Background A gap currently exists between genetic variants and the underlying cell and tissue biology of a trait,and expression quantitative trait loci(eQTL)studies provide important information to help close that gap...Background A gap currently exists between genetic variants and the underlying cell and tissue biology of a trait,and expression quantitative trait loci(eQTL)studies provide important information to help close that gap.However,two concerns that arise with eQTL analyses using RNA-sequencing data are normalization of data across samples and the data not following a normal distribution.Multiple pipelines have been suggested to address this.For instance,the most recent analysis of the human and farm Genotype-Tissue Expression(GTEx)project proposes using trimmed means of M-values(TMM)to normalize the data followed by an inverse normal transformation.Results In this study,we reasoned that eQTL analysis could be carried out using the same framework used for dif-ferential gene expression(DGE),which uses a negative binomial model,a statistical test feasible for count data.Using the GTEx framework,we identified 35 significant eQTLs(P<5×10^(–8))following the ANOVA model and 39 significant eQTLs(P<5×10^(–8))following the additive model.Using a differential gene expression framework,we identified 930 and six significant eQTLs(P<5×10^(–8))following an analytical framework equivalent to the ANOVA and additive model,respectively.When we compared the two approaches,there was no overlap of significant eQTLs between the two frameworks.Because we defined specific contrasts,we identified trans eQTLs that more closely resembled what we expect from genetic variants showing complete dominance between alleles.Yet,these were not identified by the GTEx framework.Conclusions Our results show that transforming RNA-sequencing data to fit a normal distribution prior to eQTL analysis is not required when the DGE framework is employed.Our proposed approach detected biologically relevant variants that otherwise would not have been identified due to data transformation to fit a normal distribution.展开更多
Tobacco(Nicotiana tabacum,2n=48)is a key non-food economic crop,yet its stress response and gene regulatory mechanisms remain poorly understood.By analyzing 603 transcriptome datasets,this study identified 1405 tissue...Tobacco(Nicotiana tabacum,2n=48)is a key non-food economic crop,yet its stress response and gene regulatory mechanisms remain poorly understood.By analyzing 603 transcriptome datasets,this study identified 1405 tissue-specific genes,revealing tissue-specific synthesis of terpenoids and other ecologically important secondary metabolites in sepals and other tissues.Comparative stress-response analysis highlighted distinct gene expression patterns in leaves and roots under biotic and abiotic stresses.Additionally,28,396 expression quantitative trait loci(eQTLs)were mapped in leaves,offering valuable genetic regulatory markers.These findings provide crucial insights into tobacco’s gene expression characteristics and their functional implications,serving as a foundation for future research.展开更多
A detailed understanding of genetic architecture of mRNA expression by millions of genetic variants is important for studying quantitative trait variation. In this study, we identified 1.25M SNPs with a minor allele f...A detailed understanding of genetic architecture of mRNA expression by millions of genetic variants is important for studying quantitative trait variation. In this study, we identified 1.25M SNPs with a minor allele frequency greater than 0.05 by combining reduced genome sequencing （GBS）, high- density array technologies （600K）, and previous deep RNA-sequencing data from 368 diverse inbred lines of maize. The balanced allelic frequencies and distributions in a relatively large and diverse natural panel helped to identify expression quantitative trait loci （eQTLs） associated with more than 18 000 genes （63.4% of tested genes）. We found that distant eQTLs were more frequent （~75% of all eQTLs） across the whole genome. Thirteen novel associated loci affecting maize kernel oil concentration were identified using the new dataset, among which one intergenic locus affected the kernel oil variation by controlling expression of three other known oil-related genes. Altogether, this study provides resources for expanding our understanding of cellular regulatory mechanisms of transcriptome variation and the landscape of functional variants within the maize genome, thereby enhancing the understanding of quantitative variations.展开更多
Detecting genes that affect specific traits(such as human diseases and crop yields)is important for treating complex diseases and improving crop quality.A genome-wide association study(GWAS)provides new insights and d...Detecting genes that affect specific traits(such as human diseases and crop yields)is important for treating complex diseases and improving crop quality.A genome-wide association study(GWAS)provides new insights and directions for understanding complex traits by identifying important single nucleotide polymorphisms.Many GWAS summary statistics data related to various complex traits have been gathered recently.Studies have shown that GWAS risk loci and expression quantitative trait loci(e QTLs)often have a lot of overlaps,which makes gene expression gradually become an important intermediary to reveal the regulatory role of GWAS.In this review,we review three types of gene-trait association detection methods of integrating GWAS summary statistics and e QTLs data,namely colocalization methods,transcriptome-wide association study-oriented approaches,and Mendelian randomization-related methods.At the theoretical level,we discussed the differences,relationships,advantages,and disadvantages of various algorithms in the three kinds of gene-trait association detection methods.To further discuss the performance of various methods,we summarize the significant gene sets that influence highdensity lipoprotein,low-density lipoprotein,total cholesterol,and triglyceride reported in 16 studies.We discuss the performance of various algorithms using the datasets of the four lipid traits.The advantages and limitations of various algorithms are analyzed based on experimental results,and we suggest directions for follow-up studies on detecting gene-trait associations.展开更多
Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Ge...Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.展开更多
Cattle carcass traits are economically important in the beef industry.In the present study,we identified 184 significant genes and 822 alternative genes for 7 carcass traits using genome-wide association studies(GWAS)...Cattle carcass traits are economically important in the beef industry.In the present study,we identified 184 significant genes and 822 alternative genes for 7 carcass traits using genome-wide association studies(GWAS)in 1,566 Huaxi beef cattle.We then identified 5,860 unique cis-genes and 734 trans-genes in 227 longissimus dorsi muscle(LDM)samples to better understand the genetic regulation of gene expression.Our integration study of the GWAS and cis-eQTL analysis detected 13 variants regulating 12 identical genes,in which one variant was also detected in fine-mapping analysis.Moreover,using a transcriptome-wide association study(TWAS),we identified 4 genes(TTC30B,HMGA1,PRKD3 and FXN)that were significantly related to carcass chest depth(CCD),carcass length(CL),carcass weight(CW)and dressing percentage(DP).This study identified variants and genes that may be useful for understanding the molecular mechanism of carcass traits in beef cattle.展开更多
22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding ...22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding Protein（G protein）Beta Polypeptide 1-Like（GNB1L）,located within the 1.5 Mbp 22q11.2 DS critical region,as a candidate liability gene for schizophrenia and bipolar disorder.In this study,we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium（LD） analysis to show that GNB1 L is regulated by a cis-acting genetic variant within the 3＇-region of the gene.Significantly,this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations.Contrary to our expectations,re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1 L highexpression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population.展开更多
Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ra...Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.展开更多
An expression quantitative trait locus (eQTL) is a chromosomal region where genetic variants are associated with the expression levels of specific genes that can be both nearby or distant. The identifications of eQTLs...An expression quantitative trait locus (eQTL) is a chromosomal region where genetic variants are associated with the expression levels of specific genes that can be both nearby or distant. The identifications of eQTLs for different tissues, cell types, and contexts have led to a better understanding of the dynamic regulations of gene expressions and implications of functional genes and variants for complex traits and diseases. Although most eQTL studies have been performed on data collected from bulk tissues, recent studies have demonstrated the importance of cell-type-specific and context-dependent gene regulations in biological processes and disease mechanisms. In this review, we discuss statistical methods that have been developed to enable the detection of cell-type-specific and context-dependent eQTLs from bulk tissues, purified cell types, and single cells. We also discuss the limitations of the current methods and future research opportunities.展开更多
基金partially funded by the Virginia Cattle Industry Board and the Virginia Agriculture CouncilVT Open Access Subvention Fund for the partial support of the publication fees
文摘Background A gap currently exists between genetic variants and the underlying cell and tissue biology of a trait,and expression quantitative trait loci(eQTL)studies provide important information to help close that gap.However,two concerns that arise with eQTL analyses using RNA-sequencing data are normalization of data across samples and the data not following a normal distribution.Multiple pipelines have been suggested to address this.For instance,the most recent analysis of the human and farm Genotype-Tissue Expression(GTEx)project proposes using trimmed means of M-values(TMM)to normalize the data followed by an inverse normal transformation.Results In this study,we reasoned that eQTL analysis could be carried out using the same framework used for dif-ferential gene expression(DGE),which uses a negative binomial model,a statistical test feasible for count data.Using the GTEx framework,we identified 35 significant eQTLs(P<5×10^(–8))following the ANOVA model and 39 significant eQTLs(P<5×10^(–8))following the additive model.Using a differential gene expression framework,we identified 930 and six significant eQTLs(P<5×10^(–8))following an analytical framework equivalent to the ANOVA and additive model,respectively.When we compared the two approaches,there was no overlap of significant eQTLs between the two frameworks.Because we defined specific contrasts,we identified trans eQTLs that more closely resembled what we expect from genetic variants showing complete dominance between alleles.Yet,these were not identified by the GTEx framework.Conclusions Our results show that transforming RNA-sequencing data to fit a normal distribution prior to eQTL analysis is not required when the DGE framework is employed.Our proposed approach detected biologically relevant variants that otherwise would not have been identified due to data transformation to fit a normal distribution.
