Biology subjects

Gao, Z.

Publications and source records attributed to Gao, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

scEpiTools: a database to comprehensively interrogate analytic tools for single-cell epigenomic data

Single-cell sequencing technology has enabled the characterization of cellular heterogeneity at an unprecedented resolution. To analyze single-cell RNA-sequencing data, numerous tools have been proposed for various analytic tasks, which have been systematically summarized and concluded in a comprehensive database called scRNA-tools. Although single-cell epigenomic data can effectively reveal the chromatin regulatory landscape that governs transcription, the analysis of single-cell epigenomic data presents assay-specific challenges, and an abundance of tools with varying types and functionalities have thus been developed. Nevertheless, these tools have not been well summarized, hindering retrieval, selection, and utilization of appropriate tools for specific analyses. To address the issues, we here proposed scEpiTools database with a multi-functional platform (http://health.tsinghua.edu.cn/scepitools). Specifically, based on the comprehensive collection and detailed annotation of 553 articles, scEpiTools groups articles into 14 major categories and 90 subcategories, provides task-specific recommendation for different emphases, and offers intuitive trend analysis via directed graphs, word clouds, and statistical distributions. For single-cell chromatin accessibility data analysis, we proposed a novel ensemble method named scEpiEnsemble, which, along with multiple methods as built-in kernels, can be used for flexible and efficient online analysis via the scEpiTools platform. We envision that scEpiTools will guide tool usage and development for single-cell epigenomic data and provide valuable resources for understanding regulatory mechanisms and cellular identity. Author summaryCompared to single-cell RNA-sequencing data, single-cell epigenomic data can reflect a set of epigenetic modifications at the cellular level. In general, the analysis of these data is typically divided into several steps: 1) retrieving available tools based on the omics of data and tasks; 2) selecting appropriate tools manually; and 3) utilizing the chosen tools to analyze data. However, due to the rapid development of tools and the unique complexity of the data, each of the above steps is extremely challenging for researchers. To provide researchers with great convenience, we developed scEpiTools (http://health.tsinghua.edu.cn/scepitools), a database with multiple functionalities. For instance, given the omics type and the analytic task, researchers can easily browse all the available tools via the hierarchical categorization of scEpiTools, and get recommendation scores from multiple perspectives. Considering that researchers may encounter difficulties in hardware requirements or environment setup, we also provide online analysis with various commonly used tools, as well as a novel ensemble method named scEpiEnsemble. In summary, scEpiTools represents a valuable resource for the single-cell epigenomics community, facilitating retrieval, selection and utilization of appropriate tools for diverse analyses, and helping to drive future advancements in the field.

bioinformatics↗

bioRxiv2023

Colocalization of Protein and microRNA Markers Reveals Unique Extracellular Vesicle Sub-Populations for Early Cancer Detection

Extracellular vesicles (EVs) play important roles in cell-cell communication but they are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm thus encapsulates very limited amounts of cargos. We report the technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) that utilizes NOBs, which are superparamagnetic nanorods easily handled by a magnet or a rotating magnetic field, to act as isolated "islands" for EV immobilization and cargo confinement. NOBEL-SPA permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, and can assess the colocalization of selected protein/microRNA (miRNA) pairs in the EVs produced by various cell lines or present in clinical sera samples. Specific EV sub-populations marked by the colocalization of unique protein and miRNA combinations have been revealed by the present work, which can differentiate the EVs by their cells or origin, as well as to detect early-stage breast cancer (BC). We believe NOBEL-SPA can be expanded to analyze the co-localization of other types of cargo molecules, and will be a powerful tool to study EV cargo loading and functions under different physiological conditions, and help discover distinct EV subgroups valuable in clinical examination and therapeutics development.

cancer biology↗

bioRxiv2023

Multiple sequence-alignment-based RNA language model and its application to structural inference

