Biology subjects

Wang, C.-C.

Publications and source records attributed to Wang, C.-C..

At least 19 recordsLinked to original sources

bioRxiv2026

Norepinephrine Induces Proliferation and Migration of Human Pulmonary Artery Smooth Muscle Cells via Endothelin 1

Background: Pulmonary arterial hypertension (PAH) is a serious disease with poor prognosis, especially in infants or preterm babies and there is still no optimal treatment for this disease. Noradrenalin (NE) is a vasoactive mediator which is released by sympathetic ganglion. According to previous studies, NE/1-adrenoreceptors is not only in regulating normal physiologic responses, but also in the pathogenesis of PAH. However, the mechanisms of NE in PAH are not fully understood. Methods: Human PASMC (PASMC) was used in this study. Cell viability assay and Wound healing assay were used to evaluate the proliferation and migration of PASMC. Immunoprecipitation and western blots analysis were used to investigate the mechanisms which involved in NE-induced PASMC proliferation. Results: We investigated that NE could induce human PASMC proliferation and migration. Furthermore, we first find that endothelin 1 (ET-1) signaling pathway plays an important role in NE-induced PASMC proliferation. ET1 is a critical molecular which is known for regulating cell growth and migration. We investigated that NE could increase NE-1 secretion, further enhancing ET-1 bind to its receptors. For further clarifying the downstream signals in NE/ET-1 induced PASMC proliferation, we detected the phosphorylation and expression levels of ERK and JNK. Conclusions: By combining the results from ours and previous studies, we believed that JNK/c-jun pathway may play an important role in NE-induced PASMC proliferation. Key Words: Noradrenaline; Pulmonary Arterial Hypertension; Pulmonary Artery Smooth Muscle Cells; Endothelin-1; JNK/c-Jun Signaling.

molecular biology↗

bioRxiv2026

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity

Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.

cancer biology↗

bioRxiv2026

Expanding High-Fidelity Multiplexing in Ultrasensitive Single-Molecule Protein Detection via Proximity Barcoding

The human proteome presents a vast information reservoir for basic and diagnostics research, yet the low abundances of many proteins in biofluids pose an analytical challenge. While ultrasensitive methods such as digital enzyme-linked immunosorbent assay have expanded the window of detectable proteins, multiplexing with high accuracy, sensitivity, and throughput remains limited by cross-reactivity and signal readout channels To address this challenge, we introduce PRO-MOSAIX (PROximity-barcoded Molecular On-bead Signal Amplification for Individual MultipleXing), a high-accuracy, ultrasensitive multiplex digital immunoassay platform that integrates high-throughput single-molecule protein detection with DNA barcode-based proximity ligation. PRO-MOSAIX generates "ON" signals only from matched affinity reagents in proximity, minimizing false positives from cross-reactive binding. This approach overcomes the multiplexing ceiling imposed by fluorescence spectral overlap by employing a single signal readout channel and DNA barcoding. In conjunction, we further improve multiplexing accuracy by mitigating a secondary source of false positives from DNA-based signal amplification. As a proof of principle, we establish and validate a 15-plex PRO-MOSAIX assay in human plasma, with low femtomolar sensitivities and high measurement accuracies. PRO-MOSAIX is modular and utilizes common laboratory instrumentation with a high-throughput flow cytometric readout, providing a broadly accessible tool that bridges the gap between analytical sensitivity and high-order multiplexing.

bioengineering↗

bioRxiv2025

Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-xL and Bcl-2/Bcl-xL inhibitors

Phosphodiesterase 3A (PDE3A) modulators are emerging anticancer agents for tumors that co-express PDE3A and Schlafen 12 (SLFN12), promoting the formation of a cytotoxic PDE3A-SLFN12 complex. The effect correlates with PDE3A and SLFN12 expression levels. In this study, we conducted a high-throughput screening of 526 compounds in three sarcoma cell lines to identify synergistic or antagonistic interactions with PDE3A modulators. Synergistic mechanisms were further investigated in cell lines and in patient-derived xenograft models of leiomyosarcoma and myxofibrosarcoma in mice. Several drug classes showed potential synergy, and PDE3A modulators sensitized cells to otherwise ineffective Bcl-2/xL inhibitors. The combination of a PDE3A modulator and a Bcl-xL inhibitor induced tumor regression in a patient-derived leiomyosarcoma model in vivo. Our findings reveal that PDE3A modulators synergized with several inhibitors of key cancer pathways, offering promising potential for future treatments. With further research, PDE3A modulators and combination therapies could provide effective targeted treatment options for tumors expressing both PDE3A and SLFN12, paving the way for innovative and hopeful advancements in cancer treatment.

