Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of th...Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.展开更多
We performed a genome-wide scan to detect selection signatures that showed evidence of positive selection in the domestication process by re-sequencing the whole genomes of Landrace and Yorkshire pigs.Fifteen annotate...We performed a genome-wide scan to detect selection signatures that showed evidence of positive selection in the domestication process by re-sequencing the whole genomes of Landrace and Yorkshire pigs.Fifteen annotated elements with 13 associated genes were identified using the Z-transformed FST(Z(FST))method,and 208 annotated elements with 140 associated genes were identified using the Z-transformed heterozygosity(ZHp)method.The functional analysis and the results of previous studies showed that most of the candidate genes were associated with basic metabolism,disease resistance,cellular processes,and biochemical signals,and several were related to body morphology and organs.They included PPP3CA,which plays an essential role in the transduction of intracellular Ca2+-mediated signals,and WWTR1,which plays a pivotal role in organ size control and tumor suppression.These results suggest that genes associated with body morphology were subject to selection pressure during domestication,whereas genes involved in basic metabolism and disease resistance were subject to selection during artificial breeding.Our findings provide new insights into the potential genetic variation of phenotypic diversity in different pig breeds and will help to better understand the selection effects of modern breeding in Landrace and Yorkshire pigs.展开更多
BACKGROUND Gastric cancer(GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori(H. pylori) and Epstein-Barr virus(EBV), and genetic components.AIM To investigate microbiomes and host genom...BACKGROUND Gastric cancer(GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori(H. pylori) and Epstein-Barr virus(EBV), and genetic components.AIM To investigate microbiomes and host genome instability by cost-effective,low-coverage wholegenome sequencing,as biomarkers for GC subtyping.METHODS Samples from 40 GC patients were collected from Taizhou Hospital,Zhejiang Province,affiliated with Wenzhou Medical University.DNA from the samples was subjected to low-coverage wholegenome sequencing with a median genome coverage of 1.86×(range:1.03×to 3.17×) by Illumina×10,followed by copy number analyses using a customized bioinformatics workflow ultrasensitive chromosomal aneuploidy detector.RESULTS Of the 40 GC samples,20 (50%) were found to be enriched with microbiomes.EBV DNA was detected in 5 GC patients (12.5%).H.pylori DNA was found in 15 (37.5%) patients.The other 20(50%) patients were found to have relatively higher genomic instability.Copy number amplifications of the oncogenes,ERBB2 and KRAS,were found in 9 (22.5%) and 7 (17.5%) of the GC samples,respectively.EBV enrichment was found to be associated with tumors in the gastric cardia and fundus.H.pylori enrichment was found to be associated with tumors in the pylorus and antrum.Tumors with elevated genomic instability showed no localization and could be observed in any location.Additionally,H.pylori-enriched GC was found to be associated with the Borrmann type Ⅱ/Ⅲ and gastritis history.EBV-enriched GC was not associated with gastritis.No statistically significant correlation was observed between genomic instability and gastritis.Furthermore,these three different molecular subtypes showed distinct survival outcomes (P=0.019).EBV-positive tumors had the best prognosis,whereas patients with high genomic instability (CIN+) showed the worst survival.Patients with H.pylori infection showed intermediate prognosis compared with the other two subtypes.CONCLUSION Thus,using low-coverage whole-genome sequencing,GC can be classified into three categories based on disease etiology;this classification may prove useful for GC diagnosis and precision medicine.展开更多
The common marmoset(Callithrix jacchus)has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies.Epileptic marmosets have been independ...The common marmoset(Callithrix jacchus)has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies.Epileptic marmosets have been independently reported in two Asian primate research centers.Nevertheless,the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated.Here,we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing.We identified 14558184 single nucleotide polymorphisms(SNPs)from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples.Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers.In addition,SNP and copy number variation(CNV)analyses suggested that the WW domain-containing oxidoreductase(WWOX)and Tyrosine-protein phosphatase nonreceptor type 21(PTPN21)genes may be associated with epilepsy in marmosets.Notably,KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets.This study provides valuable population genomic resources for marmosets in two Asian primate centers.Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers,while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.展开更多