Compared to proteins, DNA and RNA are more difficult languages to interpret because 4-letter-coded DNA/RNA sequences have less information content than 20-letter-coded protein sequences. While BERT (Bidirectional Encoder Representations from Transformers)-like language models have been developed for RNA, they are ineffective at capturing the evolutionary information from homologous sequences because unlike proteins, RNA sequences are less conserved. Here, we have developed an unsupervised Multiple sequence-alignment-based RNA language model (RNA-MSM) by utilizing homologous sequences from an automatic pipeline, RNAcmap. The resulting unsupervised, two-dimensional attention maps and one-dimensional embeddings from RNA-MSM can be directly mapped with high accuracy to 2D base pairing probabilities and 1D solvent accessibilities, respectively. Further fine-tuning led to significantly improved performance on these two downstream tasks over existing state-of-the-art techniques. We anticipate that the pre-trained RNA-MSM model can be fine-tuned on many other tasks related to RNA structure and function.

bioinformatics↗

bioRxiv2023

Multi-omics and Pharmacological Characterization of Patient-derived Glioma Cell Lines

Glioblastoma (GBM) is the most common brain tumor and is currently incurable. Primary GBM cultures are widely used tools for screening potentially therapeutic drugs; however, there is a lack of genomic and pharmacological characterization of these primary GBM cultures. Here, we collected 52 patient-derived glioma cell (PDGC) lines and characterized them through whole- genome sequencing (WGS), RNA-seq, and drug response screening. We identified three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Upon profiling the responses of PDGCs to 214 drugs, we found that the PN subtype PDGCs were sensitive to tyrosine kinase inhibitors, whereas the OXPHOS subtype PDGCs were sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably formed tumors in vivo upon intracranial transplantation into immunodeficient mice, while most MES subtype PDGCs were incapable of tumorigenesis in vivo. In addition, profiling and follow-up investigations showed that the serum-free culture system used for PDGCs enriched and propagated rare MYC/MYCN- amplified glioma cells. Our study provides a resource for understanding primary glioma cell cultures and aiding clinical translation. SignificanceOur study provides a resource for patient-derived glioma cell lines (PDGCs) on transcriptome, genome, drug response, and tumorigenic abilities. PDGCs are categorized into PN, MES, and OXPHOS subtypes, with MES-subtype PDGCs incapable of tumorigenesis in vivo. Notably, the serum-free culture system for PDGCs enriches glioma cells with MYC/MYCN amplification.

cancer biology↗

bioRxiv2022

High Sensitivity Top-down Proteomics Captures Single Muscle Cell Heterogeneity in Large Proteoforms

Single-cell proteomics has emerged as a powerful method to characterize cellular phenotypic heterogeneity and the cell-specific functional networks underlying biological processes. However, significant challenges remain in single-cell proteomics for the analysis of proteoforms arising from genetic mutations, alternative splicing, and post-translational modifications. Herein, we have developed a highly sensitive functionally integrated top-down proteomics method for the comprehensive analysis of proteoforms from single cells. We applied this method to single muscle fibers (SMFs) to resolve their heterogeneous functional and proteomic properties at the single cell level. Notably, we have detected single-cell heterogeneity in large proteoforms (>200 kDa) from the SMFs. Using SMFs obtained from three functionally distinct muscles, we found fiber-to-fiber heterogeneity among the sarcomeric proteoforms which can be related to the functional heterogeneity. Importantly, we reproducibly detected multiple isoforms of myosin heavy chain (~223 kDa), a motor protein that drives muscle contraction, with high mass accuracy to enable the classification of individual fiber types. This study represents the first "single-cell" top-down proteomics analysis that captures single muscle cell heterogeneity in large proteoforms and establishes a direct relationship between sarcomeric proteoforms and muscle fiber types, highlighting the potential of top-down proteomics for uncovering the molecular underpinnings of cell-to-cell variation in complex systems. Significance StatementSingle-cell technologies are revolutionizing biology and molecular medicine by allowing direct investigation of the biological variability among individual cells. Top-down proteomics is uniquely capable of dissecting biological heterogeneity at the intact protein level. Herein, we develop a highly sensitive single-cell top-down proteomics method to reveal diverse molecular variations in large proteins (>200 kDa) among individual single muscle cells. Our results both reveal and characterize the differences in protein post-translational modifications and isoform expression possible between individual muscle cells. We further integrate functional properties with proteomics and accurately measure myosin isoforms for individual muscle fiber type classification. Our study highlights the potential of top-down proteomics for understanding how single-cell protein heterogeneity contributes to cellular functions.