molecular 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

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↗

bioRxiv2022

MicroRNA-4776-5p acts as a radiosensitizer and predicts the prognosis of patients with head and neck cancer receiving radiotherapy

Head and neck cancer is the leading cancer worldwide. Radiation therapy plays important role of treatment for head and neck cancer. MicroRNAs have been shown to be related to tumor progression and radiosensitivity. However, the mechanisms are still largely unknown and evidence are still limited. In the current study, we sought to identify the miRNA related the radiosensitivity of head and neck tumor cell, which leading to the disappointed prognosis of patients with head and neck cancer receiving radiation therapy. The miRNA expression profiles and clinical information of patients with head and neck cancer were obtained from The Cancer Genome Atlas. The identification of miRNA was carried out through an integrated bioinformatics analysis. The miRNA identified in previous approach was validated through in vitro and in vivo studies. MiR-4776-5p was finally identified as the role of radio-sensitizer and predicts the prognosis of patients with head and neck cancer receiving radiotherapy. 11 of 16 genes targeted by the miR-4776-5p have been discovered to regulate the mechanisms related to radiosensitivity using functional annotation.

cancer biology↗

bioRxiv2022

Reconstructing the formation of Hmong-Mien genetic fine-structure

The linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. Nevertheless, the genetic differentiation among HM-speaking populations and the formation process behind are far from well characterized in previous studies. Here, we generated genome-wide data from 67 Yao ethnicity samples and analyzed them together with published data, particularly by leveraging haplotype-based methods. We identify that the fine-scale genetic substructure of HM-speaking populations corresponds better to linguistic classification than to geography, while the parallel of serial founder events and language differentiations can be found in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The excessive level of the genetic bottleneck of HM speakers, especially Bunu, is in agreement with their long-term practice of slash-and-burn agriculture. The inferred admixture dates in most of the HM-speaking populations overlap the reign of the Ming dynasty (1368 - 1644 CE). Besides the common genetic origin of HM speakers, their external ancestry majorly comes from neighboring Han Chinese and Kra-Dai speakers in South China. Conclusively, our analysis reveals the recent isolation and admixture events that contribute to the fine-scale genetic formation of present-day HM-speaking populations underrepresented in previous studies.

genomics↗

bioRxiv2022

Triangulation fails when neither linguistic, genetic, nor archaeological data support the Transeurasian narrative

Robbeets et al.1 argue that the dispersal of the so-called "Transeurasian" languages, a highly disputed language superfamily comprising the Turkic, Mongolian, Tungusic, Koreanic, and Japonic language families, was driven by Neolithic farmers in the West Liao River region of China. They adduce evidence from linguistics, archaeology, and genetics to support their claim. An admirable feature of the Robbeets et al.s paper is that all their datasets can be accessed. However, a closer investigation of all three types of evidence reveals fundamental problems with each of them. Robbeets et al.s analysis of the linguistic data does not conform to the minimal standards required by traditional scholarship in historical linguistics and contradicts their own stated sound correspondence principles. A reanalysis of the genetic data finds that they do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. Their archaeological data contain little phylogenetic signal, and we failed to reproduce the results supporting their core hypotheses about migrations. Given the severe problems we identify in all three parts of the "triangulation" process, we conclude that there is neither conclusive evidence for a Transeurasian language family nor for associating the five different language families with the spread of Neolithic farmers from the West Liao River region.

genetics↗

bioRxiv2021

Demographic model and biological adaptation inferred from the genome-wide SNP data reveal tripartite origins of southernmost Chinese Huis

The culturally unique Sanya Hui (SYH) people are regarded as the descendants of ancient Cham people in Central Vietnam (CV) and exhibit a scenario of complex migration and admixture history, who were likely to first migrate from Central and South Asia (CSA) to CV and then to South Hainan and finally assimilated with indigenous populations and resided in the tropical island environments since then. A long-standing hypothesis posits that SYH derives from different genetic and cultural origins, which hypothesizes that SYH people are different from the genetically attested admixture history of northern Hui people possessing major Han-related ancestry and minor western Eurasian ancestry. However, the effect of the cultural admixture from CSA and East Asia (EA) on the genetic admixture of SYH people remains unclear. Here, we reported the first batch of genome-wide SNP data from 94 SYH people from Hainan and comprehensively characterized their genetic structure, origin, and admixture history. Our results found that SYH people were genetically different from the northern Chinese Hui people and harbored a close genomic affinity with indigenous Vietnamese but a distinct relationship with Cham, which confirmed the hypothesis of documented recent historical migration from CV and assimilation with Hainan indigenous people. The fitted admixture models and reconstructed demographic frameworks revealed an additional influx of CSA and EA ancestries during the historical period, consisting of the frequent cultural communication along the Southern Maritime Silk Road and extensive interaction with EA. Analyses focused on natural-selected signatures of SYH people revealed a similar pattern with mainland East Asians, which further confirmed the possibility of admixture-induced biological adaptation of island environments. Generally, three genetically attested ancestries from CV, EA, and CSA in modern SYH people supported their tripartite model of genomic origins.

