scholarly journals The impact of sex on gene expression across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. eaba3066 ◽  
Author(s):  
Meritxell Oliva ◽  
Manuel Muñoz-Aguirre ◽  
Sarah Kim-Hellmuth ◽  
Valentin Wucher ◽  
Ariel D. H. Gewirtz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Tissue Expression ◽  
Study Data ◽  
Tissue Samples ◽  
The Impact

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

scholarly journals  ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

2018 ◽  
Author(s):  
Miguel Hueso ◽  
Josep M Cruzado ◽  
Joan Torras ◽  
Estanis Navarro
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Chaos Theory ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Structural Constraints ◽  
Linear Dynamical Systems ◽  
Alu Elements ◽  
Non Linear ◽  
The Impact

Atherosclerosis (ATH) and Coronary Artery Disease (CAD) are chronic inflammatory diseases with an important genetic background which derive from the cumulative effect of multiple common risk alleles, most of them located in genomic non-coding regions. These complex diseases behave as non-linear dynamical systems that show a high dependence on their initial conditions, so that long-term predictions of disease progression are unreliable. One likely possibility is that the non-linear nature of ATH could be dependent on non-linear correlations in the structure of the human genome. In this review we show how Chaos theory analysis highlighted genomic regions that shared specific structural constraints that could have a role in ATH progression. These regions were shown to be enriched in repetitive sequences of the Alu family, genomic parasites which colonized the human genome, which show a particular secondary structure and have been involved in the regulation of gene expression. We also review the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms by which the Alu elements could alter the inflammatory homeostasis. We devise especial attention to their relationship with the lncRNA ANRIL, the strongest risk factor for ATH, their role as miRNA sponges, and their ability to interfere with the regulatory circuitry of the NF-kB response. We aim to characterize ATH as a non-linear dynamic system in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

scholarly journals sn-spMF: matrix factorization informs tissue-specific genetic regulation of gene expression

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuan He ◽  
◽  
Surya B. Chhetri ◽  
Marios Arvanitis ◽  
Kaushik Srinivasan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Matrix Factorization ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Tissue Expression ◽  
Disease Etiology ◽  
Tissue Specific ◽  
Specific Effects ◽  
Factorization Model ◽  
Biological Similarity

Abstract Genetic regulation of gene expression, revealed by expression quantitative trait loci (eQTLs), exhibits complex patterns of tissue-specific effects. Characterization of these patterns may allow us to better understand mechanisms of gene regulation and disease etiology. We develop a constrained matrix factorization model, sn-spMF, to learn patterns of tissue-sharing and apply it to 49 human tissues from the Genotype-Tissue Expression (GTEx) project. The learned factors reflect tissues with known biological similarity and identify transcription factors that may mediate tissue-specific effects. sn-spMF, available at https://github.com/heyuan7676/ts_eQTLs, can be applied to learn biologically interpretable patterns of eQTL tissue-specificity and generate testable mechanistic hypotheses.

scholarly journals The impact of structural variation on human gene expression

2016 ◽  
Author(s):  
Colby Chiang ◽  
Alexandra J. Scott ◽  
Joe R. Davis ◽  
Emily K. Tsang ◽  
Xin Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Tissue Expression ◽  
Regulatory Elements ◽  
Causal Variant ◽  
Joint Analysis ◽  
Aberrant Expression ◽  
Order Of Magnitude ◽  
The Impact

AbstractStructural variants (SVs) are an important source of human genetic diversity but their contribution to traits, disease, and gene regulation remains unclear. The Genotype-Tissue Expression (GTEx) project presents an unprecedented opportunity to address this question due to the availability of deep whole genome sequencing (WGS) and multi-tissue RNA-seq data from 147 individuals. We used comprehensive methods to identify 24,157 high confidence SVs, and mapped cis expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single nucleotide (SNV) and short insertion/deletion (indel) variants. We identified 24,801 eQTLs affecting the expression of 10,101 distinct genes. Based on haplotype structure and heritability partitioning, we estimate that SVs are the causal variant at 3.3-7.0% of eQTLs, which is nearly an order of magnitude higher than prior estimates from low coverage WGS and represents a 26- to 54-fold enrichment relative to their scarcity in the genome. Expression-altering SVs also have significantly larger effect sizes than SNVs and indels. We identified 787 putatively causal SVs predicted to directly alter gene expression, most of which (88.3%) are noncoding variants that show significant enrichment at enhancers and other regulatory elements. By evaluating linkage disequilibrium between SVs, SNVs and indels, we nominate 49 SVs as plausible causal variants at published genome-wide association study (GWAS) loci. Remarkably, 29.9% of the common SV-eQTLs are not well tagged by flanking SNVs, and we observe a notable abundance (relative to SNVs and indels) of rare, high impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of both common and rare variant association studies.

scholarly journals Impact of the X chromosome and sex on regulatory variation

2015 ◽  
Author(s):  
Kimberly R Kukurba ◽  
Princy Parsana ◽  
Kevin S Smith ◽  
Zachary Zappala ◽  
David A Knowles ◽  
...  
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Specific Gene ◽  
Specific Expression ◽  
Regulatory Variation ◽  
Regulatory Variants ◽  
Genome Wide ◽  
The Impact