biochemistry↗

bioRxiv2022

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis (cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOE{varepsilon}4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimers, Parkinsons, schizophrenia, and educational attainment.

genomics↗

bioRxiv2022

Imaging crossing fibers in mouse, pig, monkey, and human brain using small-angle X-ray scattering

Myelinated axons (nerve fibers) efficiently transmit signals throughout the brain via action potentials. Multiple methods that are sensitive to axon orientations, from microscopy to magnetic resonance imaging, aim to reconstruct the brains structural connectome. As billions of nerve fibers traverse the brain with various possible geometries at each point, resolving fiber crossings is necessary to generate accurate structural connectivity maps. However, doing so with specificity is a challenging task because signals originating from oriented fibers can be influenced by brain (micro)structures unrelated to myelinated axons. X-ray scattering can specifically probe myelinated axons due to the periodicity of the myelin sheath, which yields distinct peaks in the scattering pattern. Here, we show that small-angle X-ray scattering (SAXS) can be used to detect myelinated, axon-specific fiber crossings. We first demonstrate the capability using strips of human corpus callosum to create artificial double- and triple-crossing fiber geometries, and we then apply the method in mouse, pig, vervet monkey, and human brains. Given its specificity, capability of 3-dimensional sampling and high resolution, SAXS can serve as a ground truth for validating MRI as well as microscopy-based methods. Statement of SignificanceTo study how the nerve fibers in our brain are interconnected, scientists need to visualize their trajectories, which often cross one another. Here, we show the unique capacity of small-angle X-ray scattering (SAXS) to study these fiber crossings without use of labelling, taking advantage of SAXSs specificity to myelin - the insulating sheath that is wrapped around nerve fibers. We use SAXS to detect double and triple crossing fibers and unveil intricate crossings in mouse, pig, vervet monkey, and human brains. This non-destructive method can uncover complex fiber trajectories and validate other less specific imaging methods (e.g., MRI or microscopy), towards accurate mapping of neuronal connectivity in the animal and human brain. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/510198v2_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@479368org.highwire.dtl.DTLVardef@11eb0c9org.highwire.dtl.DTLVardef@1e883adorg.highwire.dtl.DTLVardef@1ce024_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization

Long interspersed nuclear elements (LINEs) play essential role in shaping chromatin state, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form into a gel-like meshwork via phase-separation, providing a partially dynamic platform for chromatin spatial organization. Either depletion of MATR3 or AS L1 RNAs changes nuclear distribution of each other and leads to chromatin reorganization in the nucleus. After MATR3 depletion, topologically associating domains (TADs) that highly transcribed MATR3-associated AS L1 RNAs showed a decrease on local chromatin interactions. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause chromatin reorganization. Collectively, we revealed an essential role of meshwork formed by nuclear matrix and retrotransposon-derived RNAs in gathering chromatin in the nucleus.

cell biology↗

bioRxiv2022

Attenuation of polysialic acid biosynthesis in cells by the small molecule inhibitor 8-keto-sialic acid

Sialic acids are key mediators of cell function, particularly with regards to cellular interactions with the surrounding environment. Reagents that modulate the display of specific sialyl glycoforms at the cell surface would be useful biochemical tools and potentially allow for therapeutic intervention in numerous challenging chronic diseases. While multiple strategies are being explored for the control of cell surface sialosides, none that shows high selectivity between sialyltransferases or that targets a specific sialyl glycoform has yet to emerge. Here we describe a strategy to block the formation of 2,8-linked sialic acid chains (oligo- and polysialic acid) through the use of 8-keto-sialic acid as a chain-terminating metabolic inhibitor that, if incorporated, can not be elongated. 8-Keto-sialic acid is non-toxic at effective concentrations and serves to block polysialic acid synthesis in cancer cell lines and primary immune cells, with minimal effects on other sialyl glycoforms.

