Subtropical evergreen broad-leaved trees are usually vulnerable to freezing stress,while hexaploid wild Camellia oleifera shows strong freezing tolerance.As a valuable genetic resource of woody oil crop C.oleifera,wil...Subtropical evergreen broad-leaved trees are usually vulnerable to freezing stress,while hexaploid wild Camellia oleifera shows strong freezing tolerance.As a valuable genetic resource of woody oil crop C.oleifera,wild C.oleifera can serve as a case for studying the molecular bases of adaptive evolution to freezing stress.Here,47 wild C.oleifera from 11 natural distribution sites in China and 4 relative species of C.oleifera were selected for genome sequencing.“Min Temperature of Coldest Month”(BIO6)had the highest comprehensive contribution to wild C.oleifera distribution.The population genetic structure of wild C.oleifera could be divided into two groups:in cold winter(BIO6≤0℃)and warm winter(BIO6>0℃)areas.Wild C.oleifera in cold winter areas might have experienced stronger selection pressures and population bottlenecks with lower N_(e) than those in warm winter areas.155 singlenucleotide polymorphisms(SNPs)were significantly correlated with the key bioclimatic variables(106 SNPs significantly correlated with BIO6).Twenty key SNPs and 15 key copy number variation regions(CNVRs)were found with genotype differentiation>50%between the two groups of wild C.oleifera.Key SNPs in cis-regulatory elements might affect the expression of key genes associated with freezing tolerance,and they were also found within a CNVR suggesting interactions between them.Some key CNVRs in the exon regions were closely related to the differentially expressed genes under freezing stress.The findings suggest that rich SNPs and CNVRs in polyploid trees may contribute to the adaptive evolution to freezing stress.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,para...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).展开更多
In light of the lack of reliable molecular markers for odontogenic myxoma(OM),the detection of copy number variation(CNV)may present a more objective method for assessing ambiguous cases.In this study,we employed mult...In light of the lack of reliable molecular markers for odontogenic myxoma(OM),the detection of copy number variation(CNV)may present a more objective method for assessing ambiguous cases.In this study,we employed multiregional microdissection sequencing to integrate morphological features with genomic profiling.This allowed us to reveal the CNV profiles of OM and compare them with dental papilla(DP),dental follicle(DF),and odontogenic fibroma(OF)tissues.We identified a distinct and robustly consistent CNV pattern in 93.75%(30/32)of OM cases,characterized by CNV gain events in chromosomes 4,5,8,10,12,16,17,20,and 21.This pattern significantly differed from the CNV patterns observed in DP,DF,and OF.The Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis indicated potential links between this CNV patterns and the calcium signaling pathway and salivary secretion,while Gene Ontology(GO)term analysis implicated CNV patterns in tumor adhesion,tooth development,and cell proliferation.Comprehensive CNV analysis accurately identified a case that was initially disputable between OF and OM as OM.Our findings provide a reliable diagnostic clue and fresh insights into the molecular biological mechanism underlying OM.展开更多
Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of...Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.展开更多
Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphol...Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphological subtypes and the grading system used in lung non-mucinous adenocarcinoma(LNMA).Methods:We developed a whole genome copy number variation(WGCNV)scoring system and applied next generation sequencing to evaluate CNVs present in 91 LNMA tumor samples.Results:Higher histological grades,aggressive subtypes and more advanced TNM staging were associated with an increased WGCNV score,particularly in CNV regions enriched for tumor suppressor genes and oncogenes.In addition,we demonstrate that 24-chromosome CNV profiling can be performed reliably from specific cell types(<100 cells)isolated by sample laser capture microdissection.Conclusions:Our findings suggest that the WGCNV scoring system we developed may have potential value as an adjunct test for predicting the prognosis of patients diagnosed with LNMA.展开更多
Germline copy number variation （CNV） is considered to be an important form of human genetic poly- morphisms. Previous studies have identified amounts of CNVs in human genome by advanced technologies, such as compara...Germline copy number variation （CNV） is considered to be an important form of human genetic poly- morphisms. Previous studies have identified amounts of CNVs in human genome by advanced technologies, such as comparative genomic hybridization, single nucleotide genotyping, and high-throughput sequencing. CNV is speculated to be derived from multiple mechanisms, such as nonallelic homologous recombination （NAHR） and nonhomologous end-joining （NHEJ）. CNVs cover a much larger genome scale than single nucleotide polymorphisms （SNPs）, and may alter gene expression levels by means of gene dosage, gene fusion, gene disruption, and long-range regulation effects, thus affecting individual phenotypes and playing crucial roles in human pathogenesis. The number of studies linking CNVs with common complex diseases has increased dramatically in recent years. Here, we provide a comprehensive review of the current understanding ofgermline CNVs, and summarize the association of germline CNVs with the susceptibility to a wide variety of human diseases that were identified in recent years. We also propose potential issues that should be addressed in future studies.展开更多
