RESUMO
Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (â¼39.7%), West Asian (â¼28.6%), Siberian (â¼23.6%), and South Asian (â¼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5, OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR, SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road.
Assuntos
Povo Asiático , Humanos , Masculino , Feminino , Povo Asiático/genética , China , Genoma Humano , Sequenciamento Completo do Genoma , População da Ásia CentralRESUMO
Population admixture results in the combinations of genetic components derived from distinct ancestral populations, which may impact diversity at the genetic, transcriptomic, and phenotypic levels, as well as postadmixture adaptive evolution. Here, we systematically investigated the genomic and transcriptomic diversity in Kazaks, Uyghurs, and Huis-three admixed populations of various Eurasian ancestries living in Xinjiang, China. All three populations showed elevated genetic diversity and closer genetic distance compared with the reference populations across the Eurasian continent. However, we also observed differentiated genomic diversity and inferred different demographic histories among the three populations. Varying ancestry proportions observed in both the global and local aspects corresponded to the population-differentiated genomic diversity, with the most representative signals observed in the genes EDAR, SULT1C4, and SLC24A5. The varying local ancestry partly resulted from the postadmixture local adaptation, with the most significant signals observed in immunity- and metabolism-related pathways. Admixture-shaped genomic diversity further influenced the transcriptomic diversity in the admixed populations; in particular, population-specific regulatory effects were associated with immunity- and metabolism-involved genes such as MTHFR, FCER1G, SDHC, and BDH2. Furthermore, differentially expressed genes between the populations were identified, many of which could be explained by the population-specific regulatory properties, including genes related to health concerns (e.g., AHI1 between Kazak and Uyghurs [P < 6.92 × 10-5] and CTRC between Huis and Uyghurs [P < 2.32 × 10-4]). Our results demonstrate genetic admixture as a driving force in shaping the genomic and transcriptomic diversity of human populations.
Assuntos
Genética Populacional , Transcriptoma , Humanos , Genômica , Hidroxibutirato Desidrogenase/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10(-10)) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10(-8)). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10(-11)) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.
Assuntos
Sobrancelhas/crescimento & desenvolvimento , Loci Gênicos/genética , Fenótipo , Sistemas CRISPR-Cas/genética , Cromossomos Humanos/genética , Fatores de Transcrição Forkhead/genética , Edição de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXB1/genética , Seleção GenéticaRESUMO
The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose â¼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to â¼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese â¼15,000 to â¼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of â¼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (â¼82%), Central Asia and Siberia (â¼11%), South Asia (â¼6%), and western Eurasia and Oceania (â¼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.
Assuntos
Povo Asiático/genética , Fluxo Gênico/genética , Genoma Humano/genética , Filogenia , Altitude , Animais , China/etnologia , Etnicidade/genética , Pool Gênico , Genética Populacional , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Genéticos , Homem de Neandertal/genética , Oceania/etnologia , Seleção Genética , TibetRESUMO
BACKGROUND: This study aims to investigate the molecular mechanism of Adenovirus type 36 (Ad36) in adipocyte differentiation and glucolipid metabolism. METHODS: Rat obesity model was established by Ad36 infection and high-fat diet, respectively. Comparison of the body weight, clinical biochemical indicators, insulin sensitivity and lipid heterotopic deposition between these two models was performed. Ad36-induced adipocyte in vitro model was also established. The binding rate of FoxO1, PPARγ and its target gene promoter was detected using ChIP. The mRNA and protein expression levels of PPARγ and downstream target genes were detected by RT-PCR and Western blot, respectively. Oil red O staining was used to measure differentiation into adipocyte. Wortmannin (WM), inhibitor of PI3K, was used to act on Ad36-induced hADSCs. RESULTS: Ad36-induced obese rats did not exhibit disorders in blood glucose and blood TG, insulin resistance and lipid ectopic deposition. The expression of Adipoq, Lpin1 and Glut4 in the adipose tissue increased. Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. During this process, the binding rate of FoxO1 and PPARγ promoter regions was weakened. However, the binding rate of the transcription factor PPARγ to its target genes Acc, Adipoq, Lpin1 and Glut4 was enhanced, and thus increased the protein expression of P-FoxO1, PPARγ2, ACC, LPIN1, GLUT4 and ADIPOQ. The PI3K inhibitor Wortmannin reduced the expression of P-Akt, P-FoxO1 and PPARγ2, thereby inhibiting adipogenesis of hADSC. CONCLUSION: Ad36 may promote fatty acid and triglyceride synthesis, and improve insulin sensitivity by affecting the PI3K/Akt/FoxO1/PPARγ signaling pathway.