biochemistry↗

bioRxiv2022

Structural and mechanistic insights into inhibition of the type I-F CRISPR-Cas surveillance complex by AcrIF4

CRISPR-Cas system provides prokaryotes with protection against mobile genetic elements (MGEs) such as phages. In turn, phages deploy anti-CRISPR (Acr) proteins to evade this immunity. AcrIF4, an Acr targeting the type I-F CRISPR-Cas system, has been reported to bind the crRNA-guided surveillance (Csy) complex. However, it remains controversial whether AcrIF4 inhibits target DNA binding to the Csy complex. Here, we present structural and mechanistic studies into AcrIF4, exploring its unique anti-CRISPR mechanism. While the Csy-AcrIF4 complex displays decreased affinity for target DNA, it is still able to bind the DNA. Structural and functional analyses of the Csy-AcrIF4-dsDNA complex revealed that AcrIF4 binding prevents rotation of the helical bundle (HB) of Cas8f induced by dsDNA binding, therefore resulting in failure of Cas2/3 recruitment and DNA cleavage. Overall, our study provides an interesting example of attack on the nuclease recruitment event by an Acr, but not conventional mechanisms of blocking binding of target DNA.

molecular biology↗

bioRxiv2022

Structural and functional insights into the type III-E CRISPR-Cas immunity

The type III-E CRISPR-Cas system comprises a Cas effector (gRAMP), a TPR-CHAT and several ancillary proteins. However, both the structural features of gRAMP and the immunity mechanism remain unknown for this system. Here, we report a series of structures of gRAMP-crRNA, either its alone or in complex with target RNA or TPR-CHAT (called Craspase), and Craspase complexed with cognate (CTR) or non-cognate target RNA (NTR). Importantly, the 3 anti-tag region of NTR and CTR bind at two distinct channels in the Craspase, and CTR with a non-complementary 3 anti-tag induces a marked conformational change of the TPR-CHAT, which allosterically activates its protease activity to cleave an ancillary protein Csx30. This cleavage then triggers an abortive infection as the antiviral strategy of the type III-E system. Together, our study provides crucial insights into both the catalytic mechanism of the gRAMP and the immunity mechanism of the type III-E CRISPR-Cas system.

molecular biology↗

bioRxiv2022

Swim bladder resonance enhances hearing in crucian carp (Carassius auratus)

Sound sensing is vital for fish and more effort is necessary to address the hearing mechanism in fish. Here, we performed auditory evoked potentials (AEP) measurement, micro-computed tomography (Micro-CT) scanning, and numerical simulation to investigate the resonance of swim bladder and its influence on auditory sensitivity in crucian carp (Carassius auratus). The AEP results showed that at the tested frequency range up to 1000 Hz, the mean auditory thresholds of control fishes with an intact swim bladder were lower than that of treated fishes with a deflated swim bladder by 0.38-30.52 dB re 1 Pa. At the high frequency end, control fishes had a high but measurable auditory threshold. Correspondingly, numerical simulations showed that the intact swim bladder had a mean resonance frequency of 826{+/-}13.6 Hz, ranging from 810 to 840 Hz while the deflated swim bladder had no predominant resonance peak below 1000 Hz. The amplitude of received sound pressure at the resonance frequency for a sample in control group was 34.3 dB re 1 Pa higher than that for a treated sample, and the acceleration at the asteriscus of the control fish was higher than the treat fish by 43.13 dB re 1 m s-2. Both AEP experiment and modeling results showed that hearing sensitivity is enhanced through resonance of swim bladder in crucian carp and provided additional understandings on hearing mechanism in fish. Summary statementWe used AEP measurement, Micro-CT scanning, and numerical simulation to demonstrate that the resonance of swim bladder can enhance hearing in crucian carp.