基金supported by the Guizhou Provincial Basic Research Program(Natural Science)[(2024)648]the Program of China National Tobacco Corporation(110202101032(JY-09),110202201003(JY-03))+2 种基金the Program of Guizhou Branch of China National Tobacco Corporation(2023XM02,2022XM05 and 2024XM01)the Qiankehe Platform Project(ZSYS[2025]028)the Program of China National Tobacco Corporation(110202102034).
文摘Tobacco(Nicotiana tabacum,2n=48)is a key non-food economic crop,yet its stress response and gene regulatory mechanisms remain poorly understood.By analyzing 603 transcriptome datasets,this study identified 1405 tissue-specific genes,revealing tissue-specific synthesis of terpenoids and other ecologically important secondary metabolites in sepals and other tissues.Comparative stress-response analysis highlighted distinct gene expression patterns in leaves and roots under biotic and abiotic stresses.Additionally,28,396 expression quantitative trait loci(eQTLs)were mapped in leaves,offering valuable genetic regulatory markers.These findings provide crucial insights into tobacco’s gene expression characteristics and their functional implications,serving as a foundation for future research.
文摘A detailed understanding of genetic architecture of mRNA expression by millions of genetic variants is important for studying quantitative trait variation. In this study, we identified 1.25M SNPs with a minor allele frequency greater than 0.05 by combining reduced genome sequencing （GBS）, high- density array technologies （600K）, and previous deep RNA-sequencing data from 368 diverse inbred lines of maize. The balanced allelic frequencies and distributions in a relatively large and diverse natural panel helped to identify expression quantitative trait loci （eQTLs） associated with more than 18 000 genes （63.4% of tested genes）. We found that distant eQTLs were more frequent （~75% of all eQTLs） across the whole genome. Thirteen novel associated loci affecting maize kernel oil concentration were identified using the new dataset, among which one intergenic locus affected the kernel oil variation by controlling expression of three other known oil-related genes. Altogether, this study provides resources for expanding our understanding of cellular regulatory mechanisms of transcriptome variation and the landscape of functional variants within the maize genome, thereby enhancing the understanding of quantitative variations.
基金supported by the National Key Research and Development Program of China(2022YFD1201504)the Fundamental Research Funds for the Central Universities(2662022YLYJ010,2021ZKPY018,2662021JC008,SZYJY2021003)+2 种基金the Major Science and Technology Project of Hubei Province(2021AFB002)the Major Project of Hubei Hongshan Laboratory(2022HSZD031)the Yingzi Tech&Huazhong Agricultural University Intelligent Research Institute of Food Health(IRIFH202209)。
文摘Detecting genes that affect specific traits(such as human diseases and crop yields)is important for treating complex diseases and improving crop quality.A genome-wide association study(GWAS)provides new insights and directions for understanding complex traits by identifying important single nucleotide polymorphisms.Many GWAS summary statistics data related to various complex traits have been gathered recently.Studies have shown that GWAS risk loci and expression quantitative trait loci(e QTLs)often have a lot of overlaps,which makes gene expression gradually become an important intermediary to reveal the regulatory role of GWAS.In this review,we review three types of gene-trait association detection methods of integrating GWAS summary statistics and e QTLs data,namely colocalization methods,transcriptome-wide association study-oriented approaches,and Mendelian randomization-related methods.At the theoretical level,we discussed the differences,relationships,advantages,and disadvantages of various algorithms in the three kinds of gene-trait association detection methods.To further discuss the performance of various methods,we summarize the significant gene sets that influence highdensity lipoprotein,low-density lipoprotein,total cholesterol,and triglyceride reported in 16 studies.We discuss the performance of various algorithms using the datasets of the four lipid traits.The advantages and limitations of various algorithms are analyzed based on experimental results,and we suggest directions for follow-up studies on detecting gene-trait associations.