Assuntos
Tecido Adiposo/metabolismo , Obesidade/genética , PPAR gama/genética , Células-Tronco/citologia , Adipócitos/metabolismo , Adipócitos/virologia , Adiponectina/genética , Tecido Adiposo/citologia , Tecido Adiposo/virologia , Animais , Diferenciação Celular/genética , Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica no Desenvolvimento , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Humanos , Metabolismo dos Lipídeos/genética , Obesidade/metabolismo , Obesidade/patologia , Obesidade/virologia , Fosfatidato Fosfatase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/virologia , Wortmanina/administração & dosagemRESUMO
The Uyghur people residing in Xinjiang, a territory located in the far west of China and crossed by the Silk Road, are a key ethnic group for understanding the history of human dispersion in Eurasia. Here we assessed the genetic structure and ancestry of 951 Xinjiang's Uyghurs (XJU) representing 14 geographical subpopulations. We observed a southwest and northeast differentiation within XJU, which was likely shaped jointly by the Tianshan Mountains, which traverses from east to west as a natural barrier, and gene flow from both east and west directions. In XJU, we identified four major ancestral components that were potentially derived from two earlier admixed groups: one from the West, harboring European (25-37%) and South Asian ancestries (12-20%), and the other from the East, with Siberian (15-17%) and East Asian (29-47%) ancestries. By using a newly developed method, MultiWaver, the complex admixture history of XJU was modeled as a two-wave admixture. An ancient wave was dated back to â¼3,750 years ago (ya), which is much earlier than that estimated by previous studies, but fits within the range of dating of mummies that exhibited European features that were discovered in the Tarim basin, which is situated in southern Xinjiang (4,000-2,000 ya); a more recent wave occurred around 750 ya, which is in agreement with the estimate from a recent study using other methods. We unveiled a more complex scenario of ancestral origins and admixture history in XJU than previously reported, which further suggests Bronze Age massive migrations in Eurasia and East-West contacts across the Silk Road.
Assuntos
Povo Asiático/genética , Etnicidade/genética , Genética Populacional/métodos , China/etnologia , Fluxo Gênico , Geografia , Haplótipos/genética , Humanos , Filogeografia , Polimorfismo de Nucleotídeo Único/genética , População Branca/genéticaRESUMO
Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.
Assuntos
Adaptação Biológica/genética , Altitude , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Variações do Número de Cópias de DNA/genética , Etnicidade/genética , Evolução Molecular , Hominidae/genética , Algoritmos , Animais , Sequência de Bases , Genética Populacional , Hemoglobinas/genética , Hemoglobinas/metabolismo , Humanos , Desequilíbrio de Ligação , Análise em Microsséries/métodos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA , TibetRESUMO
AIMS: To determine the role of lncRNA HOXA11-AS1 on adipocyte differentiation. METHODS: Human adipose-derived stem cells (hADSCs) were isolated from adipose tissues of patients and cultured in vitro, followed by knockdown of HOXA11-AS1. Then, adipocyte differentiation and expression of adipogenic-related genes (CEBP-α, DGAT2, CIDEC, and perilipin) were measured by RT-qPCR and Western blot. RESULTS: We demonstrated that knockdown of HOXA11-AS1 inhibited adipocyte differentiation, leading to suppression of adipogenic-related gene (CEBP-α, DGAT2, CIDEC, and perilipin) transcription, as well as decreased lipid accumulation in hADSCs. In addition, lncRNA HOXA11-AS1 was highly expressed in obese patients and significantly increased during the process of adipocyte differentiation. CONCLUSION: The results provide new insight into the molecular mechanism by which lncRNA HOXA11-AS1 is involved in adipogenesis and may have implications for the treatment of obesity and associated disorders.