animal behavior and cognition↗

bioRxiv2022

Human iPSC-derived neuron of 16p11.2 deletion reveals haplotype-specific expression of MAPK3 and its contribution to variable NDD phenotypes

Recurrent proximal 16p11.2 deletion (16p11.2del) is risk factor of diverse neurodevelopmental disorders (NDDs) with variable penetrance. Although previous human induced pluripotent stem cell (hiPSC) models of 16p11.2del confirmed disrupted neuron development, it is not known which gene(s) at this interval are mainly responsible for the abnormal cellular phenotypes and how the NDD penetrance is regulated. After haplotype phasing of 16p11.2 region, we generated hiPSCs for two 16p11.2del families with distinct residual haplotypes and variable NDD phenotypes. We also differentiated the hiPSCs to cortical neural cells and demonstrated MAPK3 as a driver signal of 16p11.2 region contributing to the dysfunctions in multiple pathways related to neuron development, which leads to altered morphological or electrophysiological properties in neuron cells. Furthermore, residual haplotype-specific MAPK3 expression was identified in 16p11.2del neuron cells, associating MAPK3 down-expression with the minor allele of the residual haplotype. Ten SNPs of the residual haplotype are mapped as enhancer SNPs (enSNPs) of MAPK3, eight enSNPs were functionally validated by luciferase assays, implying enSNPs contribute to residual haplotype-specific MAPK3 expression via cis-regulation. Finally, the analyses of three different patient cohorts showed that the residual haplotype of 16p11.2del is associated with variable NDD phenotypes.

genetics↗

bioRxiv2022

Timing and causes of the evolution of the germline mutation spectrum in humans

Recent studies have suggested that the human germline mutation rate and spectrum evolve rapidly. Variation in generation time has been linked to these changes, though its contribution remains unclear. We develop a framework to characterize temporal changes in polymorphisms within and between populations, while controlling for the effects of natural selection and biased gene conversion. Application to the 1000 Genomes Project dataset reveals multiple independent changes that arose after the split of continental groups, including a previously reported, transient elevation in TCC>TTC mutations in Europeans and novel signals of divergence in C>G and T>A mutation rates among population samples. We also find a significant difference between groups sampled in and outside of Africa, in old T>C polymorphisms that predate the out-of-Africa migration. This surprising signal is driven by TpG>CpG mutations, and stems in part from mis-polarized CpG transitions, which are more likely to undergo recurrent mutations. Finally, by relating the mutation spectrum of polymorphisms to parental age effects on de novo mutations, we show that plausible changes in the generation time cannot explain the patterns observed for different mutation types jointly. Thus, other factors--genetic modifiers or environmental exposures--must have had a non-negligible impact on the human mutation landscape.

evolutionary biology↗

bioRxiv2022

A Parabrachial to Hypothalamic Neurocircuit Mediates Defensive Behavior

Defensive behaviors are critical for animals survival. Both the paraventricular nucleus of the hypothalamus (PVN) and the parabrachial nucleus (PBN) have been shown to be involved in defensive behaviors. However, whether there are direct connections between them to mediate defensive behaviors remains unclear. Here, by retrograde and anterograde tracing, we uncover that cholecystokinin (CCK)-expressing neurons in the lateral PBN (LPBCCK) directly project to the PVN. By in vivo fiber photometry recording, we found that LPBCCK neurons actively respond to various threat stimuli. Selective photoactivation of LPBCCK neurons promotes aversion and defensive behaviors. Conversely, photoinhibition of LPBCCK neurons attenuates rat or looming stimuli-induced flight responses. Optogenetic activation of LPBCCK axon terminals within the PVN or PVN glutamatergic neurons promote defensive behaviors. Whereas chemogenetic and pharmacological inhibition of local PVN neurons prevent LPBCCK-PVN pathway activation-driven flight responses. These data suggest that LPBCCK neurons recruit downstream PVN neurons to actively engage in flight responses. Our study identifies a previously unrecognized role for the LPBCCK-PVN pathway in controlling defensive behaviors.