The application of microorganisms as probiotics is limited due to lack of safety evaluation.Here,a novel multi-stress-tolerant yeast Meyerozyma guilliermondii GXDK6 with aroma-producing properties was identified from ...The application of microorganisms as probiotics is limited due to lack of safety evaluation.Here,a novel multi-stress-tolerant yeast Meyerozyma guilliermondii GXDK6 with aroma-producing properties was identified from marine mangrove microorganisms.Its safety and probiotic properties were assessed in accordance with phenotype and whole-genome sequencing analysis.Results showed that the genes and phenotypic expression of related virulence,antibiotic resistance and retroelement were rarely found.Hyphal morphogenesis genes(SIT4,HOG1,SPA2,ERK1,ICL1,CST20,HSP104,TPS1,and RHO1)and phospholipase secretion gene(VPS4)were annotated.True hyphae and phospholipase were absent.Only one retroelement(Tad1-65_BG)was found.Major biogenic amines(BAs)encoding genes were absent,except for spermidine synthase(JA9_002594),spermine synthase(JA9_004690),and tyrosine decarboxylase(inx).The production of single BAs and total BAs was far below the food-defined thresholds.GXDK6 had no resistance to common antifungal drugs.Virulence enzymes,such as gelatinase,DNase,hemolytic,lecithinase,and thrombin were absent.Acute toxicity test with mice demonstrated that GXDK6 is safe.GXDK6 has a good reproduction ability in the simulation gastrointestinal tract.GXDK6 also has a strong antioxidant ability,β-glucosidase,and inulinase activity.To sum up,GXDK6 is considered as a safe probiotic for human consumption and food fermentation.展开更多
The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes....The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes.Here,we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis(Chinese sturgeon),a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes.Our results show that A.sinensis is a complex autooctoploid species containing four kinds of octovalents(8n),a hexavalent(6n),two tetravalents(4n),and a divalent(2n).An analysis taking into account delayed rediploidization reveals that the octoploid genome composition of Chinese sturgeon results from two rounds of homologous WGDs,and further provides insights into the timing of its ploidy evolution.This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy compositions and evolutionary trajectories of polyploid fishes.展开更多
Using double-stranded RNA(dsRNA)technology and sequence-independent amplification(SIA),the molecular identification on infected Rehmannia glutinosa in the field with mosaic symptoms was performed and the whole-genome ...Using double-stranded RNA(dsRNA)technology and sequence-independent amplification(SIA),the molecular identification on infected Rehmannia glutinosa in the field with mosaic symptoms was performed and the whole-genome of the Rehmannia mosaic virus(ReMV)Shanxi isolate(ReMV-SX)was sequenced.Sequencing analysis showed that the virus that infected Rehmannia glutinosa was Rehmannia mosaic virus(ReMV).The full-length of the obtained ReMV-SX sequence(GenBank accession no.JX575184)was 6395 nt,containing four open reading frames(ORFs).The sequence homology analysis of the complete nucleotide sequence showed that ReMV-SX was 93.8%-97.0%homologous to ReMV in Tobamovirus subgroup Ⅰ,while only 49.8%-58.9%homologous to the isolates in subgroups Ⅱ and Ⅲ of the same genus.Phylogenetic analysis showed that ReMV-SX and ReMV-Henan formed a separate branch and had the closest genetic relationship.The results laid the foundation for ongoing researches in the taxonomic status and evolution of ReMV and for further investigating the pathogenic mechanism of ReMV infecting Rehmannia glutinosa.展开更多
Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progres...Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.展开更多
Sheep(Ovis aries),among the first domesticated species,are now globally widespread and exhibit remarkable adaptability to diverse environments.In this study,we perform whole-genome sequencing of266 animals from 18 dis...Sheep(Ovis aries),among the first domesticated species,are now globally widespread and exhibit remarkable adaptability to diverse environments.In this study,we perform whole-genome sequencing of266 animals from 18 distinct Chinese sheep populations,each displaying unique phenotypes indicative of adaptation to varying environmental conditions.Integrating 131 environmental factors with single nucleotide polymorphism variations,we conduct a comprehensive genetic-environmental association analysis.This analysis identifies 35 key genes likely integral to the environmental adaptation of sheep.The functions of these genes include fat tail formation(HOXA10,HOXA11,JAZF1),wool characteristics(FER,FGF5,MITF,PDE4B),horn phenotypes(RXFP2),reproduction(HIBADH,TRIM71,C6H4orf22),and growth traits(ADGRL3,TRHDE).Notably,we observe a significant correlation between the frequency of missense mutations in the PAPSS2 and RXFP2 genes and variations in altitude.Our study reveals candidate genes for adaptive variation in sheep and demonstrates the diversity in how sheep adapt to their environment.展开更多
