthesis pathways, coinciding with a breakdown in placental structural integrity and the accumulation of immune cells and cytokines in the amniotic fluid. One such cytokine, IL-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a pro-inflammatory maternal-fetal interface in a vulnerable subset of male embryos, producing acute, sex-restricted developmental deficits. We propose that male embryos may express unique proteins capable of triggering this inflammatory response, which--combined with MIA-induced loss of maternal immunosuppression--selectively derails male embryonic development.

developmental biology↗

bioRxiv2026

ALK R1275Q mutation drives expansion of SCP-like cells during sympathoadrenal commitment and primes neuroblastoma initiation.

Neuroblastoma (NB) is a pediatric malignancy developing in the sympathoadrenal lineage of the neural crest, characterized by clinical heterogeneity ranging from spontaneous regression to poor outcomes. Activating mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) are frequently observed in both sporadic and familial NB, yet the functional role of ALK in tumor initiation is not fully understood. Using a patient-derived human induced pluripotent stem cell (iPSC) model of sympathoadrenal development, we show that upon sympathoadrenal lineage commitment, ALK R1275Q, the most common hotspot mutation found in familial NB, sustain a proliferative, immature Schwann cell precursor (SCP)-like cell state with elevated ALK signaling and increased susceptibility to MYCN-driven transformation. While ALK-mutant cells alone did not form tumors in vivo, they cooperated with MYCN to accelerate tumor initiation, suggesting that ALK R1275Q creates a permissive but insufficient state for transformation. These findings define an ALK-driven cell progenitor-like state that facilitates the initiation of NB during embryonal development.

cancer biology↗

bioRxiv2025

Human resistin is critical to activation of the NLRP3 inflammasome in macrophages

Elevated levels of human resistin (hResistin) have been associated with diverse inflammatory diseases, but the precise mechanisms through which hResistins many inflammatory effects contribute to the progression of these diseases remain poorly understood. NLRP3 inflammasome activation is essential in many of these inflammatory conditions; however, there is an unmet explanation connecting hResistin with the NLRP3 inflammatory pathway. Here we describe a unique role of hResistin and its rodent homolog, resistin-like molecule alpha (RELM) in priming and activating the NLRP3 inflammasome. Through qPCR and western blot analysis, we found that hResistin-dependent expression and secretion of high mobility group box 1 (HMGB1) in human macrophages primes the expression of NLRP3, pro-capsase-1, pro-interleukin(IL)-1{beta}, and pro-IL-18. Co-immunoprecipitation showed that hResistin binds to Brutons tyrosine kinase (BTK), which causes the kinase to autophosphorylate, allowing BTK to phosphorylate NLRP3, leading to its assembly and activation with subsequent cleavage of pro-caspase-1, pro-IL-1{beta}, and pro-IL-18, causing initiation of the inflammasome cascade. The hResistin-dependent activation and secretion of IL-1{beta} and IL-18 was critical to the proliferation of human pulmonary vascular smooth muscle cells. For confirmation in vivo, we studied rodent and human pulmonary hypertension (PH). Chronic hypoxia-induced PH in wild-type and RELM KO mice showed RELM-dependent upregulation of HMGB1, BTK, and NLRP3 in mouse lung and was linked to vascular remodeling pathways. Immunohistochemistry revealed that the majority of NLRP3-expressing cells were macrophages and the colocalization of hResistin, BTK, and NLRP3 in macrophages was increased in PH patients lungs. Our work reveals a novel immune mechanism demonstrating hResistin is essential to the priming and activation of NLRP3. Inhibiting NLRP3 activation by blocking hResistin with a human monoclonal antibody suggests a likely therapeutic pathway for NLRP3-driven inflammatory diseases.

immunology↗

bioRxiv2025

A multi-tissue atlas of genetic regulatory effects in sheep

Characterizing the impact of genomic variants on genome function and ultimately complex traits in livestock is essential for the development of sustainable precision agriculture and comparative genomics. Here, as part of the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we present the pilot phase of the SheepGTEx resource through analyzing 6,761 RNA-sequencing samples of 51 primary tissues in a multi-breed population of sheep. We identify millions of regulatory variants associated with seven types of molecular phenotypes, and fine-map 322,468 primary and 114,017 non-primary effects, revealing a high degree of regulatory allelic heterogeneity. We systematically characterize the pleiotropic effects of these variants on molecular phenotypes, assess their context-specific regulatory patterns across tissues, breeds, sexes, and developmental stages, as well as explore their evolutionary constraints across mammals. Finally, we demonstrate the substantial potential of the SheepGTEx resource (https://sheepgtex.farmgtex.org), by providing examples of regulatory mechanisms underpinning 34 complex traits, population divergence between European and Asian breeds, and adaptive evolution in sheep over the past ten millennia.

genomics↗