scholarly journals Local genetic effects on gene expression across 44 human tissues

2016 ◽  
Author(s):  
François Aguet ◽  
Andrew A. Brown ◽  
Stephane E. Castel ◽  
Joe R. Davis ◽  
Pejman Mohammadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Large Scale ◽  
Genetic Diseases ◽  
Tissue Expression ◽  
Specific Expression ◽  
Tissue Specific ◽  
Regulatory Variation ◽  
Functional Variants ◽  
Trait Locus

AbstractExpression quantitative trait locus (eQTL) mapping provides a powerful means to identify functional variants influencing gene expression and disease pathogenesis. We report the identification of cis-eQTLs from 7,051 post-mortem samples representing 44 tissues and 449 individuals as part of the Genotype-Tissue Expression (GTEx) project. We find a cis-eQTL for 88% of all annotated protein-coding genes, with one-third having multiple independent effects. We identify numerous tissue-specific cis-eQTLs, highlighting the unique functional impact of regulatory variation in diverse tissues. By integrating large-scale functional genomics data and state-of-the-art fine-mapping algorithms, we identify multiple features predictive of tissue-specific and shared regulatory effects. We improve estimates of cis-eQTL sharing and effect sizes using allele specific expression across tissues. Finally, we demonstrate the utility of this large compendium of cis-eQTLs for understanding the tissue-specific etiology of complex traits, including coronary artery disease. The GTEx project provides an exceptional resource that has improved our understanding of gene regulation across tissues and the role of regulatory variation in human genetic diseases.

scholarly journals Tissue-specific sex differences in human gene expression

2019 ◽  
Vol 28 (17) ◽  
pp. 2976-2986 ◽  
Author(s):  
Irfahan Kassam ◽  
Yang Wu ◽  
Jian Yang ◽  
Peter M Visscher ◽  
Allan F McRae
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Complex Traits ◽  
Tissue Expression ◽  
Regulatory Elements ◽  
Tissue Specific ◽  
Significance Threshold ◽  
Expression Of Genes ◽  
Causal Variants ◽  
Similar Distance

Abstract Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

scholarly journals The genetic basis of evolutionary change in gene expression levels

2010 ◽  
Vol 365 (1552) ◽  
pp. 2581-2590 ◽  
Author(s):  
J. J. Emerson ◽  
Wen-Hsiung Li
Keyword(s):  
Gene Expression ◽  
Genetic Basis ◽  
Regulation Of Gene Expression ◽  
Specific Expression ◽  
Genetic Changes ◽  
Expression Variation ◽  
Regulatory Variation ◽  
Global Mapping ◽  
History Of ◽  
Trait Locus

The regulation of gene expression is an important determinant of organismal phenotype and evolution. However, the widespread recognition of this fact occurred long after the synthesis of evolution and genetics. Here, we give a brief sketch of thoughts regarding gene regulation in the history of evolution and genetics. We then review the development of genome-wide studies of gene regulatory variation in the context of the location and mode of action of the causative genetic changes. In particular, we review mapping of the genetic basis of expression variation through expression quantitative trait locus studies and measuring the cis / trans component of expression variation in allele-specific expression studies. We conclude by proposing a systematic integration of ideas that combines global mapping studies, cis / trans tests and modern population genetics methodologies, in order to directly estimate the forces acting on regulatory variation within and between species.

CpG islands in genes showing tissue-specific expression

1990 ◽  
Vol 326 (1235) ◽  
pp. 207-215 ◽  
Keyword(s):  
Gene Expression ◽  
Cpg Islands ◽  
Housekeeping Genes ◽  
Tissue Expression ◽  
Proximal Promoter ◽  
Cell Type ◽  
Promoter Regions ◽  
Specific Expression ◽  
Tissue Specific ◽  
Single Cell Type

Patterns of DNA methylation at GpG dinucleotides and their relations with gene expression are complex. Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. However, in the human carbonic anhydrase (CA) gene family, both the ubiquitously expressed CAII and the muscle specific CAIII appear to have such CpG islands although erythrocyte-specific CAI does not. The CAII island is quantitatively more CpG rich than that of CAIII, with a CpG :GpC ratio of 0.94 compared with 0.82 for CAIII. Estimation of CpG:GpC ratios in the proximal-promoter regions of 44 vertebrate genes suggest that 40% of genes with tissue-specific or limited tissue distribution may show methylation-free CpG clusters in their promoter regions. In many cases the CpG:GpC ratio is less than that found in housekeeping genes and this may reflect variation in the interaction of CpG clusters with regulatory factors that define different patterns of tissue expression.

scholarly journals A probabilistic framework to dissect functional cell-type-specific regulatory elements and risk loci underlying the genetics of complex traits

2016 ◽  
Author(s):  
Yue Li ◽  
Jose Davila-Velderrain ◽  
Manolis Kellis
Keyword(s):  
Complex Traits ◽  
Large Scale ◽  
Learning Algorithm ◽  
Cell Types ◽  
Regulatory Elements ◽  
Probabilistic Framework ◽  
Cell Type ◽  
Tissue Specific ◽  
Functional Variants ◽  
Cell Type Specific

AbstractDissecting the physiological circuitry underlying diverse human complex traits associated with heritable common mutations is an ongoing effort. The primary challenge involves identifying the relevant cell types and the causal variants among the vast majority of the associated mutations in the noncoding regions. To address this challenge, we developed an efficient probabilistic framework. First, we propose a sparse group-guided learning algorithm to infer cell-type-specific enrichments. Second, we propose a fine-mapping Bayesian model that incorporates as Bayesian priors the sparse enrichments to infer risk variants. Using the proposed framework to analyze 32 complex human traits revealed meaningful tissue-specific epigenomic enrichments indicative of the relevant disease pathologies. The prioritized variants exhibit prominent tissue-specific epigenomic signatures and significant enrichments for eQTL and conserved elements. Together, we demonstrate the general benefits of the proposed integrative framework in elucidating meaningful tissue-specific epigenomic elements from large-scale correlated annotations and the implicated functional variants for future experimental interrogation.

Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation

2018 ◽  
Author(s):  
Timothy J. Cherry ◽  
Marty G. Yang ◽  
David A. Harmin ◽  
Peter Tao ◽  
Andrew E. Timms ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Complex Traits ◽  
Retinal Pigment ◽  
Regulatory Elements ◽  
Human Vision ◽  
Specific Gene ◽  
Tissue Specific ◽  
Complex Disorders ◽  
Regulatory Variation

ABSTRACTCis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.

scholarly journals Computational Assessment of the Regulation-Modulating Potential for Noncoding Variants

2019 ◽  
Author(s):  
Fang-Yuan Shi ◽  
Yu Wang ◽  
Dong Huang ◽  
Yu Liang ◽  
Nan Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Genetic Diseases ◽  
Superior Performance ◽  
Massive Datasets ◽  
Functional Variants ◽  
False Discovery ◽  
Genome Wide ◽  
Causal Variants ◽  
Higher Sensitivity

AbstractLarge-scale genome-wide association and expression quantitative trait loci studies have identified multiple noncoding variants associated with genetic diseases via affecting gene expression. However, effectively and efficiently pinpointing causal variants remains a serious challenge. Here, we developed CARMEN, a novel algorithm to identify functional noncoding expression-modulating variants. Multiple evaluations demonstrated CARMEN’s superior performance over state-of-the-art tools. Its higher sensitivity and low false discovery rate enable CARMEN to identify multiple causal expression-modulating variants that other tools simply missed. Meanwhile, benefitting from extensive annotations generated, CARMEN provides mechanism hints on predicted expression-modulating variants, enabling effectively characterizing functional variants involved in gene expression and disease-related phenotypes. CARMEN scales well with the massive datasets and is available online as a Web server at http://carmen.gao-lab.org.

scholarly journals The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma

2021 ◽  
Author(s):  
Ekaterina Bourova-Flin ◽  
Samira Derakhshan ◽  
Afsaneh Goudarzi ◽  
Tao Wang ◽  
Anne-Laure Vitte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Specific Gene ◽  
Specific Expression ◽  
Intrinsic Nature ◽  
Independent Cohort

Abstract Background Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. Methods A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. Results A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. Discussion The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.

scholarly journals Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent

2000 ◽  
Vol 20 (9) ◽  
pp. 3316-3329 ◽  
Author(s):  
Carsten Müller ◽  
Carol Readhead ◽  
Sven Diederichs ◽  
Gregory Idos ◽  
Rong Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Trichostatin A ◽  
Specific Gene ◽  
Cyclin A1 ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression

ABSTRACT Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation.

Human globin gene promoter sequences are sufficient for specific expression of a hybrid gene transfected into tissue culture cells

1987 ◽  
Vol 7 (1) ◽  
pp. 398-402
Author(s):  
T Rutherford ◽  
A W Nienhuis
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Gene Promoter ◽  
Gene Promoters ◽  
Globin Genes ◽  
Specific Expression ◽  
Tissue Specific ◽  
Promoter Sequences ◽  
Erythroleukemia Cells ◽  
Murine Erythroleukemia

The contribution of the human globin gene promoters to tissue-specific transcription was studied by using globin promoters to transcribe the neo (G418 resistance) gene. After transfection into different cell types, neo gene expression was assayed by scoring colony formation in the presence of G418. In K562 human erythroleukemia cells, which express fetal and embryonic globin genes but not the adult beta-globin gene, the neo gene was expressed strongly from a fetal gamma- or embryonic zeta-globin gene promoter but only weakly from the beta promoter. In murine erythroleukemia cells which express the endogenous mouse beta genes, the neo gene was strongly expressed from both beta and gamma promoters. In two nonerythroid cell lines, human HeLa cells and mouse 3T3 fibroblasts, the globin gene promoters did not allow neo gene expression. Globin-neo genes were integrated in the erythroleukemia cell genomes mostly as a single copy per cell and were transcribed from the appropriate globin gene cap site. We conclude that globin gene promoter sequences extending from -373 to +48 base pairs (bp) (relative to the cap site) for the beta gene, -385 to +34 bp for the gamma gene, and -555 to +38 bp for the zeta gene are sufficient for tissue-specific and perhaps developmentally specific transcription.

scholarly journals Large Scale Gene Expression Meta-Analysis Reveals Tissue-Specific, Sex-Biased Gene Expression in Humans

2016 ◽  
Vol 7 ◽  
Author(s):  
Benjamin T. Mayne ◽  
Tina Bianco-Miotto ◽  
Sam Buckberry ◽  
James Breen ◽  
Vicki Clifton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Meta Analysis ◽  
Tissue Specific
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