Autism spectrum disorder(ASD)is a neurodevelopmental disorder with high genetic heritability but heterogeneity.Fully understanding its genetics requires whole-genome sequencing(WGS),but the ASD studies utilizing WGS d...Autism spectrum disorder(ASD)is a neurodevelopmental disorder with high genetic heritability but heterogeneity.Fully understanding its genetics requires whole-genome sequencing(WGS),but the ASD studies utilizing WGS data in Chinese population are limited.In this study,we present a WGS study for 334 individuals,including 112 ASD patients and their non-ASD parents.We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions.By integrating these variants with an association model,we identified 33 potential risk genes(P<0.001)enriched in neuron and regulation related biological process.Besides the well-known ASD genes(SCN2A,NF1,SHANK3,CHD8 etc.),several high confidence genes were highlighted by a series of functional analyses,including CTNND1,DGKZ,LRP1,DDN,ZNF483,NR4A2,SMAD6,INTS1,and MRPL12,with more supported evidence from GO enrichment,expression and network analysis.We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression.We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype.Regarding variants in noncoding regions,a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence,which were mapped to specific genes or regulatory features.The number of de novo variants found in patient was significantly associated with the parents’ages at the birth of the child,and gender with trend.We also identified small de novo structural variants in ASD trios.The results in this study provided important evidence for understanding the genetic mechanism of ASD.展开更多
Background Congenital malformations of the female genital tract(CM-FGT)are characterized by abnormal development of the fallopian tubes,uterus,and vagina,often accompanied by malformations in the urinary system,bones ...Background Congenital malformations of the female genital tract(CM-FGT)are characterized by abnormal development of the fallopian tubes,uterus,and vagina,often accompanied by malformations in the urinary system,bones and hearing.However,no definitive pathogenic genes and molecular genetic causes have been identified.Methods We present the largest whole-genome sequencing study of CM-FGT to date,analyzing 590 individuals in China:95 patients,442 case–controls,and 53 familial controls.Results Among the patients,5.3% carried known CM-FGT-related variants.Pedigree and case–control analyses in two dimensions of coding and non-coding regulatory regions revealed seven novel de novo copy number variations,12 rare single-nucleotide variations,and 10 rare 3'untranslated region(UTR)mutations in genes related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.Single-cell sequencing data showed that the majority of CM-FGT-related risk genes are spatiotemporally specifically expressed early in uterus development.Conclusions In conclusion,this study identified novel variants related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.The findings provide insights into the genetic variants underlying CM-FGT,with single-cell sequencing data revealing spatiotemporal specific expression patterns of key risk genes early in uterine development.This study significantly advances the understanding of CM-FGT etiology and genetic landscape,offering new opportunities for prenatal screening.展开更多
Previously we isolated three Fusarium strains(a F.sacchari strain namely GXUF-1,and another two F.commune strains namely GXUF-2 and GXUF-3),and we verified that GXUF-3 was able to cause sugarcane root rot to the chewi...Previously we isolated three Fusarium strains(a F.sacchari strain namely GXUF-1,and another two F.commune strains namely GXUF-2 and GXUF-3),and we verified that GXUF-3 was able to cause sugarcane root rot to the chewing cane cultivar Badila.Considering that Fusarium spp.are a group of widely distributed fungal pathogens,we tested whether these three Fusarium isolates were able to cause root rot to Badila as well as sugar-making cane cultivar(Guitang42),using a suitable inoculation method established based on infection assays using Badila.We found that the three Fusarium strains were able to cause root rot symptoms to both Badila and Guitang42,to different extents.To better investigate the potential pathogenicity mechanisms,we performed Illumina high-throughput sequencing and analyzed the whole genomic sequence data of these three Fusarium strains.The results reveal that the assembly sizes of the three Fusarium strains were in a range of 44.7-48.2 Mb,with G+C contents of 48.0-48.5%,and 14,154-15,175 coding genes.The coding genes were annotated by multiple public databases,and potential pathogenic genes were predicted using proprietary databases(such as PHI,DFVF,CAZy,etc.).Furthermore,based on evolutionary analysis of the coding sequence,we found that contraction and expansion of gene families occurred in the three Fusarium strains.Overall,our results suggest a potential risk that the root rot disease may occur to the sugar-making canes although it was initially spotted from fruit cane,and provide clues to understand the pathogenic mechanisms of Fusarium spp.causing sugarcane root rot.展开更多
