ANALYSIS OF GENE EXPRESSION VARIANCE AND GENETIC REGULATION OF GENE EXPRESSION BASED ON VARIANCE ASSOCIATION MAPPING

2019 ◽  
Vol 29 ◽  
pp. S797
Author(s):  
Roberto Visintainer ◽  
Michele Filosi ◽  
The CommonMind Consortium (CMC) ◽  
Enrico Domenici
Keyword(s):  
Gene Expression ◽  
Association Mapping ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Expression Variance

scholarly journals On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model

2018 ◽  
Author(s):  
Yizhen Zhong ◽  
Minoli Perera ◽  
Eric R. Gamazon
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Type I ◽  
Eqtl Mapping ◽  
Entire Genome ◽  
Local Ancestry ◽  
Heritability Estimation

AbstractBackgroundUnderstanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of use of local ancestry on high-dimensional omics analyses, including most prominently expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored.ResultsHere we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We estimate the trait variance explained by ancestry using local admixture relatedness between individuals. Using National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that use of local ancestry can substantially improve eQTL mapping and heritability estimation and characterize the sparse versus polygenic component of gene expression in admixed and multiethnic populations respectively. Using simulations of diverse genetic architectures to estimate trait heritability and the level of confounding, we show improved accuracy given individual-level data and evaluate a summary statistics based approach. Furthermore, we provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches.ConclusionOur study has important methodological implications on genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

scholarly journals How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2611
Author(s):  
Jayron J. Habibe ◽  
Maria P. Clemente-Olivo ◽  
Carlie J. de Vries
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Current Knowledge ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Lim Domain ◽  
Multifactorial Diseases ◽  
Lim Domains ◽  
Age Related

Susceptibility to complex pathological conditions such as obesity, type 2 diabetes and cardiovascular disease is highly variable among individuals and arises from specific changes in gene expression in combination with external factors. The regulation of gene expression is determined by genetic variation (SNPs) and epigenetic marks that are influenced by environmental factors. Aging is a major risk factor for many multifactorial diseases and is increasingly associated with changes in DNA methylation, leading to differences in gene expression. Four and a half LIM domains 2 (FHL2) is a key regulator of intracellular signal transduction pathways and the FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging. Remarkably, FHL2 expression increases with methylation. This was demonstrated in relevant metabolic tissues: white adipose tissue, pancreatic β-cells, and skeletal muscle. In this review, we provide an overview of the current knowledge on regulation of FHL2 by genetic variation and epigenetic DNA modification, and the potential consequences for age-related complex multifactorial diseases.

scholarly journals Tissue specific regulation of transcription in endometrium and association with disease

2020 ◽  
Vol 35 (2) ◽  
pp. 377-393 ◽  
Author(s):  
Sally Mortlock ◽  
Raden I Kendarsari ◽  
Jenny N Fung ◽  
Greg Gibson ◽  
Fei Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Study ◽  
Genetic Variants ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Enrichment Analysis ◽  
Reproductive Traits ◽  
Genetic Effects ◽  
Genotype Data ◽  
Tissue Specific