Assuntos
Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Obesidade/metabolismo , RNA Longo não Codificante/metabolismo , Células-Tronco/fisiologia , Adipócitos/patologia , Tecido Adiposo/patologia , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Células-Tronco/patologiaRESUMO
This study is to investigate the role of adenovirus 36 (Ad36) in regulating expression of peroxisome proliferator-activated receptor γ (PPARγ) and cell death-inducing DFFA-like effector c (CIDEC) in Ad36-induced adipocyte differentiation. Human adipose-derived mesenchymal stem cells (hAMSCs) were isolated and cultured, and then infected with Ad36. Ad36-induced adipocytes were identified using quantitative real-time PCR and Oil red O staining. The expression levels of PPARγ and CIDEC in Ad36-induced adipocytes were determined by quantitative real-time PCR and Western blot analysis. Glucose uptake and intracellular triglyceride content were also determined in these induced cells. Our results from the Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. Moreover, the medium glucose concentration was significantly decreased, while the intracellular triglyceride content was significantly increased, in the Ad36-induced adipocytes, compared with the control group. Furthermore, our results showed that, the mRNA and protein expression levels of PPARγ and CIDEC were significantly upregulated in Ad36-induced adipocytes, in a time-dependent manner. On the other hand, compared with the control group, the CIDEC expression was downregulated when the Ad36-induced adipocytes were treated with the PPARγ inhibitor, GW9662. Ad36 could upregulate the expression level of CIDEC through increasing PPARγ expression during the adipocyte differentiation process.
Assuntos
Adenoviridae/fisiologia , Adipócitos/citologia , Células-Tronco Mesenquimais/virologia , PPAR gama/genética , Proteínas/genética , Adipócitos/metabolismo , Adipócitos/virologia , Anilidas/farmacologia , Proteínas Reguladoras de Apoptose , Diferenciação Celular , Células Cultivadas , Glucose/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , PPAR gama/metabolismo , Proteínas/metabolismo , Fatores de Tempo , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 × 10 (-6) ) and type of chin (P = 9.23 × 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 × 10 (-7) ), double incisors shoveling (P = 1.86 × 10 (-12) ) and hair straightness (P = 3.99 × 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution.
Assuntos
Povo Asiático/genética , Etnicidade/genética , Fácies , Receptores da Ectodisplasina/genética , População Branca/genética , Adolescente , Adulto , Alelos , China , Feminino , Humanos , Masculino , Fenótipo , Adulto JovemRESUMO
Hair straightness/curliness is one of the most conspicuous features of human variation and is particularly diverse among populations. A recent genome-wide scan found common variants in the Trichohyalin (TCHH) gene that are associated with hair straightness in Europeans, but different genes might affect this phenotype in other populations. By sampling 2899 Han Chinese, we performed the first genome-wide scan of hair straightness in East Asians, and found EDAR (rs3827760) as the predominant gene (P = 4.67 × 10-16), accounting for 3.66 % of the total variance. The candidate gene approach did not find further significant associations, suggesting that hair straightness may be affected by a large number of genes with subtle effects. Notably, genetic variants associated with hair straightness in Europeans are generally low in frequency in Han Chinese, and vice versa. To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 × 10-12) and TCHH (rs11803731: P = 1.46 × 10-3) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). We found no significant interaction between EDAR and TCHH (P = 0.645), suggesting that these two genes affect hair straightness through different mechanisms. Furthermore, haplotype analysis indicates that TCHH is not subject to selection. While EDAR is under strong selection in East Asia, it does not appear to be subject to selection after the admixture in Uyghurs. These suggest that hair straightness is unlikely a trait under selection.