The fall armyworm(FAW),Spodoptera frugiperda,is a major pest native to the Americas that has recently invaded the Old World.Point mutations in the target-site proteins acetylcholinesterase-1(ace-1),voltage-gated sodiu...The fall armyworm(FAW),Spodoptera frugiperda,is a major pest native to the Americas that has recently invaded the Old World.Point mutations in the target-site proteins acetylcholinesterase-1(ace-1),voltage-gated sodium channel(VGSC)and ryanodine receptor(RyR)have been identified in S.frugiperda as major resistance mechanisms to organophosphate,pyrethroid and diamide insecticides respectively.Mutations in the adenosine triphosphate-binding cassette transporter C2 gene(ABCC2)have also been identified to confer resistance to Cry IF protein.In this study,we applied a whole-genome sequencing(WGS)approach to identify point mutations in the target-site genes in 150 FAW individuals collected from China,Malawi,Uganda and Brazil.This approach revealed three amino acid substitutions(A201S,G227A and F290V)of S.frugiperda ace-1,which are known to be associated with organophosphate resistance.The Brazilian population had all three ace-1 point mutations and the 227A allele(mean frequency=0.54)was the most common.Populations from China,Malawi and Uganda harbored two of the three ace-1 point mutations(A201S and F290V)with the 290V allele(0.47-0.58)as the dominant allele.Point mutations in VGSC(T929I,L932F and L1014F)and RyR(I4790M and G4946E)were not detected in any of the 150 individuals.A novel 12-bp insertion mutation in exon 15 of the ABCC2 gene was identified in some of the Brazilian individuals but absent in the invasive populations.Our results not only demonstrate robustness of the WGS-based genomic approach for detection of resistance mutations,but also provide insights for improvement of resistance management tactics in S.frugiperda.展开更多
Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant ...Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.展开更多
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) datas...Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P<2.2×10^(-16)) in exonic (1.37×10^(-8)) and 3'-UTR regions (1.42×10^(-8)) was revealed in comparison with that of whole genome (1.05×10^(-8)).Using an integrated model,we identified 87 potentially risk genes (P<0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.展开更多
基金funded by the National Key R&D Program of China [2022YFC2305200]Natural Science Foundation of Xinjiang Uygur Autonomous Region [2021A01D145 and 2022D01A115]Applied Technology Research and Development Programing Project of Kashgar Prefecture [KS2021031 and KS2021034]。
文摘Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.
基金supported by the grants from the Sichuan Science and Technology Program,China(2020YFN0024)the earmarked fund for the China Agriculture Research System(CARS-35-01A)+2 种基金the National Key R&D Program of China(2018YFD0501204)the National Natural Science Foundation of China(C170102)the Sichuan Innovation Team of Pig,China(sccxtd-2021-08)。
文摘We performed a genome-wide scan to detect selection signatures that showed evidence of positive selection in the domestication process by re-sequencing the whole genomes of Landrace and Yorkshire pigs.Fifteen annotated elements with 13 associated genes were identified using the Z-transformed FST(Z(FST))method,and 208 annotated elements with 140 associated genes were identified using the Z-transformed heterozygosity(ZHp)method.The functional analysis and the results of previous studies showed that most of the candidate genes were associated with basic metabolism,disease resistance,cellular processes,and biochemical signals,and several were related to body morphology and organs.They included PPP3CA,which plays an essential role in the transduction of intracellular Ca2+-mediated signals,and WWTR1,which plays a pivotal role in organ size control and tumor suppression.These results suggest that genes associated with body morphology were subject to selection pressure during domestication,whereas genes involved in basic metabolism and disease resistance were subject to selection during artificial breeding.Our findings provide new insights into the potential genetic variation of phenotypic diversity in different pig breeds and will help to better understand the selection effects of modern breeding in Landrace and Yorkshire pigs.