genetics↗

bioRxiv2021

Genomic insights into the population history and biological adaptation of Southwestern Chinese Hmong-Mien people

Hmong-Mien-speaking (HM) populations, widely distributed in South China, North of Thailand, Laos and Vietnam, have experienced different settlement environments, dietary habits and pathogen exposure. However, their specific biological adaptation also remained largely uncharacterized, which is important in the population evolutionary genetics and Trans-Omics for regional Precision Medicine. Besides, the origin and genetic diversity of HM people and their phylogenetic relationship with surrounding modern and ancient populations are unknown. Here, we reported genome-wide SNPs in 52 representative Miao people and combined them with 144 HM people from 13 geographically representative populations to characterize the full genetic admixture and adaptive landscape of HM speakers. We found that obvious genetic substructures existed in geographically different HM populations and also identified one new ancestral lineage specifically exited in HM people, which spatially distributed from Sichuan and Guizhou in the North to Thailand in the South and temporally dated to at least 500 years. The sharing patterns of the newly-identified homogeneous ancestry component combined the estimated admixture times via the decay of Linkage Disequilibrium and haplotype sharing in GLOBETROTTER suggested that the modern HM-speaking populations originated from Southwest China and migrated southward recently, which is consistent with the reconstructed phenomena of linguistic and archeological documents. Additionally, we identified specific adaptive signatures associated with several important human nervous system biological functions. Our pilot work emphasized the importance of anthropologically-informed sampling and deeply genetic structure reconstruction via whole-genome sequencing in the next step in the deep Chinese population genomic diversity project (CPGDP), especially in the ethnolinguistic regions.

genetics↗

bioRxiv2021

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

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

genetics↗

bioRxiv2021

Genomic insights into the differentiated population admixture structure and demographic history of North East Asians

North China and South Siberia, mainly populated by Altaic-speaking populations, possess extensive ethnolinguistic diversity and serve as the crossroad for the initial peopling of America and western-eastern trans-continental communication. Yet, the complex scenarios of genetic origin, population structure, and admixture history of North-East Asia remain to be fully characterized, especially for Mongolic people in China with a genome-wide perspective. Thus, we genotyped genome-wide SNPs for 510 individuals from 38 Chinese Mongolic, Tungusic, and Sinitic populations to explore the sharing alleles and haplotypes within the studied groups and following merged it with 3508 modern and ancient Eurasian individuals to reconstruct the deep evolutionary and natural selection history of northern East Asians. We identified significant substructures within Altaic-speaking populations with the primary common ancestry linked to the Neolithic northern East Asians: Western Turkic people harbored more western Eurasian ancestry; Northern Mongolic people in Siberia and eastern Tungusic people in Amur River Basin (ARB) possessed dominant Neolithic Mongolian Plateau (MP) or ARB ancestry; Southern Mongolic people in China owned obvious genetic impact from Neolithic Yellow River Basin (YRB) farmers. Additionally, we found the differentiated admixture history between western and eastern Mongolians and geographically close Northeast Hans: the former received a genetic impact from western Eurasians and the latter retained the dominant YRB and ARB Neolithic ancestry. Moreover, we demonstrated that Kalmyk people from the northern Caucasus Mountain possessed a strong genetic affinity with Neolithic MP people, supporting the hypothesis of their eastern Eurasian origin and long-distance migration history. We also illuminated that historic pastoral empires in the MP contributed considerably to the gene pool of northern Mongolic people but rarely to southern ones. We finally found natural signatures in Mongolians associated with alcohol metabolism. Generally, our results not only illuminated that complex population migration and admixture of Neolithic ancestral sources from the MP or ARB played an important role in the spread of Altaic-speaking populations and Proto-Altaic language, which partly supported the Northeast Asia-origin hypothesis, but also demonstrated that the observed multi-sources of genetic diversity contributed significantly to the modern existing extensive ethnolinguistic diversity in North-East Asia.