Abstract STUDY QUESTION Are genetic effects on endometrial gene expression tissue specific and/or associated with reproductive traits and diseases? SUMMARY ANSWER Analyses of RNA-sequence data and individual genotype data from the endometrium identified novel and disease associated, genetic mechanisms regulating gene expression in the endometrium and showed evidence that these mechanisms are shared across biologically similar tissues. WHAT IS KNOWN ALREADY The endometrium is a complex tissue vital for female reproduction and is a hypothesized source of cells initiating endometriosis. Understanding genetic regulation specific to, and shared between, tissue types can aid the identification of genes involved in complex genetic diseases. STUDY DESIGN, SIZE, DURATION RNA-sequence and genotype data from 206 individuals was analysed and results were compared with large publicly available datasets. PARTICIPANTS/MATERIALS, SETTING, METHODS RNA-sequencing and genotype data from 206 endometrial samples was used to identify the influence of genetic variants on gene expression, via expression quantitative trait loci (eQTL) analysis and to compare these endometrial eQTLs with those in other tissues. To investigate the association between endometrial gene expression regulation and reproductive traits and diseases, we conducted a tissue enrichment analysis, transcriptome-wide association study (TWAS) and summary data-based Mendelian randomisation (SMR) analyses. Transcriptomic data was used to test differential gene expression between women with and without endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE A tissue enrichment analysis with endometriosis genome-wide association study summary statistics showed that genes surrounding endometriosis risk loci were significantly enriched in reproductive tissues. A total of 444 sentinel cis-eQTLs (P < 2.57 × 10−9) and 30 trans-eQTLs (P < 4.65 × 10−13) were detected, including 327 novel cis-eQTLs in endometrium. A large proportion (85%) of endometrial eQTLs are present in other tissues. Genetic effects on endometrial gene expression were highly correlated with the genetic effects on reproductive (e.g. uterus, ovary) and digestive tissues (e.g. salivary gland, stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. The TWAS analysis indicated that gene expression at 39 loci is associated with endometriosis, including five known endometriosis risk loci. SMR analyses identified potential target genes pleiotropically or causally associated with reproductive traits and diseases including endometriosis. However, without taking account of genetic variants, a direct comparison between women with and without endometriosis showed no significant difference in endometrial gene expression. LARGE SCALE DATA The eQTL dataset generated in this study is available at http://reproductivegenomics.com.au/shiny/endo_eqtl_rna/. Additional datasets supporting the conclusions of this article are included within the article and the supplementary information files, or are available on reasonable request. LIMITATIONS, REASONS FOR CAUTION Data are derived from fresh tissue samples and expression levels are an average of expression from different cell types within the endometrium. Subtle cell-specifc expression changes may not be detected and differences in cell composition between samples and across the menstrual cycle will contribute to sample variability. Power to detect tissue specific eQTLs and differences between women with and without endometriosis was limited by the sample size in this study. The statistical approaches used in this study identify the likely gene targets for specific genetic risk factors, but not the functional mechanism by which changes in gene expression may influence disease risk. WIDER IMPLICATIONS OF THE FINDINGS Our results identify novel genetic variants that regulate gene expression in endometrium and the majority of these are shared across tissues. This allows analysis with large publicly available datasets to identify targets for female reproductive traits and diseases. Much larger studies will be required to identify genetic regulation of gene expression that will be specific to endometrium. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Health and Medical Research Council (NHMRC) under project grants GNT1026033, GNT1049472, GNT1046880, GNT1050208, GNT1105321, GNT1083405 and GNT1107258. G.W.M is supported by a NHMRC Fellowship (GNT1078399). J.Y is supported by an ARC Fellowship (FT180100186). There are no competing interests.

scholarly journals Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity

2021 ◽  
Author(s):  
Marios Arvanitis ◽  
Karl Tayeb ◽  
Benjamin J Strober ◽  
Alexis Battle
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Tissue Specificity ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Genetic Effects ◽  
Allelic Heterogeneity ◽  
Common Genetic Variants ◽  
Causal Variants ◽  
Disease Loci

Understanding the mechanisms that underlie genetic regulation of gene expression is crucial to explaining the diversity that governs complex traits. Large scale expression quantitative trait locus (eQTL) studies have been instrumental in identifying genetic variants that influence the expression of target genes. However, a large fraction of disease-associated genetic variants have not been clearly explained by current eQTL data, frustrating attempts to use these data to comprehensively characterize disease loci. One notable observation from recent studies is that cis-eQTL effects are often shared across different cell types and tissues. This would suggest that common genetic variants impacting steady-state, adult gene expression are largely tolerated, shared across tissues, and less relevant to disease. However, allelic heterogeneity and complex patterns of linkage disequilibrium (LD) within each locus may skew the quantification of sharing of genetic effects between tissues, impede our ability to identify causal variants, and hinder the identification of regulatory effects for disease-associated genetic variants. Indeed, recent research suggests that multiple causal variants are often present in many eQTL and complex trait associated loci. Here, we re-analyze tissue-specificity of genetic effects in the presence of LD and allelic heterogeneity, proposing a novel method, CAFEH, that improves the identification of causal regulatory variants across tissues and their relationship to disease loci.

scholarly journals Genetic regulation of gene expression of MIF family members in lung tissue

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Florez-Sampedro ◽  
Corry-Anke Brandsma ◽  
Maaike de Vries ◽  
Wim Timens ◽  
Rene Bults ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Splice Variants ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Chronic Obstructive ◽  
Nucleotide Polymorphisms ◽  
Related Factors ◽  
Dopachrome Tautomerase ◽  
Copd Patients