基金Supported by Program of Taizhou Science and Technology Grant,No.20ywb29Medical Health Science and Technology Project of Zhejiang Province,No.2021PY083+2 种基金Key Technology Research and Development Program of Zhejiang Province,No.2019C03040Open Project Program of Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province,No.21SZDSYS01 and 21SZDSYS09Major Research Program of Taizhou Enze Medical Center Grant,No.19EZZDA2
文摘BACKGROUND Gastric cancer(GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori(H. pylori) and Epstein-Barr virus(EBV), and genetic components.AIM To investigate microbiomes and host genome instability by cost-effective,low-coverage wholegenome sequencing,as biomarkers for GC subtyping.METHODS Samples from 40 GC patients were collected from Taizhou Hospital,Zhejiang Province,affiliated with Wenzhou Medical University.DNA from the samples was subjected to low-coverage wholegenome sequencing with a median genome coverage of 1.86×(range:1.03×to 3.17×) by Illumina×10,followed by copy number analyses using a customized bioinformatics workflow ultrasensitive chromosomal aneuploidy detector.RESULTS Of the 40 GC samples,20 (50%) were found to be enriched with microbiomes.EBV DNA was detected in 5 GC patients (12.5%).H.pylori DNA was found in 15 (37.5%) patients.The other 20(50%) patients were found to have relatively higher genomic instability.Copy number amplifications of the oncogenes,ERBB2 and KRAS,were found in 9 (22.5%) and 7 (17.5%) of the GC samples,respectively.EBV enrichment was found to be associated with tumors in the gastric cardia and fundus.H.pylori enrichment was found to be associated with tumors in the pylorus and antrum.Tumors with elevated genomic instability showed no localization and could be observed in any location.Additionally,H.pylori-enriched GC was found to be associated with the Borrmann type Ⅱ/Ⅲ and gastritis history.EBV-enriched GC was not associated with gastritis.No statistically significant correlation was observed between genomic instability and gastritis.Furthermore,these three different molecular subtypes showed distinct survival outcomes (P=0.019).EBV-positive tumors had the best prognosis,whereas patients with high genomic instability (CIN+) showed the worst survival.Patients with H.pylori infection showed intermediate prognosis compared with the other two subtypes.CONCLUSION Thus,using low-coverage whole-genome sequencing,GC can be classified into three categories based on disease etiology;this classification may prove useful for GC diagnosis and precision medicine.
基金supported by the National Natural Science Foundation of China (82001372)National Key Research and Development Program of China (2018YFE0126700)+3 种基金Shanghai Jiao Tong University 2030 Initiative (WH510363001-7)Shanghai Municipal Commission of Science and Technology Program (21dz2210100)Shanghai Education Commission Research and Innovation Program (2019-01-07-00-02-E00037)a National Institutes of Health (NIH)grant (5R01HG002385)to E.E.E。
文摘The common marmoset(Callithrix jacchus)has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies.Epileptic marmosets have been independently reported in two Asian primate research centers.Nevertheless,the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated.Here,we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing.We identified 14558184 single nucleotide polymorphisms(SNPs)from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples.Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers.In addition,SNP and copy number variation(CNV)analyses suggested that the WW domain-containing oxidoreductase(WWOX)and Tyrosine-protein phosphatase nonreceptor type 21(PTPN21)genes may be associated with epilepsy in marmosets.Notably,KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets.This study provides valuable population genomic resources for marmosets in two Asian primate centers.Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers,while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.