genomics↗

bioRxiv2021

The genomic formation of Tanka people, an isolated 'Gypsies in water' in the coastal region of Southeast China

ObjectivesThree different hypotheses proposed via the controversial evidence from cultural, anthropological and uniparental genetic analysis respectively stated that Tanka people probably originated from Han Chinese, ancient Baiyue tribe, or the admixture of them. Therefore, the genetic origin and admixture history of the Tanka people, an isolated "Gypsies in water" in the coastal region of Southeast China, are needed to be genetically clarified. Materials and methodsTo elucidate the genetic origin of the Southeast Tanka people and explore their genetic relationship with surrounding indigenous Tai-Kadai and Austronesian people and Neolithic-to-historic ancients from the Yellow River Basin (YRB) and Fujian, we conducted a large-scale population genomic study among 1498 modern and ancient Eurasians, in which 73 Tanka and 4 Han people were first reported here. Both allele-shared and haplotype-based statistical methods were used here, including PCA, ADMIXTURE, f-statistics, ALDER, qpGraph-/TreeMix and qpAdm/qpWave, ChromoPainter and FineSTRUCTURE ResultsWe found a specific genetic cline in PCA plots and detected the Tanka-specific homogeneous ancestry in model-based ADMIXTURE results, suggesting differentiated demographic history between Tanka and surrounding Hans. Formal tests based on sharing allele patterns showed a close relationship between Tanka people and Han Chinese, but the Tanka population harbored more southern East Asian ancestry related to Austronesian and Tai-Kadai people compared with southern Hans. Besides, the reconstructed differentiated demographic history revealed that southern Xinshizhou Tanka harbored more ancestry related to the Tai-Kadai or coastal ancient Neolithic to Bronze Age East Asians compared with northern Shacheng Tanka. The qpGraph-/TreeMix-based phylogenetic framework, qpAdm/qpWave-based admixture modeling and FineSTRUCTURE-based dendrogram among ancient northern and southern East Asians further demonstrated that the primary ancestry of modern Tanka derived from ancient millet farmers in the YRB with additional admixture from multiple southern East Asian sources. DiscussionSharing ancestry estimated from the f-statistics and sharing haplotypic landscape inferred from the ChromoPainter and FineSTRUCTURE showed that Southeast Tanka people not only had a close genetic relationship with both Northern Hans and YRB millet farmers but also possessed more southern East Asian ancestry related to Austronesian, Tai-Kadai and Hmong-Mien people. Our genomic data and fitted admixture models supported modern Tanka originated from ancient North China and obtained additional gene flow from ancient southern East Asians in the processes of southward migrations.

genetics↗

bioRxiv2021

Genomic history and forensic characteristics of Sherpa highlanders on the Tibetan Plateau inferred from high-resolution genome-wide InDels and SNPs

Sherpa people, one of the high-altitude hypoxic adaptive populations, mainly reside in Nepal and the southern Tibet Autonomous Region. The genetic origin and detailed evolutionary profiles of Sherpas remain to be further explored and comprehensively characterized. Here we analyzed the newly-generated InDel genotype data from 628 Dingjie Sherpa people by merging with 4222 worldwide InDel profiles and collected genome-wide SNP data (approximately 600K SNPs) from 3324 individuals in 382 modern and ancient populations to explore and reconstruct the fine-scale genetic structure of Sherpas and their relationships with nearby modern and ancient East Asians based on the shared alleles and haplotypes. The forensic parameters of 57 autosomal InDels (A-InDels) included in our used new-generation InDel amplification system showed that this updated InDel panel is informative and polymorphic in Sherpas, suggesting that it can be used as the supplementary tool for forensic personal identification and parentage testing in the highland East Asians. Descriptive findings from the PCA, ADMIXTURE and TreeMix-based phylogeny suggested that Sherpas showed excess allele sharing with neighboring Tibeto-Burman Tibetans. Furthermore, patterns of allele sharing in f-statistics demonstrated that Sherpa people had a different evolutionary history compared with their neighbors from Nepal (Newar and Gurung) but showed genetic similarity with 2700-year-old Chokhopani and modern Tibet Tibetans. QpAdm/qpGraph-based admixture sources and models further showed that Sherpa, core Tibetans and Chokhopani formed one clade which could be fitted as having the main ancestry from late Neolithic Qijia millet farmers and other deep ancestries from early Asians. Chromosome painting profiles and shared IBD fragments inferred from FineStructure and ChromoPainter not only confirmed the abovementioned genomic affinity patterns but also revealed the fine-scale microstructures among Sino-Tibetan speakers. Finally, natural-selection signals revealed via iHS, nSL, and iHH12 showed signatures associated with disease susceptibility in Sherpa people. Generally, we provided the comprehensive landscape of admixture and evolutionary history of Sherpa people based on the shared alleles and haplotypes from the low-density forensic markers and high-density genome-wide SNP data. The more detailed genetic landscape of Sherpa people should be further confirmed and characterized via ancient genomes or single-molecule real-time sequencing technology.