In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and t...In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and their evolutionary history remain unclear.We scanned PERVs in the current pig reference genome(assembly Build 11.1),and identified 36 long complete or near-complete PERVs(lc PERVs)and 23 short incomplete PERVs(si PERVs).Besides three known PERVs(PERV-A,-B,and-C),four novel types(PERV-JX1,-JX2,-JX3,and-JX4)were detected in this study.According to evolutionary analyses,the newly discovered PERVs were more ancient,and PERV-Bs probably experienced a bottleneck~0.5 million years ago(Ma).By analyzing63 high-quality porcine whole-genome resequencing data,we found that the PERV copy numbers in Chinese pigs were lower(32.0±4.0)than in Western pigs(49.1±6.5).Additionally,the PERV sequence diversity was lower in Chinese pigs than in Western pigs.Regarding the lc PERV copy numbers,PERV-A and-JX2 in Western pigs were higher than in Chinese pigs.Notably,Bama Xiang(BMX)pigs had the lowest PERV copy number(27.8±5.1),and a BMX individual had no PERV-C and the lowest PERV copy number(23),suggesting that BMX pigs were more suitable for screening and/or modification as xenograft donors.Furthermore,we identified 451 PERV transposon insertion polymorphisms(TIPs),of which 86 were shared by all 10 Chinese and Western pig breeds.Our findings provide systematic insights into the genomic distribution,variation,evolution,and possible biological function of PERVs.展开更多
Copy number variations(CNVs), which can affect the role of long non-coding RNAs(lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between l...Copy number variations(CNVs), which can affect the role of long non-coding RNAs(lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between lncRNAs and prognosis in bladder cancer(BLCA). Messenger RNA(mRNA) expression levels, DNA methylation, and DNA copy number data of 408 BLCA patients were subjected to integrative bioinformatics analysis. Cluster analysis was performed to obtain different subtypes and differently expressed lncRNAs and coding genes. Weighted gene co-expression network analysis(WGCNA) was performed to identify the co-expression gene and lncRNA modules. CNV-associated lncRNA data and their influence on cancer prognosis were assessed with Kaplan-Meier survival curve. Multi-omics integration analysis revealed five prognostic lncRNAs with CNV, namely NR2 F1-AS1, LINC01138, THUMPD3-AS1, LOC101928489, and TMEM147-AS1, and a risk-score signature related to overall survival in BLCA was identified. Moreover, validated results in another independent Gene Expression Omnibus(GEO) dataset, GSE31684, were consistent with these results. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis revealed that the mitogen-activated protein kinase(MAPK) signaling pathway, focal adhesion pathway, and Janus kinase-signal transducers and activators of transcription(JAK-STAT) signaling pathway were enriched in a high-risk score pattern, suggesting that imbalance in these pathways is closely related to tumor development. We revealed the prognosis-related lncRNAs by analyzing the expression profiles of lncRNAs and CNVs, which can be used as prognostic biomarkers for BLCA.展开更多
Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present stu...Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations(CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types,respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.展开更多
AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males ...AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males and 128 females) with chronic hepatitis B virus infection (CHB) and 300 patients (135 females and 165 males) with acute hepatitis B virus infection (AHB) as controls. All CHB patients were further categorized according to disease progression after HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). Copy numbers of the TLR7 gene were measured using the AccuCopy method chi(2) tests were used to evaluate the association between TLR7 CNVs and infection type. P values, odds ratios, and 95% confidence intervals (CIs) were used to estimate the effects of risk. RESULTS Among male patients, there were significant differences between the AHB group and CHB group in the distribution of TLR7 CNVs. Low copy numberof TLR7 was significantly associated with chronic HBV infection (OR = 0.329, 95% CI: 0.229-0.473, P > 0.001). Difference in TLR7 copy number was also found between AHB and CHB female patients, with low copy number again associated with an increased risk of chronic HBV infection (OR = 0.292, 95% CI: 0.173- 0.492, P < 0.001). However, there were no significant differences in TLR7 copy number among the three types of chronic HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). In addition, there was no association between TLR7 copy number and titer of the HBV e antigen. CONCLUSION Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.展开更多
Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify...Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify loci associated with awn length.Bulked-segregant RNA sequencing and linkage mapping identified a single dominant locus in a 0.3 cM interval on chromosome 5AL.Five genes were in the interval,including the recently cloned awn inhibitor B1.Although a single copy of the B1 gene was detected in 7D12,SY20 carried five copies of the gene.Increased copy number of B1 in SY20enhanced gene expression.Based on sequence variation among the promoter regions of five B1 gene copies in SY20,two dominant markers were developed and found to cosegregate with B1 in a population of 931 wheat accessions.All 77 awnless accessions harbored sequence variations in the B1 promoter regions similar to those of SY20 and thus carried multiple copies of the gene,whereas 15 randomly selected awned wheats carried only one copy.These results suggest that an increase in copy number of the B1 gene is associated with inhibition of awn length.展开更多
As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),wh...As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),which focus mainly on the single-nucleotide polymorphisms.Little attention has been paid to examine the role of copy number variations(CNVs)in refractive error and myopia.This study adopted a systematic strategy to investigate the role of CNVs in high myopia.In the discovery phase,a pilot GWAS suggests putative CNVs for follow-up.Multiplex ligation-dependent probe amplification was then used to quantify the copy number of 89 CNV segments in 737 case-control samples in the second phase and then 24 top-ranking CNVs in a second group of 1,029 case-control samples in the final validation phase.This validation phase identified 22 significant CNVs.Further work is needed to examine the role of these few CNVs in myopia development.展开更多
Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent...Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.展开更多
Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laborato...Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laboratory tests,treatment process,and outcomes of three patients with positive cytomegalovirus load detected by CNV-seq for fetal chromosomes and cytomegalovirus load,and literature review was done simutaneoubly.Results:In all three cases,the amniotic fluid cytomegalovirus load was less than 105 Copies/ml,and there were no significant neurological abnormalities observed during pregnancy or postpartum follow-up.There is no literature review on the application of CNV-seq technology in the detection of cytomegalovirus infection,only literature reports on genome analysis of CMV-DNA in confirmed patients were available.Conclusion:CNV-seq can be used to detect cytomegalovirus load,which may have a certain degree of predictive value for fetal outcome.CNV-seq can simultaneously detect fetal chromosomes and pathogenic microorganisms,which is of great significance for the prevention and control of birth defects.展开更多
Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic...Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic and local therapeutic approaches.Using The Cancer Genome Atlas(TCGA),we examined the relationship between copy number variation(CNV)of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1(SMARCC1)and distant metastatic illness in patients with CC.Methods Genetic sequencing data of all relevant CC patients and clinical features were collected from TCGA using R.There were 506 CC patients with CNV and clinical outcome data.The CNV of SMARCC1 was examined for its correlation with distant metastatic disease using the TCGA CC dataset(M1 vs.M0).After adjusting for age,sex,T stage,N stage,adjuvant chemotherapy,microsatellite instability(MSI),and surgical margin status,univariate and multivariate logistic regression analyses were performed.Results SMARCC1 CNV was linked to distant metastatic disease(P=0.012 and 0.008 in univariate and multivariate analysis,respectively);positive lymph nodes and margin status were also associated with distal metastases(all P<0.01).MSI,T stage,N stage,adjuvant treatment,sex,race,and MSI were not associated with metastases(all P>0.05).Conclusion SMARCC1 CNV is associated with distant metastatic disease in patients with CC.In individuals with CC,such genetic profiles might be utilized therapeutically to support optimal systemic treatment options against local treatments for CC,such as radiation therapy,pending additional confirmation.展开更多
Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was th...Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.展开更多
Maize(Zea mays ssp.mays)was domesticated approximately 9,000 years ago from Zea mays ssp.parviglumis,a lowland teosinte native to southwestern Mexico(Matsuoka et al.,2002).From the tropical origin,maize has spread int...Maize(Zea mays ssp.mays)was domesticated approximately 9,000 years ago from Zea mays ssp.parviglumis,a lowland teosinte native to southwestern Mexico(Matsuoka et al.,2002).From the tropical origin,maize has spread into a wide range of temperate regions with high latitudes and altitudes.Flowering time is a critical trait determining plant local adaptation.Several flowering time genes contributing to maize latitudinal adaptation have been identified(Yang et al.,2013;Guo et al.,2018;Huang et al.,2018;Liang et al.,2019;Wu et al.,2023).In contrast,the genetic mechanisms enabling maize adaptation to high-altitude environments remain poorly understood.展开更多