基金This research was supported by the Funding Project of Chinese Central Government Guiding to the Guangxi Local Science and Technology Development(GUIKEZY21195021)the Natural Science Fund for Distinguished Young Scholars of Guangxi Zhuang Autonomous Region of China(2019GXNSFFA245011)+3 种基金the Funding Project of Chinese Central Government Guiding to the Nanning Local Science and Technology Development(20231012)the Funding Projects of Guangxi Key Research and Development Plan(GUIKE AB23075173)the Funding Project of Technological Development from Angel Yeast(Chongzuo)Co.,Ltd.(JS1006020230722019)the Innovation Project of Guangxi Graduate Education(YCBZ2021012).
文摘The application of microorganisms as probiotics is limited due to lack of safety evaluation.Here,a novel multi-stress-tolerant yeast Meyerozyma guilliermondii GXDK6 with aroma-producing properties was identified from marine mangrove microorganisms.Its safety and probiotic properties were assessed in accordance with phenotype and whole-genome sequencing analysis.Results showed that the genes and phenotypic expression of related virulence,antibiotic resistance and retroelement were rarely found.Hyphal morphogenesis genes(SIT4,HOG1,SPA2,ERK1,ICL1,CST20,HSP104,TPS1,and RHO1)and phospholipase secretion gene(VPS4)were annotated.True hyphae and phospholipase were absent.Only one retroelement(Tad1-65_BG)was found.Major biogenic amines(BAs)encoding genes were absent,except for spermidine synthase(JA9_002594),spermine synthase(JA9_004690),and tyrosine decarboxylase(inx).The production of single BAs and total BAs was far below the food-defined thresholds.GXDK6 had no resistance to common antifungal drugs.Virulence enzymes,such as gelatinase,DNase,hemolytic,lecithinase,and thrombin were absent.Acute toxicity test with mice demonstrated that GXDK6 is safe.GXDK6 has a good reproduction ability in the simulation gastrointestinal tract.GXDK6 also has a strong antioxidant ability,β-glucosidase,and inulinase activity.To sum up,GXDK6 is considered as a safe probiotic for human consumption and food fermentation.
基金supported by the Three Gorges Environmental Funds of China Three Gorges Corporation(Grant No.XN270)。
文摘The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes.Here,we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis(Chinese sturgeon),a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes.Our results show that A.sinensis is a complex autooctoploid species containing four kinds of octovalents(8n),a hexavalent(6n),two tetravalents(4n),and a divalent(2n).An analysis taking into account delayed rediploidization reveals that the octoploid genome composition of Chinese sturgeon results from two rounds of homologous WGDs,and further provides insights into the timing of its ploidy evolution.This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy compositions and evolutionary trajectories of polyploid fishes.
基金Supported by the National Natural Science Foundation of China(31772130)China Agriculture Research System(CARS-21)。
文摘Using double-stranded RNA(dsRNA)technology and sequence-independent amplification(SIA),the molecular identification on infected Rehmannia glutinosa in the field with mosaic symptoms was performed and the whole-genome of the Rehmannia mosaic virus(ReMV)Shanxi isolate(ReMV-SX)was sequenced.Sequencing analysis showed that the virus that infected Rehmannia glutinosa was Rehmannia mosaic virus(ReMV).The full-length of the obtained ReMV-SX sequence(GenBank accession no.JX575184)was 6395 nt,containing four open reading frames(ORFs).The sequence homology analysis of the complete nucleotide sequence showed that ReMV-SX was 93.8%-97.0%homologous to ReMV in Tobamovirus subgroup Ⅰ,while only 49.8%-58.9%homologous to the isolates in subgroups Ⅱ and Ⅲ of the same genus.Phylogenetic analysis showed that ReMV-SX and ReMV-Henan formed a separate branch and had the closest genetic relationship.The results laid the foundation for ongoing researches in the taxonomic status and evolution of ReMV and for further investigating the pathogenic mechanism of ReMV infecting Rehmannia glutinosa.
文摘Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.