genetics↗

bioRxiv2021

Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1

Post tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1. Significance StatementA leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

neuroscience↗

bioRxiv2020

Forensic features and genetic legacy of the Baloch population of Pakistan and the Hazara population across Durand-line revealed by Y chromosomal STRs

Hazara population across Durand-line has experienced extensive interaction with Central Asian and East Asian populations. Hazara individuals have typical Mongolian facial appearances and they called themselves descendants of Genghis Khans army. The people who speak the Balochi language are called Baloch. Previously, a worldwide analysis of Y-chromosomal haplotype diversity for rapidly mutating (RM) Y-STRs and with PowerPlex Y23 System (Promega Corporation Madison, USA) kit was created with collaborative efforts, but Baloch and Hazara population from Pakistan and Hazara population from Afghanistan were missing. A limited data with limited number of markers and samples is available which poorly define these populations. So, in the current study, Yfiler Plus PCR Amplification Kit loci were examined in 260 unrelated Hazara individuals from Afghanistan, 153 Hazara individuals, and 111 Balochi individuals from Baluchistan Pakistan. For the Hazara population from Afghanistan and Pakistan overall, 380 different haplotypes were observed on these 27 Y-STR loci, gene diversities ranged from 0.51288 (DYS389I) to 0.9257 (DYF387S1) and haplotype diversity was 0.9992 +/- 0.0004. For the Baloch population, every individual was unique at 27 Y-STR loci, gene diversity ranged from 0.5718 (DYS460) to 0.9371(DYF387S1). Twelve haplotypes shared between 178 individuals while only two haplotypes among these twelve were shared between 87 individuals in Hazara populations. Rst and Fst pairwise genetic distance analyses, multidimensional scaling (MDS) plot, Neighbor-joining (NJ) tree, linear discriminatory analysis (LDA), and median-joining network (MJNs) were performed, which shed light on the history of Hazara and Baloch populations. Interestingly null alleles were observed at DYS448 with specific mutation patterns in Hazara populations. The results of our study showed that the Yfiler Plus PCR Amplification Kit marker set provided substantially stronger discriminatory power in the Baloch population of Pakistan and the Hazara population across the Durand-line.

evolutionary biology↗

bioRxiv2020

Genomic Insights into the Demographic History of Southern Chinese

Southern China is the birthplace of rice-cultivating agriculture, different language families, and human migrations that facilitated these cultural diffusions. The fine-scale demographic history in situ, however, remains unclear. To comprehensively cover the genetic diversity in East and Southeast Asia, we generated genome-wide SNP data from 211 present-day Southern Chinese and co-analyzed them with more than 1,200 ancient and modern genomes. We discover that the previously described Southern East Asian or Yangtze River Farmer lineage is monophyletic but not homogeneous, comprising four regionally differentiated sub-ancestries. These ancestries are respectively responsible for the transmission of Austronesian, Kra-Dai, Hmong-Mien, and Austroasiatic languages and their original homelands successively distributed from East to West in Southern China. Multiple phylogenetic analyses support that the earliest living branching among East Asian-related populations is First Americans ([~]27,700 BP), followed by the pre-LGM differentiation between Northern and Southern East Asians ([~]23,400 BP) and the pre-Neolithic split between Coastal and Inland Southern East Asians ([~]16,400 BP). In North China, distinct coastal and inland routes of south-to-north gene flow had established by the Holocene, and further migration and admixture formed the genetic profile of Sinitic speakers by [~]4,000 BP. Four subsequent massive migrations finalized the complete genetic structure of present-day Southern Chinese. First, a southward Sinitic migration and the admixture with Kra-Dai speakers formed the Sinitic Cline. Second, a bi-directional admixture between Hmong-Mien and Kra-Dai speakers gave rise to the Hmong-Mien Cline in the interior of South China between [~]2,000 and [~]1,000 BP. Third, a southwestward migration of Kra-Dai speakers in recent [~]2,000 years impacted the genetic profile for the majority of Mainland Southeast Asians. Finally, an admixture between Tibeto-Burman incomers and indigenous Austroasiatic speakers formed the Tibeto-Burman speakers in Southeast Asia by [~]2,000 BP.

genomics↗