Abstract Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

scholarly journals Genetic Regulation of Gene Expression During Shoot Development in Arabidopsis

Genetics ◽  
2005 ◽  
Vol 172 (2) ◽  
pp. 1155-1164 ◽  
Author(s):  
Rhonda DeCook ◽  
Sonia Lall ◽  
Dan Nettleton ◽  
Stephen H. Howell
Keyword(s):  
Gene Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Shoot Development

scholarly journals On the role of DNA biomechanics in the regulation of gene expression

2011 ◽  
Vol 8 (65) ◽  
pp. 1673-1681 ◽  
Author(s):  
J. N. Milstein ◽  
J.-C. Meiners
Keyword(s):  
Gene Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Cellular Functions ◽  
Biochemical Processes ◽  
Regulatory Processes ◽  
Linear Sequence ◽  
Cellular Environment ◽  
Cellular Dna

DNA is traditionally seen as a linear sequence of instructions for cellular functions that are expressed through biochemical processes. Cellular DNA, however, is also organized as a complex hierarchical structure with a mosaic of mechanical features, and a growing body of evidence is now emerging to imply that these mechanical features are connected to genetic function. Mechanical tension, for instance, which must be felt by DNA within the heavily constrained and continually fluctuating cellular environment, can affect a number of regulatory processes implicating a role for biomechanics in gene expression complementary to that of biochemical regulation. In this article, we review evidence for such mechanical pathways of genetic regulation.

scholarly journals Regulation by the Modulation of Gene Expression Variability

2015 ◽  
Vol 197 (12) ◽  
pp. 1974-1975 ◽  
Author(s):  
David Dubnau
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Content Type ◽  
Expression Variability ◽  
Link Type ◽  
Article Type ◽  
Modulation Of Gene Expression ◽  
The Mean ◽  
Cell Changes ◽  
Expression Variance

Classically, transcription is regulated so that the average expression per cell changes, often with a distribution that extends across the population. Roggiani and Goulian (M. Roggiani and M. Goulian, J. Bacteriol. 197:1976–1987, 2015, doi:http://dx.doi.org/10.1128/JB.00074-15) have shown that this is what happens when thetorCADoperon ofEscherichia coliis induced anaerobically by the addition of trimethylamine-N-oxide (TMAO). However, when the same inducer is added to aerobically growing cells, only a subset of the cells respond, although the mean expression per cell is similar to that obtained anaerobically. Thus, in the presence of oxygen, the variance but not the expression mean is altered. The regulation of gene expression variance appears to be due to noise in the phosphorelay that governstorCADtranscription.

scholarly journals β-Catenin–dependent mechanotransduction dates back to the common ancestor of Cnidaria and Bilateria

2018 ◽  
Vol 115 (24) ◽  
pp. 6231-6236 ◽  
Author(s):  
Ekaterina Pukhlyakova ◽  
Andrew J. Aman ◽  
Kareem Elsayad ◽  
Ulrich Technau
Keyword(s):  
Gene Expression ◽  
Common Ancestor ◽  
Marker Gene ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Model Organism ◽  
The Common ◽  
Gene Regulatory ◽  
Ancient Gene

Although the genetic regulation of cellular differentiation processes is well established, recent studies have revealed the role of mechanotransduction on a variety of biological processes, including regulation of gene expression. However, it remains unclear how universal and widespread mechanotransduction is in embryonic development of animals. Here, we investigate mechanosensitive gene expression during gastrulation of the starlet sea anemone Nematostella vectensis, a cnidarian model organism. We show that the blastoporal marker gene brachyury is down-regulated by blocking myosin II-dependent gastrulation movements. Brachyury expression can be restored by applying external mechanical force. Using CRISPR/Cas9 and morpholino antisense technology, we also show that mechanotransduction leading to brachyury expression is β-catenin dependent, similar to recent findings in fish and Drosophila [Brunet T, et al. (2013) Nat Commun 4:1–15]. Finally, we demonstrate that prolonged application of mechanical stress on the embryo leads to ectopic brachyury expression. Thus, our data indicate that β-catenin–dependent mechanotransduction is an ancient gene regulatory mechanism, which was present in the common ancestor of cnidarians and bilaterians, at least 600 million years ago.

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