DNA-segment copy number variations(DSCNVs),such as deletions and duplications,are important sources of genomic structural variation.However,the types and sizes of DSCNVs,as well as their genome-wide distribution and p...DNA-segment copy number variations(DSCNVs),such as deletions and duplications,are important sources of genomic structural variation.However,the types and sizes of DSCNVs,as well as their genome-wide distribution and potential functions,are poorly understood in wheat.Here,we identified 198985 DSCNVs by investigating 491 genomes of common wheat and found that they account for 20%of the entire genome.Interestingly,approximately 38%of genes are linked to DSCNVs.The number of DSCNVs within each accession ranges from 47366 to 96342,and their total sizes vary from 421.3 to 1267.9 Mb.We found that 957 and 1304 DSCNVs have been favored by breeders in China and the United States,respectively.By conducting DSCNV-based genome-wide association studies for the principal components of plant developmental and yield-component traits,we identified 34 loci as directly or indirectly involved in controlling the formation of multiple traits.Notably,a newly discovered DSCNV covering TaFT-D1 is significantly associated with flowering time and other agronomic traits.Overall,our findings highlight the potential of DSCNVs to drive fundamental discoveries in plant science.The comprehensive DSCNV map and the DSCNV-associated genes will also facilitate future research efforts to improve wheat yield,quality,and adaptation.展开更多
Background:Single-cell RNA-sequencing(scRNA-seq)has emerged as a powerful tool for cancer research,enabling in-depth characterization of tumor heterogeneity at the single-cell level.Recently,several scRNA-seq copy num...Background:Single-cell RNA-sequencing(scRNA-seq)has emerged as a powerful tool for cancer research,enabling in-depth characterization of tumor heterogeneity at the single-cell level.Recently,several scRNA-seq copy number variation(scCNV)inference methods have been developed,expanding the application of scRNA-seq to study genetic heterogeneity in cancer using transcriptomic data.However,the fidelity of these methods has not been investigated systematically.Methods:We benchmarked five commonly used scCNV inference methods:HoneyBADGER,CopyKAT,CaSpER,inferCNV,and sciCNV.We evaluated their performance across four different scRNA-seq platforms using data from our previous multicenter study.We evaluated scCNV performance further using scRNA-seq datasets derived from mixed samples consisting of five human lung adenocarcinoma cell lines and also sequenced tissues from a small cell lung cancer patient and used the data to validate our findings with a clinical scRNA-seq dataset.Results:We found that the sensitivity and specificity of the five scCNV inference methods varied,depending on the selection of reference data,sequencing depth,and read length.CopyKAT and CaSpER outperformed other methods overall,while inferCNV,sciCNV,and CopyKAT performed better than other methods in subclone identification.We found that batch effects significantly affected the performance of subclone identification in mixed datasets in most methods we tested.Conclusion:Our benchmarking study revealed the strengths and weaknesses of each of these scCNV inference methods and provided guidance for selecting the optimal CNV inference method using scRNA-seq data.展开更多
Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful b...Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.展开更多
基金funded by the National Natural Science Foundation of China(grant no.32270238 and 31870311).
文摘Subtropical evergreen broad-leaved trees are usually vulnerable to freezing stress,while hexaploid wild Camellia oleifera shows strong freezing tolerance.As a valuable genetic resource of woody oil crop C.oleifera,wild C.oleifera can serve as a case for studying the molecular bases of adaptive evolution to freezing stress.Here,47 wild C.oleifera from 11 natural distribution sites in China and 4 relative species of C.oleifera were selected for genome sequencing.“Min Temperature of Coldest Month”(BIO6)had the highest comprehensive contribution to wild C.oleifera distribution.The population genetic structure of wild C.oleifera could be divided into two groups:in cold winter(BIO6≤0℃)and warm winter(BIO6>0℃)areas.Wild C.oleifera in cold winter areas might have experienced stronger selection pressures and population bottlenecks with lower N_(e) than those in warm winter areas.155 singlenucleotide polymorphisms(SNPs)were significantly correlated with the key bioclimatic variables(106 SNPs significantly correlated with BIO6).Twenty key SNPs and 15 key copy number variation regions(CNVRs)were found with genotype differentiation>50%between the two groups of wild C.oleifera.Key SNPs in cis-regulatory elements might affect the expression of key genes associated with freezing tolerance,and they were also found within a CNVR suggesting interactions between them.Some key CNVRs in the exon regions were closely related to the differentially expressed genes under freezing stress.The findings suggest that rich SNPs and CNVRs in polyploid trees may contribute to the adaptive evolution to freezing stress.