基金supported by the Ministry of Higher Education(MOHE)Malaysia through Fundamental Research Grant Scheme(FRGS)with project code:FRGS/1/2021/STG01/UCSI/01/.SX was funded by the National Natural Science Foundation of China(NSFC)grants 32030020 and 32288101funded by the NSFC grant 32270665.
文摘Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.
基金supported by the National Natural Science Foundation of China(32372833 and 32202652)the Agricultural Science and Technology Innovation Program in the Chinese Academy of Agricultural Sciences(ASTIP-IAS03 and CAASZDRW202102)+1 种基金the Program of National Beef Cattle and Yak Industrial Technology System,China(CARS-37)the Science and Technology Project of Inner Mongolia Autonomus Region,China(2020GG0210)。
文摘Cattle carcass traits are economically important in the beef industry.In the present study,we identified 184 significant genes and 822 alternative genes for 7 carcass traits using genome-wide association studies(GWAS)in 1,566 Huaxi beef cattle.We then identified 5,860 unique cis-genes and 734 trans-genes in 227 longissimus dorsi muscle(LDM)samples to better understand the genetic regulation of gene expression.Our integration study of the GWAS and cis-eQTL analysis detected 13 variants regulating 12 identical genes,in which one variant was also detected in fine-mapping analysis.Moreover,using a transcriptome-wide association study(TWAS),we identified 4 genes(TTC30B,HMGA1,PRKD3 and FXN)that were significantly related to carcass chest depth(CCD),carcass length(CL),carcass weight(CW)and dressing percentage(DP).This study identified variants and genes that may be useful for understanding the molecular mechanism of carcass traits in beef cattle.
基金supported by the 985 Program of Ministry of Education,Chinathe National Basic Research Development Program(973 Program)of China(2009CB522007 and 2010CB529601)the National Natural Science Foundation of China(30870899 and 81070908)
文摘22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding Protein（G protein）Beta Polypeptide 1-Like（GNB1L）,located within the 1.5 Mbp 22q11.2 DS critical region,as a candidate liability gene for schizophrenia and bipolar disorder.In this study,we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium（LD） analysis to show that GNB1 L is regulated by a cis-acting genetic variant within the 3＇-region of the gene.Significantly,this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations.Contrary to our expectations,re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1 L highexpression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population.
基金supported by grants from the Central Public-interest Scientific Institution Basal Research Fund(2020-YWF-YB-02)the Young Scientists Fund of the National Natural Science Foundation of China(32202652)+1 种基金China Agriculture Research System of MOF and MARA(CARS-37)the Science and Technology Project of Inner Mongolia Autonomous Region(2020GG0210).
文摘Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.
文摘An expression quantitative trait locus (eQTL) is a chromosomal region where genetic variants are associated with the expression levels of specific genes that can be both nearby or distant. The identifications of eQTLs for different tissues, cell types, and contexts have led to a better understanding of the dynamic regulations of gene expressions and implications of functional genes and variants for complex traits and diseases. Although most eQTL studies have been performed on data collected from bulk tissues, recent studies have demonstrated the importance of cell-type-specific and context-dependent gene regulations in biological processes and disease mechanisms. In this review, we discuss statistical methods that have been developed to enable the detection of cell-type-specific and context-dependent eQTLs from bulk tissues, purified cell types, and single cells. We also discuss the limitations of the current methods and future research opportunities.