Assuntos
Antígenos/genética , Receptor Edar/genética , Estudo de Associação Genômica Ampla , Cabelo , Proteínas de Filamentos Intermediários/genética , Povo Asiático/genética , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Cabelo/ultraestrutura , Haplótipos , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Over the last decade, a larger number of type 2 diabetes mellitus (T2DM) susceptible candidate genes have been reported by numerous genome-wide association studies (GWAS). Understanding the genetic diversity of these candidate genes among worldwide populations not only facilitates to elucidating the genetic mechanism of T2DM, but also provides guidance to further studies of pathogenesis of T2DM in any certain population. In this study, we identified 170 genes or genomic regions associated with T2DM by searching the GWAS databases and related literatures. We next analyzed the genetic diversity of these genes (or genomic regions) among present-day human populations by curetting the 1000 Genomes Projects phase1 dataset covering 14 worldwide populations. We further compared the characteristics of T2DM genes in different populations. No significant differences of genetic diversity were observed among the 14 worldwide populations between the T2DM candidate genes and the non-T2DM genes in terms of overall pattern. However, we observed some genes, such as IL20RA, RNMTL1-NXN, NOTCH2, ADRA2A-BTBD7P2, TBC1D4, RBM38-HMGB1P1, UBE2E2, and PPARD, show considerable differentiation between populations. In particular, IL20RA (FST=0.1521) displays the greatest population difference which is mainly contributed by that between Africans and non-Africans. Moreover, we revealed genetic differences between East Asians and Europeans on some candidate genes such as DGKB-AGMO (FST=0.173) and JAZF1 (FST=0.182). Our results indicate that some T2DM susceptible candidate genes harbor highly-differentiated variants between populations. These analyses, despite preliminary, should advance our understanding of the population difference of susceptibility to T2DM and provide insightful reference that future studies can relay on.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , África , Povo Asiático/genética , Europa (Continente) , Estudo de Associação Genômica Ampla/métodos , Genótipo , HumanosRESUMO
OBJECTIVE: To extract exosomes from obese and non-obese mice, screen specifically expressed microRNAs by high-throughput sequencing and explore their roles. METHODS: An animal obesity model was constructed, and the successful construction of the obesity model was verified by HE staining, Western Blot and RT-qPCR. In addition, exosomes were extracted and verified by Western Blot. High-throughput sequencing was performed on the extracted serum exosomes to screen for differentially expressed microRNAs. fluorescence quantitative RT-PCR (RT-qPCR) was used to validate the differentially expressed miRNAs and explore their functions. RESULTS: 8 microRNAs were up-regulated and 11 microRNAs were down-regulated. mmu-miR-674-5p and X_28316 were significantly down-regulated and had the greatest impact on protein pathways. 8_13258 was significantly up-regulated and affected multiple protein pathways. GO enrichment analysis suggested that the differentially expressed microRNAs were mainly involved in the cleavage of microtubule activity, transferase activity/transferase pentameric acid. GO enrichment analysis suggested that differentially expressed microRNAs were mainly involved in the processes of cleavage microtubule activity, transferase activity/transfer pentamer, and threonine phosphatase/threonine kinase activity.KEGG pathway enrichment analysis showed that differentially expressed microRNAs were mainly involved in the processes of regulating the phosphorylation of TP53 activity, the G2/M DNA damage checkpoint, and the processing of the ends of DNA double-strand breaks. Protein interaction networks were enriched for Stat3, Fgr, Camk2b, Rac1, Asb6, and Ankfy1. Suggesting that they may be mediated by differential genes to participate in the process of insulin resistance. qRT-PCR results showed that the expression trend of mmu-miR-674-5p was consistent with the sequencing results. It suggests that it may be able to participate in the regulation of insulin resistance as a target gene. CONCLUSION: microRNAs were differentially expressed in serum exosomes of obese and non-obese mice and might be involved in the specific regulation of insulin resistance. mmu-miR-674-5p was differentially expressed significantly and the validation trend was consistent with it, suggesting that it might be able to participate in the regulation of insulin resistance as a target gene.