文摘Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).
基金supported by the National Natural Science Foundation of China(Nos.81671006 and 81300894)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-038)the Program for New Clinical Techniques and Therapies of Peking University Hospital of Stomatology(No.PKUSSNCT 22A14),China。
文摘In light of the lack of reliable molecular markers for odontogenic myxoma(OM),the detection of copy number variation(CNV)may present a more objective method for assessing ambiguous cases.In this study,we employed multiregional microdissection sequencing to integrate morphological features with genomic profiling.This allowed us to reveal the CNV profiles of OM and compare them with dental papilla(DP),dental follicle(DF),and odontogenic fibroma(OF)tissues.We identified a distinct and robustly consistent CNV pattern in 93.75%(30/32)of OM cases,characterized by CNV gain events in chromosomes 4,5,8,10,12,16,17,20,and 21.This pattern significantly differed from the CNV patterns observed in DP,DF,and OF.The Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis indicated potential links between this CNV patterns and the calcium signaling pathway and salivary secretion,while Gene Ontology(GO)term analysis implicated CNV patterns in tumor adhesion,tooth development,and cell proliferation.Comprehensive CNV analysis accurately identified a case that was initially disputable between OF and OM as OM.Our findings provide a reliable diagnostic clue and fresh insights into the molecular biological mechanism underlying OM.
基金Dongguan City Social Development Project(Project number:20161081101023)。
文摘Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.
基金grants from Beijing Hospital Key Research Program(121 Research Program,No.BJ2019-195)。
文摘Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphological subtypes and the grading system used in lung non-mucinous adenocarcinoma(LNMA).Methods:We developed a whole genome copy number variation(WGCNV)scoring system and applied next generation sequencing to evaluate CNVs present in 91 LNMA tumor samples.Results:Higher histological grades,aggressive subtypes and more advanced TNM staging were associated with an increased WGCNV score,particularly in CNV regions enriched for tumor suppressor genes and oncogenes.In addition,we demonstrate that 24-chromosome CNV profiling can be performed reliably from specific cell types(<100 cells)isolated by sample laser capture microdissection.Conclusions:Our findings suggest that the WGCNV scoring system we developed may have potential value as an adjunct test for predicting the prognosis of patients diagnosed with LNMA.
基金supported by the Basic Research Program of Jiangsu Province (BK20160606)
文摘Germline copy number variation （CNV） is considered to be an important form of human genetic poly- morphisms. Previous studies have identified amounts of CNVs in human genome by advanced technologies, such as comparative genomic hybridization, single nucleotide genotyping, and high-throughput sequencing. CNV is speculated to be derived from multiple mechanisms, such as nonallelic homologous recombination （NAHR） and nonhomologous end-joining （NHEJ）. CNVs cover a much larger genome scale than single nucleotide polymorphisms （SNPs）, and may alter gene expression levels by means of gene dosage, gene fusion, gene disruption, and long-range regulation effects, thus affecting individual phenotypes and playing crucial roles in human pathogenesis. The number of studies linking CNVs with common complex diseases has increased dramatically in recent years. Here, we provide a comprehensive review of the current understanding ofgermline CNVs, and summarize the association of germline CNVs with the susceptibility to a wide variety of human diseases that were identified in recent years. We also propose potential issues that should be addressed in future studies.
基金supported by the National Swine Industry and Technology System of China(nycytx-009)National Natural Science Foundation of China(31672383)。
文摘In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and their evolutionary history remain unclear.We scanned PERVs in the current pig reference genome(assembly Build 11.1),and identified 36 long complete or near-complete PERVs(lc PERVs)and 23 short incomplete PERVs(si PERVs).Besides three known PERVs(PERV-A,-B,and-C),four novel types(PERV-JX1,-JX2,-JX3,and-JX4)were detected in this study.According to evolutionary analyses,the newly discovered PERVs were more ancient,and PERV-Bs probably experienced a bottleneck~0.5 million years ago(Ma).By analyzing63 high-quality porcine whole-genome resequencing data,we found that the PERV copy numbers in Chinese pigs were lower(32.0±4.0)than in Western pigs(49.1±6.5).Additionally,the PERV sequence diversity was lower in Chinese pigs than in Western pigs.Regarding the lc PERV copy numbers,PERV-A and-JX2 in Western pigs were higher than in Chinese pigs.Notably,Bama Xiang(BMX)pigs had the lowest PERV copy number(27.8±5.1),and a BMX individual had no PERV-C and the lowest PERV copy number(23),suggesting that BMX pigs were more suitable for screening and/or modification as xenograft donors.Furthermore,we identified 451 PERV transposon insertion polymorphisms(TIPs),of which 86 were shared by all 10 Chinese and Western pig breeds.Our findings provide systematic insights into the genomic distribution,variation,evolution,and possible biological function of PERVs.