基金supported by the National Natural Science Foundation of China(32222079,31961143021)the earmarked fund for the Modern Agro-industry Technology Research System(CARS-39-01)+1 种基金the Science and Technology Innovation Project of the Chinese Academy of Agricultural Sciences(ASTIP-IAS01)National Key Research and Development Program of China(2022YFF1000104-3)。
文摘Sheep(Ovis aries),among the first domesticated species,are now globally widespread and exhibit remarkable adaptability to diverse environments.In this study,we perform whole-genome sequencing of266 animals from 18 distinct Chinese sheep populations,each displaying unique phenotypes indicative of adaptation to varying environmental conditions.Integrating 131 environmental factors with single nucleotide polymorphism variations,we conduct a comprehensive genetic-environmental association analysis.This analysis identifies 35 key genes likely integral to the environmental adaptation of sheep.The functions of these genes include fat tail formation(HOXA10,HOXA11,JAZF1),wool characteristics(FER,FGF5,MITF,PDE4B),horn phenotypes(RXFP2),reproduction(HIBADH,TRIM71,C6H4orf22),and growth traits(ADGRL3,TRHDE).Notably,we observe a significant correlation between the frequency of missense mutations in the PAPSS2 and RXFP2 genes and variations in altitude.Our study reveals candidate genes for adaptive variation in sheep and demonstrates the diversity in how sheep adapt to their environment.
基金supported by the National Program for Brain Science and Brain-like Intelligence Technology of China (2021ZD0200800)Beijing Municipal Science and Technology Commission (Z181100001518005)+1 种基金the National Natural Science Foundation of China (31401139, 32170613, 81671358, 81873803)the Natural Science Foundation of Beijing Municipality (7232225)
文摘Autism spectrum disorder(ASD)is a neurodevelopmental disorder with high genetic heritability but heterogeneity.Fully understanding its genetics requires whole-genome sequencing(WGS),but the ASD studies utilizing WGS data in Chinese population are limited.In this study,we present a WGS study for 334 individuals,including 112 ASD patients and their non-ASD parents.We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions.By integrating these variants with an association model,we identified 33 potential risk genes(P<0.001)enriched in neuron and regulation related biological process.Besides the well-known ASD genes(SCN2A,NF1,SHANK3,CHD8 etc.),several high confidence genes were highlighted by a series of functional analyses,including CTNND1,DGKZ,LRP1,DDN,ZNF483,NR4A2,SMAD6,INTS1,and MRPL12,with more supported evidence from GO enrichment,expression and network analysis.We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression.We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype.Regarding variants in noncoding regions,a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence,which were mapped to specific genes or regulatory features.The number of de novo variants found in patient was significantly associated with the parents’ages at the birth of the child,and gender with trend.We also identified small de novo structural variants in ASD trios.The results in this study provided important evidence for understanding the genetic mechanism of ASD.
基金The National Key R&D Program of China(2021YFC2701400 and 2021YFC2701404).
文摘Background Congenital malformations of the female genital tract(CM-FGT)are characterized by abnormal development of the fallopian tubes,uterus,and vagina,often accompanied by malformations in the urinary system,bones and hearing.However,no definitive pathogenic genes and molecular genetic causes have been identified.Methods We present the largest whole-genome sequencing study of CM-FGT to date,analyzing 590 individuals in China:95 patients,442 case–controls,and 53 familial controls.Results Among the patients,5.3% carried known CM-FGT-related variants.Pedigree and case–control analyses in two dimensions of coding and non-coding regulatory regions revealed seven novel de novo copy number variations,12 rare single-nucleotide variations,and 10 rare 3'untranslated region(UTR)mutations in genes related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.Single-cell sequencing data showed that the majority of CM-FGT-related risk genes are spatiotemporally specifically expressed early in uterus development.Conclusions In conclusion,this study identified novel variants related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.The findings provide insights into the genetic variants underlying CM-FGT,with single-cell sequencing data revealing spatiotemporal specific expression patterns of key risk genes early in uterine development.This study significantly advances the understanding of CM-FGT etiology and genetic landscape,offering new opportunities for prenatal screening.