Assuntos
Exossomos , MicroRNAs , Obesidade , Animais , Exossomos/metabolismo , Exossomos/genética , Camundongos , MicroRNAs/genética , MicroRNAs/sangue , Obesidade/genética , Obesidade/sangue , Obesidade/metabolismo , Masculino , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos Obesos , Perfilação da Expressão Gênica/métodos , Camundongos Endogâmicos C57BL , Regulação da Expressão Gênica , Modelos Animais de DoençasRESUMO
Tick-borne microorganisms in many tick species and many areas of China are still not thoroughly investigated. In this study, 224 ticks including two species (Haemaphysalis longicornis and Haemaphysalis qinghaiensis) were collected from four cities in Hebei, Shandong, and Qinghai provinces, China. Ticks were screened for the presence of tick-borne bacterial microorganisms including Rickettsia, Anaplasmataceae (Anaplasma, Ehrlichia, Neoehrlichia, etc.), Coxiella, Borrelia, and Bartonella. Two Anaplasma species (Anaplasma ovis and Anaplasma capra) were detected in H. longicornis from Xingtai City of Hebei Province, with a positive rate of 3 % and 8 %, respectively. A Coxiella species was detected in H. longicornis ticks from all three locations in Hebei and Shandong provinces, with the positive rate ranging from 30 to 75 %. All the 16S and rpoB sequences were very similar (99.77-100 % identity) to Coxiella endosymbiont of Haemaphysalis ticks. An Ehrlichia species was detected in H. qinghaiensis (6/66, 9 %) from Xining City, Qinghai Province. The 16S and groEL sequences had 100 % and 97.40-97.85 % nucleotide identities to "Candidatus Ehrlichia pampeana" strains, respectively, suggesting that it may be a variant of "Candidatus Ehrlichia pampeana". All the ticks were negative for Rickettsia, Borrelia, and Bartonella. Because all the ticks were removed from goats or humans and were partially or fully engorged, it is possible that the microorganisms were from the blood meal but not vectored by the ticks. Our results may provide some information on the diversity and distribution of tick-borne pathogens in China.
Assuntos
Anaplasmataceae , Bartonella , Borrelia , Ixodidae , Rickettsia , Doenças Transmitidas por Carrapatos , Carrapatos , Animais , Humanos , Carrapatos/microbiologia , Ixodidae/microbiologia , Rickettsia/genética , Anaplasma/genética , Ehrlichia/genética , Bartonella/genética , Anaplasmataceae/genética , Borrelia/genética , Cabras , China/epidemiologia , Doenças Transmitidas por Carrapatos/epidemiologia , Doenças Transmitidas por Carrapatos/veterinária , Doenças Transmitidas por Carrapatos/microbiologiaRESUMO
LIMA1 is a LIM domain and Actin binding 1 protein that acts as a skeleton protein to promote cholesterol absorption, which makes it an ideal target for interfering with lipid metabolism. However, the detailed regulation of LIMA1 remains unclear. Here, we identified that ring finger protein 40 (RNF40), an E3 ubiquitin ligase previously known as an epigenetic modifier to increase H2B ubiquitination, mediated the ubiquitination of LIMA1 and thereby promoted its degradation in a proteasome-dependent manner. Fraction studies revealed that the 1-166aa fragment of LIMA1 was indispensable for the interaction with RNF40, and at least two domains of RNF40 might mediate the association of RNF40 with LIMA1. Notably, treatment with simvastatin dramatically decreased the levels of CHO and TG in control cells rather than cells with overexpressed LIMA1. Moreover, RNF40 significantly decreased lipid content, which could be reversed by LIMA1 overexpression. These findings suggest that E3 ubiquitin ligase RNF40 could directly target LIMA1 and promote its protein degradation in cytoplasm, leading to the suppression of lipid accumulation mediated by LIMA1. Collectively, this study unveils that RNF40 is a novel E3 ubiquitin ligase of LIMA1, which underpins its high therapeutic value to combat dysregulation of lipid metabolism.