基金supported by the Natural Science Foundation of Guangdong Province (No. 2017A030313898)the Guangzhou Science and Technology Plan Projects (No. 201707010113), China。
文摘Copy number variations(CNVs), which can affect the role of long non-coding RNAs(lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between lncRNAs and prognosis in bladder cancer(BLCA). Messenger RNA(mRNA) expression levels, DNA methylation, and DNA copy number data of 408 BLCA patients were subjected to integrative bioinformatics analysis. Cluster analysis was performed to obtain different subtypes and differently expressed lncRNAs and coding genes. Weighted gene co-expression network analysis(WGCNA) was performed to identify the co-expression gene and lncRNA modules. CNV-associated lncRNA data and their influence on cancer prognosis were assessed with Kaplan-Meier survival curve. Multi-omics integration analysis revealed five prognostic lncRNAs with CNV, namely NR2 F1-AS1, LINC01138, THUMPD3-AS1, LOC101928489, and TMEM147-AS1, and a risk-score signature related to overall survival in BLCA was identified. Moreover, validated results in another independent Gene Expression Omnibus(GEO) dataset, GSE31684, were consistent with these results. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis revealed that the mitogen-activated protein kinase(MAPK) signaling pathway, focal adhesion pathway, and Janus kinase-signal transducers and activators of transcription(JAK-STAT) signaling pathway were enriched in a high-risk score pattern, suggesting that imbalance in these pathways is closely related to tumor development. We revealed the prognosis-related lncRNAs by analyzing the expression profiles of lncRNAs and CNVs, which can be used as prognostic biomarkers for BLCA.
基金supported by grants to HX from University Grants Council(SRF116SC01UROP18SC06+10 种基金UROP20SC07)Innovation and Technology Commission(ITS/085/10ITS113/15FPITCPD/17-9ITT/023/17GPITT/026/18GP)of Hong Kong SARShenzhen Municipal Council of Science and Technology,Guangdong(JCYJ20170818113656988)Guangdong Province Basic and Applied Basic Research Fund(2021A1515011169)Shandong Province First Class Disciple Development Grant and Tai-Shan Scholar Program,Shandongand Ministry of Science and Technology(National Science and Technology Major Project,No.2017ZX09301064,2017ZX09301064004)People’s Republic of China,as well as grants from National Natural Science Foundation of China to M.Q.(8157151623)and J.W.(81603510)。
文摘Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations(CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types,respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.
基金Supportedby National Natural Science Foundation of China,No.81273142
文摘AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males and 128 females) with chronic hepatitis B virus infection (CHB) and 300 patients (135 females and 165 males) with acute hepatitis B virus infection (AHB) as controls. All CHB patients were further categorized according to disease progression after HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). Copy numbers of the TLR7 gene were measured using the AccuCopy method chi(2) tests were used to evaluate the association between TLR7 CNVs and infection type. P values, odds ratios, and 95% confidence intervals (CIs) were used to estimate the effects of risk. RESULTS Among male patients, there were significant differences between the AHB group and CHB group in the distribution of TLR7 CNVs. Low copy numberof TLR7 was significantly associated with chronic HBV infection (OR = 0.329, 95% CI: 0.229-0.473, P > 0.001). Difference in TLR7 copy number was also found between AHB and CHB female patients, with low copy number again associated with an increased risk of chronic HBV infection (OR = 0.292, 95% CI: 0.173- 0.492, P < 0.001). However, there were no significant differences in TLR7 copy number among the three types of chronic HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). In addition, there was no association between TLR7 copy number and titer of the HBV e antigen. CONCLUSION Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.
