scholarly journals Decision letter: Alternative polyadenylation mediates genetic regulation of gene expression

2020 ◽  
Keyword(s):  
Gene Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation

scholarly journals Alternative polyadenylation mediates genetic regulation of gene expression

2019 ◽  
Author(s):  
Briana Mittleman ◽  
Sebastian Pott ◽  
Shane Warland ◽  
Tony Zeng ◽  
Mayher Kaur ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Protein Expression ◽  
Mrna Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation ◽  
Genetic Effects ◽  
Nuclear Fraction ◽  
Expression Levels

AbstractWith the exception of mRNA splicing, little is known about co-transcriptional or post-transcriptional regulatory mechanisms that link noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3’ Seq to characterize alternative polyadenylation (APA) in the nuclear and total RNA fractions of 52 HapMap Yoruba lymphoblastoid cell lines, which we have studied extensively in the past. We identified thousands of polyadenylation sites that are differentially detected in nuclear mRNA and whole cell mRNA, and found that APA is an important mediator of genetic effects on gene regulation and complex traits. Specifically, we mapped 602 apaQTLs at 10% FDR, of which 152 were found only in the nuclear fraction. Nuclear-specific apaQTLs are highly enriched in introns and are also often associated with changes in steady-state expression levels, suggesting a widespread mechanism whereby genetic variants decrease mRNA expression levels by increasing usage of intronic PAS. We identified 24 apaQTLs associated with protein expression levels, but not mRNA expression, and found that eQTLs that are not associated with chromatin QTLs are enriched in apaQTLs. These findings support multiple independent pathways through which genetic effects on APA can impact gene regulation. Finally, we found that 19% of apaQTLs were also previously associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression levels, protein expression levels, and disease risk, and reveals uncharted modes of genetic regulation.

scholarly journals Author response: Alternative polyadenylation mediates genetic regulation of gene expression

2020 ◽  
Author(s):  
Briana E Mittleman ◽  
Sebastian Pott ◽  
Shane Warland ◽  
Tony Zeng ◽  
Zepeng Mu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation ◽  
Author Response ◽  
Response Alternative

scholarly journals Alternative polyadenylation mediates genetic regulation of gene expression

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Briana E Mittleman ◽  
Sebastian Pott ◽  
Shane Warland ◽  
Tony Zeng ◽  
Zepeng Mu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Mrna Expression ◽  
Disease Risk ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Specific Effect ◽  
Alternative Polyadenylation ◽  
Effect Sizes ◽  
The Impact

Little is known about co-transcriptional or post-transcriptional regulatory mechanisms linking noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3’ Seq to study the impact of genetic variation on alternative polyadenylation (APA) in the nuclear and total mRNA fractions of 52 HapMap Yoruba human lymphoblastoid cell lines. We mapped 602 APA quantitative trait loci (apaQTLs) at 10% FDR, of which 152 were nuclear specific. Effect sizes at intronic apaQTLs are negatively correlated with eQTL effect sizes. These observations suggest genetic variants can decrease mRNA expression levels by increasing usage of intronic PAS. We also identified 24 apaQTLs associated with protein levels, but not mRNA expression. Finally, we found that 19% of apaQTLs can be associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression, protein expression, and disease risk, and reveals uncharted modes of genetic regulation.

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 Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development

2009 ◽  
Vol 106 (17) ◽  
pp. 7028-7033 ◽  
Author(s):  
Zhe Ji ◽  
Ju Youn Lee ◽  
Zhenhua Pan ◽  
Bingjun Jiang ◽  
Bin Tian
Keyword(s):  
Gene Expression ◽  
Embryonic Development ◽  
Posttranscriptional Regulation ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation ◽  
Untranslated Regions ◽  
C2c12 Myoblast ◽  
Control Of Gene Expression ◽  
Differentiation And Proliferation

The 3′ untranslated regions (3′ UTRs) of mRNAs containcis-acting elements for posttranscriptional regulation of gene expression. Here, we report that mouse genes tend to express mRNAs with longer 3′ UTRs as embryonic development progresses. This global regulation is controlled by alternative polyadenylation and coordinates with initiation of organogenesis and aspects of embryonic development, including morphogenesis, differentiation, and proliferation. Using myogenesis of C2C12 myoblast cells as a model, we recapitulated this process in vitro and found that 3′ UTR lengthening is likely caused by weakening of mRNA polyadenylation activity. Because alternative 3′ UTR sequences are typically longer and have higher AU content than constitutive ones, our results suggest that lengthening of 3′ UTR can significantly augment posttranscriptional control of gene expression during embryonic development, such as microRNA-mediated regulation.

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.

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