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Background: The blood-feeding behavior of kissing bugs (subfamily Triatominae, family Reduviidae, order Hemiptera) means they are potential vectors of multiple humans pathogens. However, investigations of vector-borne pathogens harbored by kissing bugs are rare. Methods: In the current study, 22 adult kissing bugs (Triatoma rubrofasciata) were captured in Huizhou City, Guangdong Province, south China. The presence of vector-borne pathogens in the kissing bugs was tested, and the genetic diversity of these potential pathogens was investigated. Results: All the kissing bugs were negative for Anaplasmataceae bacteria, Rickettsia, and Coxiella. Bartonella DNA was detected in 36.4% (8/22) of the kissing bugs. The sequences of the Bartonella gltA genes divided into two clades in a phylogenetic tree, with close relationships to B. tribocorum and uncultured Bartonella sp. clone MYR-283, respectively. All the groEL sequences were closely related to those of B. kosoyi (identity 98.75%-100%). The ftsZ and rpoB sequences were most closely related to those of B. elizabethae, a recognized human pathogen, with nucleotide similarities of 98.70%-100% and 99.45%-100%, respectively. Conclusions: We report the detection of Bartonella DNA in Triatoma kissing bugs in southern China. Although the sample size is limited, the high positive rate of detection of Bartonella DNA, the close relationship of the gene sequences to those of zoonotic Bartonella species, and the distribution of the kissing bugs near human residences, hint at a risk to public health.
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It remains unknown and debatable how European-Asian-differentiated alleles affect individual phenotypes. Here, we made the first effort to analyze the expression profiles of highly differentiated genes with eastern and western origins in 90 Uyghurs using whole-genome (30× to 60×) and transcriptome data. We screened 921 872 east-west highly differentiated genetic variants, of which â¼4.32% were expression quantitative trait loci (eQTLs), â¼0.12% were alternative splicing quantitative trait loci (sQTLs), and â¼0.12% showed allele-specific expression (ASE). The 8305 highly differentiated eQTLs of strong effects appear to have undergone natural selection, associated with immunity and metabolism. European-origin alleles tend to be more biasedly expressed; highly differentiated ASEs were enriched in diabetes-associated genes, likely affecting the diabetes susceptibility in the Uyghurs. We proposed an admixture-induced expression model to dissect the highly differentiated expression profiles. We provide new insights into the genetic basis of phenotypic differentiation between Western and Eastern populations, advancing our understanding of the impact of genetic admixture.
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Background: Major depressive disorder is a frequent mental illness, which is common in patients with type 2 diabetes. Type 2 diabetes comorbid with depression has a worse prognosis. There are multiple risk factors for depression, and genetic studies have shown that gene polymorphism may play an important role in the pathogenesis of depression. Methods: A total of 874 patients with type 2 diabetes were recruited for this study and divided into two groups: depressive group (DDM group, n = 234) and non-depressive group (NDDM group, n = 640). HTR1A gene polymorphisms (rs6295, rs878567, rs1800044) genotyping work was performed using a custom by design 48-Plex SNPscanTM Kit. Results: The rs6295, rs878567, and rs1800044 SNPs were not associated with type 2 diabetes comorbid with depression. Female sex, age, and FBG level increased the risk of depression in patients with type 2 diabetes. Conclusion: HTR1A rs6295, rs878567, and rs1800044 SNPs polymorphism is not associated with type 2 diabetes comorbid with depression. Rather, female sex, age, and FBG level are risk factors for depression among patients with type 2 diabetes. Larger studies are needed to further confirm our findings.