基金supported by the National Key Research and Development Program of China(2018YFD0300501)。
文摘Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify loci associated with awn length.Bulked-segregant RNA sequencing and linkage mapping identified a single dominant locus in a 0.3 cM interval on chromosome 5AL.Five genes were in the interval,including the recently cloned awn inhibitor B1.Although a single copy of the B1 gene was detected in 7D12,SY20 carried five copies of the gene.Increased copy number of B1 in SY20enhanced gene expression.Based on sequence variation among the promoter regions of five B1 gene copies in SY20,two dominant markers were developed and found to cosegregate with B1 in a population of 931 wheat accessions.All 77 awnless accessions harbored sequence variations in the B1 promoter regions similar to those of SY20 and thus carried multiple copies of the gene,whereas 15 randomly selected awned wheats carried only one copy.These results suggest that an increase in copy number of the B1 gene is associated with inhibition of awn length.
文摘As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),which focus mainly on the single-nucleotide polymorphisms.Little attention has been paid to examine the role of copy number variations(CNVs)in refractive error and myopia.This study adopted a systematic strategy to investigate the role of CNVs in high myopia.In the discovery phase,a pilot GWAS suggests putative CNVs for follow-up.Multiplex ligation-dependent probe amplification was then used to quantify the copy number of 89 CNV segments in 737 case-control samples in the second phase and then 24 top-ranking CNVs in a second group of 1,029 case-control samples in the final validation phase.This validation phase identified 22 significant CNVs.Further work is needed to examine the role of these few CNVs in myopia development.
基金supported by the National Basic Research Program of China(No.2012CB944600)the National Key Research and Development Program of China(No.2016YFC0905100)+1 种基金the National Natural Science Foundation of China(Nos.31521003,31625015,31571297,31601046,31525014 and 91331204)the Science and Technology Commission of Shanghai Municipality(No.16YF1413900)
文摘Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.
基金Hainan Natural Science Foundation(821RC699)Hainan Natural Science Foundation(822RC825)+1 种基金Hainan Provincial Health Industry Research Project(22A200242)Key R&D Plan of Hainan Province(ZDYF2020225)。
文摘Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laboratory tests,treatment process,and outcomes of three patients with positive cytomegalovirus load detected by CNV-seq for fetal chromosomes and cytomegalovirus load,and literature review was done simutaneoubly.Results:In all three cases,the amniotic fluid cytomegalovirus load was less than 105 Copies/ml,and there were no significant neurological abnormalities observed during pregnancy or postpartum follow-up.There is no literature review on the application of CNV-seq technology in the detection of cytomegalovirus infection,only literature reports on genome analysis of CMV-DNA in confirmed patients were available.Conclusion:CNV-seq can be used to detect cytomegalovirus load,which may have a certain degree of predictive value for fetal outcome.CNV-seq can simultaneously detect fetal chromosomes and pathogenic microorganisms,which is of great significance for the prevention and control of birth defects.
基金Supported by a grant from the Joint Project of Southwest Medical University-Three Affiliated Hospitals(No.2017-ZRQN-028).
文摘Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic and local therapeutic approaches.Using The Cancer Genome Atlas(TCGA),we examined the relationship between copy number variation(CNV)of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1(SMARCC1)and distant metastatic illness in patients with CC.Methods Genetic sequencing data of all relevant CC patients and clinical features were collected from TCGA using R.There were 506 CC patients with CNV and clinical outcome data.The CNV of SMARCC1 was examined for its correlation with distant metastatic disease using the TCGA CC dataset(M1 vs.M0).After adjusting for age,sex,T stage,N stage,adjuvant chemotherapy,microsatellite instability(MSI),and surgical margin status,univariate and multivariate logistic regression analyses were performed.Results SMARCC1 CNV was linked to distant metastatic disease(P=0.012 and 0.008 in univariate and multivariate analysis,respectively);positive lymph nodes and margin status were also associated with distal metastases(all P<0.01).MSI,T stage,N stage,adjuvant treatment,sex,race,and MSI were not associated with metastases(all P>0.05).Conclusion SMARCC1 CNV is associated with distant metastatic disease in patients with CC.In individuals with CC,such genetic profiles might be utilized therapeutically to support optimal systemic treatment options against local treatments for CC,such as radiation therapy,pending additional confirmation.
基金Supported in parts by grants from the Swedish Cancer Society(CAN 2010/255),the Swedish Research Council(08712),Tore Nilson Foundation,Assar Gabrielsson Foundation(AB Volvo),Jubileumskliniken Foundation,IngaBritt&Arne Lundberg Research Foundation,Swedish and Gothenburg Medical Societies and the Medical Faculty,University of Gothenburg,VGR 19/00,1019/00.
文摘Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.