基金supported by National Natural Science Foundation of China(U23A20148)Key Projects of Guangzhou Science and Technology Plan(201904020010)。
文摘Previously we isolated three Fusarium strains(a F.sacchari strain namely GXUF-1,and another two F.commune strains namely GXUF-2 and GXUF-3),and we verified that GXUF-3 was able to cause sugarcane root rot to the chewing cane cultivar Badila.Considering that Fusarium spp.are a group of widely distributed fungal pathogens,we tested whether these three Fusarium isolates were able to cause root rot to Badila as well as sugar-making cane cultivar(Guitang42),using a suitable inoculation method established based on infection assays using Badila.We found that the three Fusarium strains were able to cause root rot symptoms to both Badila and Guitang42,to different extents.To better investigate the potential pathogenicity mechanisms,we performed Illumina high-throughput sequencing and analyzed the whole genomic sequence data of these three Fusarium strains.The results reveal that the assembly sizes of the three Fusarium strains were in a range of 44.7-48.2 Mb,with G+C contents of 48.0-48.5%,and 14,154-15,175 coding genes.The coding genes were annotated by multiple public databases,and potential pathogenic genes were predicted using proprietary databases(such as PHI,DFVF,CAZy,etc.).Furthermore,based on evolutionary analysis of the coding sequence,we found that contraction and expansion of gene families occurred in the three Fusarium strains.Overall,our results suggest a potential risk that the root rot disease may occur to the sugar-making canes although it was initially spotted from fruit cane,and provide clues to understand the pathogenic mechanisms of Fusarium spp.causing sugarcane root rot.
基金National Key Research Development Program of China(No.2019YFD0300103 to YW)the Fundamental Research Funds for the Central Universities of China(KYZ201920 to YW).
文摘The fall armyworm(FAW),Spodoptera frugiperda,is a major pest native to the Americas that has recently invaded the Old World.Point mutations in the target-site proteins acetylcholinesterase-1(ace-1),voltage-gated sodium channel(VGSC)and ryanodine receptor(RyR)have been identified in S.frugiperda as major resistance mechanisms to organophosphate,pyrethroid and diamide insecticides respectively.Mutations in the adenosine triphosphate-binding cassette transporter C2 gene(ABCC2)have also been identified to confer resistance to Cry IF protein.In this study,we applied a whole-genome sequencing(WGS)approach to identify point mutations in the target-site genes in 150 FAW individuals collected from China,Malawi,Uganda and Brazil.This approach revealed three amino acid substitutions(A201S,G227A and F290V)of S.frugiperda ace-1,which are known to be associated with organophosphate resistance.The Brazilian population had all three ace-1 point mutations and the 227A allele(mean frequency=0.54)was the most common.Populations from China,Malawi and Uganda harbored two of the three ace-1 point mutations(A201S and F290V)with the 290V allele(0.47-0.58)as the dominant allele.Point mutations in VGSC(T929I,L932F and L1014F)and RyR(I4790M and G4946E)were not detected in any of the 150 individuals.A novel 12-bp insertion mutation in exon 15 of the ABCC2 gene was identified in some of the Brazilian individuals but absent in the invasive populations.Our results not only demonstrate robustness of the WGS-based genomic approach for detection of resistance mutations,but also provide insights for improvement of resistance management tactics in S.frugiperda.
基金supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 and XDB02030002)the Bureau of Frontier Sciences and Education,Chinese Academy of Sciences (QYZDJ-SSW-SMC005)+3 种基金the National Natural Science Foundation of China (Nos. 81088001,81271484,81471361 and 81371480)the Beijing Training Project for the Leading Talents in S & T (Z151100000315020)the National Key Basic Research and Development Program (973) (2012CB517904)the CAS/SAFEA International Partnership Programme for Creative Research Teams (Y2CX131003)
文摘Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.
基金supported by the grants from the Major State Basic Research Development Program of China(2012CB517902 and 2012CB517904)National Key Technology Research and Development Program of China(2012BAI03B00)+3 种基金Special Research Program of National Health and Family Planning Commission of China(201302002)International S&T Cooperation Program of China(2011DFA30670)National Natural Science Foundation of China(31571357/31771404)supported in part by research funding from AstraZeneca Innovation Center China and Wenzhou Medical University
文摘Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P<2.2×10^(-16)) in exonic (1.37×10^(-8)) and 3'-UTR regions (1.42×10^(-8)) was revealed in comparison with that of whole genome (1.05×10^(-8)).Using an integrated model,we identified 87 potentially risk genes (P<0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.