neuroscience↗

bioRxiv2022

Representing linguistic communicative goals in the premotor cortex

Linguistic communication is often regarded as an action conveying the speakers communicative goal to the addressee. With both correlational (an fMRI study) and causal (a lesion study) evidence, we demonstrated that communicative goals are represented in human premotor cortex. Participants read scripts each containing a sentence said by the speaker with a goal of either a promise, a request, or a reply. The fMRI results showed that the premotor cortex represented more information on communicative goals than the perisylvian language regions. The lesion study results showed that, relative to healthy controls, the understanding of communicative goals was impaired in patients with lesions in the premotor cortex, whereas no reliable difference between the healthy controls and lesion controls. These findings convergently suggest that the premotor cortex is crucial for representing the goals conveyed by language, supporting the theoretical view that linguistic communication can be seen as a goal-directed action.

neuroscience↗

bioRxiv2022

Minimally invasive delivery of peptides to the spinal cord for behavior modulation

The blood-spinal cord barrier (BSCB) tightly regulates molecular transport from the blood to the spinal cord. Herein, we present a novel approach for transient modulation of BSCB permeability and localized delivery of peptides into the spinal cord for behavior modulation with high spatial resolution. This approach utilizes optical stimulation of vasculature-targeted nanoparticles and allows delivery of BSCB-nonpermeable molecules into the spinal cord without significant glial activation or impact on animal locomotor behavior. We demonstrate minimally invasive light delivery into the spinal cord using an optical fiber and BSCB permeability modulation in the lumbar region. Our method of BSCB modulation allows delivery of bombesin, a centrally-acting and itch-inducing peptide, into the spinal cord and induces a rapid and transient increase in itching behaviors in mice. This minimally invasive approach enables behavior modulation without genetic modifications and is promising for delivering a wide range of biologics into the spinal cord for behavior modulation and potentially therapy. Significance StatementSpinal cord diseases and disorders are common and cause significant disability, including chronic pain, paralysis, cognitive impairment, and mortality. The blood-spinal cord barrier is a considerable challenge for delivery by systemic therapeutic administration. We developed an optical approach for effectively and safely delivering molecules to the spinal cord to overcome this barrier. The fiberoptic method is minimally invasive and overcomes challenges that previous technologies face, including the complicated bone structure and standing waves that complicate BSCB opening using ultrasound. Optical stimulation offers unprecedented spatial resolution for the precise delivery in intricate spinal cord structures. Significantly, our approach modulates animal behavior (i.e., itch) without genetic modifications and demonstrates the potential for delivery of biologics such as peptides into the spinal cord.

neuroscience↗

bioRxiv2022

Stable population structure in Europe since the Iron Age, despite high mobility

Ancient DNA research in the past decade has revealed that European population structure changed dramatically in the prehistoric period (14,000-3,000 years before present, YBP), reflecting the widespread introduction of Neolithic farmer and Bronze Age Steppe ancestries. However, little is known about how population structure changed from the historical period onward (3,000 YBP - present). To address this, we collected whole genomes from 204 individuals from Europe and the Mediterranean, many of which are the first historical period genomes from their region (e.g. Armenia and France). We found that most regions show remarkable inter-individual heterogeneity. At least 7% of historical individuals carry ancestry uncommon in the region where they were sampled, some indicating cross-Mediterranean contacts. Despite this high level of mobility, overall population structure across western Eurasia is relatively stable through the historical period up to the present, mirroring geography. We show that, under standard population genetics models with local panmixia, the observed level of dispersal would lead to a collapse of population structure. Persistent population structure thus suggests a lower effective migration rate than indicated by the observed dispersal. We hypothesize that this phenomenon can be explained by extensive transient dispersal arising from drastically improved transportation networks and the Roman Empires mobilization of people for trade, labor, and military. This work highlights the utility of ancient DNA in elucidating finer scale human population dynamics in recent history.

genetics↗