基金supported by the National Key Research and Development Program of China(2023YFF1000401)the National Natural Science Foundation of China(32025027),Pinduoduo-China Agricultural University Research Fund(PC2023A01003)+2 种基金New Cornerstone Science Foundation through the XPLORER PRIZE,Hainan Yazhou Bay Seed Laboratory(B21HJ0111)Sanya Yazhouwan Science and Technology City Administration(SYND-2022-26)the Chinese Universities Scientific Fund(2020TC149 and 2022TC138).
文摘Maize(Zea mays ssp.mays)was domesticated approximately 9,000 years ago from Zea mays ssp.parviglumis,a lowland teosinte native to southwestern Mexico(Matsuoka et al.,2002).From the tropical origin,maize has spread into a wide range of temperate regions with high latitudes and altitudes.Flowering time is a critical trait determining plant local adaptation.Several flowering time genes contributing to maize latitudinal adaptation have been identified(Yang et al.,2013;Guo et al.,2018;Huang et al.,2018;Liang et al.,2019;Wu et al.,2023).In contrast,the genetic mechanisms enabling maize adaptation to high-altitude environments remain poorly understood.
基金supported by the National Natural Science Foundation of China(grant nos.31991211,31921005,and 32201745)the Strategic Pri-ority Research Program of the Chinese Academy of Sciences(XDA24010104)+1 种基金the Hainan Seed Industry Laboratory(B23C1000402)the Major Basic Research Program of Shandong Natural Science Foundation(ZR2019ZD15).
文摘DNA-segment copy number variations(DSCNVs),such as deletions and duplications,are important sources of genomic structural variation.However,the types and sizes of DSCNVs,as well as their genome-wide distribution and potential functions,are poorly understood in wheat.Here,we identified 198985 DSCNVs by investigating 491 genomes of common wheat and found that they account for 20%of the entire genome.Interestingly,approximately 38%of genes are linked to DSCNVs.The number of DSCNVs within each accession ranges from 47366 to 96342,and their total sizes vary from 421.3 to 1267.9 Mb.We found that 957 and 1304 DSCNVs have been favored by breeders in China and the United States,respectively.By conducting DSCNV-based genome-wide association studies for the principal components of plant developmental and yield-component traits,we identified 34 loci as directly or indirectly involved in controlling the formation of multiple traits.Notably,a newly discovered DSCNV covering TaFT-D1 is significantly associated with flowering time and other agronomic traits.Overall,our findings highlight the potential of DSCNVs to drive fundamental discoveries in plant science.The comprehensive DSCNV map and the DSCNV-associated genes will also facilitate future research efforts to improve wheat yield,quality,and adaptation.
基金carried out at the LLU Center for Genomics was funded in part by the Ardmore Institute of Health grant 2150141(CW)and Dr.Charles A.Sims’gift to LLU Center for Genomicssupported by the National Center for Biotechnology Information of the National Library of Medicine(NLM),National Institutes of Healt。
文摘Background:Single-cell RNA-sequencing(scRNA-seq)has emerged as a powerful tool for cancer research,enabling in-depth characterization of tumor heterogeneity at the single-cell level.Recently,several scRNA-seq copy number variation(scCNV)inference methods have been developed,expanding the application of scRNA-seq to study genetic heterogeneity in cancer using transcriptomic data.However,the fidelity of these methods has not been investigated systematically.Methods:We benchmarked five commonly used scCNV inference methods:HoneyBADGER,CopyKAT,CaSpER,inferCNV,and sciCNV.We evaluated their performance across four different scRNA-seq platforms using data from our previous multicenter study.We evaluated scCNV performance further using scRNA-seq datasets derived from mixed samples consisting of five human lung adenocarcinoma cell lines and also sequenced tissues from a small cell lung cancer patient and used the data to validate our findings with a clinical scRNA-seq dataset.Results:We found that the sensitivity and specificity of the five scCNV inference methods varied,depending on the selection of reference data,sequencing depth,and read length.CopyKAT and CaSpER outperformed other methods overall,while inferCNV,sciCNV,and CopyKAT performed better than other methods in subclone identification.We found that batch effects significantly affected the performance of subclone identification in mixed datasets in most methods we tested.Conclusion:Our benchmarking study revealed the strengths and weaknesses of each of these scCNV inference methods and provided guidance for selecting the optimal CNV inference method using scRNA-seq data.
基金Beijing Natural Science Foundation(No.7181002)Capital’s Funds for Health Improvement and Research(No.2018-1-1021)National Key Research&Development Program of China(No.2016YFC0901404)
文摘Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.