RESUMO
BACKGROUND: Impaired glucose regulation (IGR) represents the prediabetic state and is associated with gut microbiota (GM) dysbiosis and chronic inflammation. Tangning Ziyabitusi Tablet (TZT) is a Chinese Uyghur herbal medicine with preventative and therapeutic effects on diabetes, but its hypoglycemic mechanisms are unclear. METHODS: Thirty-six male Wistar rats were divided into the normal diet (ND) and IGR groups. The IGR group was given a high-fat diet (HFD). After the IGR model establishment, the ND group was divided into ND and ND+TZT groups, and the IGR group into IGR and IGR+TZT groups. After 8 weeks of TZT administration, 16S rRNA sequencing and untargeted metabolomics were performed on fecal samples. Mesenteric lymph nodes were also collected, and T lymphocytes separated after rats were sacrificed. Flow cytometry was used to characterize different CD4+ T cell subsets in mesenteric lymph nodes. Finally, we analyzed the correlation between GM and characteristic fecal metabolites. RESULTS: Impaired glucose tolerance and insulin resistance were improved in the IGR+TZT group when compared with the IGR group. Bacterial 16S rRNA sequencing results showed that Sobs and Chao1 indices in the IGR group were significantly decreased, but were increased in the IGR+TZT group. The relative abundance of Bacteroidetes was decreased while the relative abundance of Firmicutes was increased in the IGR group. Adlercreutzia abundance was decreased after TZT administration, while the abundance of Christensenellaceae_R-7_group, norank_f_norank_o_Clostridia_UCG-014, UCG-005, and Eubacterium_nodatum_group was increased in the IGR+TZT group. Lymph node CD4+ T cell proportions in the IGR group were significantly increased, while they were significantly decreased in the IGR+TZT group. Correlation analysis showed that tumor necrosis factor-α, interleukin-6, T helper cells (Th1, Th2, Treg), and insulin had a greater impact on GM community structure. CONCLUSIONS: TZT improved glucose tolerance and ameliorated GM dysbiosis in IGR rats. Additionally, TZT significantly modulated CD4+ T cell subset proportions in rat mesenteric lymph nodes and fecal metabolism. Moreover, correlation analysis showed that key microbiota was closely related to IGR indices. Thus, TZT modulated GM composition and immune functions of the intestinal mucosa. We provide useful information for the investigation of active mechanisms and the clinical application of TZT.
Assuntos
Microbioma Gastrointestinal , Insulinas , Animais , Disbiose/microbiologia , Glucose/farmacologia , Hipoglicemiantes/farmacologia , Insulinas/farmacologia , Insulinas/uso terapêutico , Interleucina-6 , Masculino , RNA Ribossômico 16S/genética , Ratos , Ratos Wistar , Subpopulações de Linfócitos T/metabolismo , Comprimidos/farmacologia , Comprimidos/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
Population admixture results in genome-wide combinations of genetic variants derived from different ancestral populations of distinct ancestry, thus providing a unique opportunity for understanding the genetic determinants of phenotypic variation in humans. Here, we used whole-genome sequencing of 92 individuals with high coverage (30-60×) to systematically investigate genomic diversity in the Uyghurs living in Xinjiang, China (XJU), an admixed population of both European-like and East-Asian-like ancestry. The XJU population shows greater genetic diversity, especially a higher proportion of rare variants, compared with their ancestral source populations, corresponding to greater phenotypic diversity of XJU. Admixture-induced functional variants in EDAR were associated with the diversity of facial morphology in XJU. Interestingly, the interaction of functional variants between SLC24A5 and OCA2 likely influences the diversity of skin pigmentation. Notably, selection has seemingly been relaxed or canceled in several genes with significantly biased ancestry, such as HERC2-OCA2. Moreover, signatures of post-admixture adaptation in XJU were identified, including genes related to metabolism (e.g. CYP2D6), digestion (e.g. COL11A1), olfactory perception (e.g. ANO2) and immunity (e.g. HLA). Our results demonstrated population admixture as a driving force, locally or globally, in shaping human genetic and phenotypic diversity as well as in adaptive evolution.