The X chromosome, with its unique mode of inheritance, contributes to differences between the sexes at a molecular level, including sex-specific gene expression and sex-specific impact of genetic variation. We have conducted an analysis of the impact of both sex and the X chromosome on patterns of gene expression identified through transcriptome sequencing of whole blood from 922 individuals. We identified that genes on the X chromosome are more likely to have sex-specific expression compared to the autosomal genes. Furthermore, we identified a depletion of regulatory variants on the X chromosome, especially among genes under high selective constraint. In contrast, we discovered an enrichment of sex-specific regulatory variants on the X chromosome. To resolve the molecular mechanisms underlying such effects, we generated and connected sex-specific chromatin accessibility to sex-specific expression and regulatory variation. As sex-specific regulatory variants can inform sex differences in genetic disease prevalence, we have integrated our data with genome-wide association study data for multiple immune traits and to identify traits with significant sex biases. Together, our study provides genome-wide insight into how the X chromosome and sex shape human gene regulation and disease.

scholarly journals Tissue Expression of Methyltransferases in Response to Acute and Long-term Exercise in Sedentary Men

2021 ◽  
Author(s):  
Thomas Olsen ◽  
Sindre Lee ◽  
Kathrine Vinknes ◽  
Frode Norheim ◽  
Marit Hjorth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Exercise ◽  
Exercise Intervention ◽  
Regulation Of Gene Expression ◽  
Cell Communication ◽  
Tissue Expression ◽  
Differentially Expressed ◽  
Lysine Methylation ◽  
Tissue Samples

Abstract Exercise influences epigenetic regulation of gene expression by modulating tissue methyltransferase activity, whereas effects on methyltransferases with other crucial biological functions have not been elucidated. We performed RNA sequencing of skeletal muscle (SkM) and white adipose tissue (WAT) obtained from 26 sedentary men undergoing acute exercise (AE) and a long-term, 12-week exercise intervention (LTE). We investigated exercise effects on tissue methyltransferase transcripts and a plasma marker of methylation capacity (methionine/homocysteine ratio). Blood and tissue samples were obtained before, just after and 2 h after AE (blood and SkM), and before and after LTE (blood, SkM, WAT). Differential expression analyses revealed that 43 (15 up; 26 down) and 55 (31 up; 23 down) methyltransferases were differentially expressed in SkM just after and 2 h after AE, respectively. After LTE, 69 methyltransferases (13 up; 55 down) were differentially expressed in SkM. Upregulated methyltransferases were implicated in histone and peptidyl-lysine methylation (AE, 0 h), RNA processing (AE, 2 h), and cell communication (LTE). Downregulated methyltransferases were implicated in gene expression (AE, 0 h) and mRNA processing (LTE). Plasma methionine/homocysteine decreased after AE, but was elevated after LTE. In conclusion, AE and LTE influence SkM but not WAT methyltransferase transcript levels and plasma methionine/homocysteine.

scholarly journals Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data

2021 ◽  
Author(s):  
Emily Flynn ◽  
Annie Chang ◽  
Bridget M. Nugent ◽  
Russ Altman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Gene Expression Data ◽  
Airway Epithelium ◽  
Molecular Mechanisms ◽  
Smoking History ◽  
Expression Data ◽  
Initial Examination ◽  
Tissue Samples ◽  
Additional Group

ABSTRACTSmoking greatly reduces life expectancy in both men and women, but with different patterns of morbidity. After adjusting for smoking history, women have higher risk of respiratory effects and diabetes from smoking, while men show greater mortality from smoking-related cancers. While many smoking-related sex differences have been documented, the underlying molecular mechanisms are not well understood. To date, identification of sex differences in response to smoking has been limited to a small number of studies and the resulting smoking-related effects require further validation. Publicly available gene expression data present a unique opportunity to examine molecular-level sex and smoking effects across many tissues and studies. We performed a systematic search to identify smoking-related studies from healthy tissue samples and found 31 separate studies as well as an additional group of overlapping studies that in total span 2,177 samples and 12 tissues. These samples and studies were overall male-biased. In smoking, while effects appeared to be somewhat tissue-specific and largely autosomal, we identified a small number of genes that were consistently differentially expressed across tissues, including AHRR and GZMH. We also identified one gene, AKR1C3, encoding an aldo-keto reductase, which showed strong opposite direction, smoking-related effects in blood and airway epithelium, with higher expression in airway epithelium and lower expression in blood of smokers versus non-smokers. By contrast, at similar significance thresholds, sex-related effects were entirely sex chromosomal and consistent across tissues, providing evidence of stronger effects of smoking than sex on autosomal expression. Due to sample size limitations, we only examined interaction effects in the largest study, where we identified 30 genes with sex differential effects in response to smoking, only one of which, CAPN9, replicated in a held-out analysis. Overall these results present a comprehensive analysis of smoking-related effects across tissues and an initial examination of sex differential smoking effects in public gene expression data.

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 Cell–cell coupling and DNA methylation abnormal phenotypes in the after-hours mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Federico Tinarelli ◽  
Elena Ivanova ◽  
Ilaria Colombi ◽  
Erica Barini ◽  
Edoardo Balzani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Neuronal Networks ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Neuronal Cultures ◽  
Functional Impairments ◽  
After Hours ◽  
The Impact

Abstract Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.

scholarly journals Endurance Training Regulates Expression of Some Angiogenesis-Related Genes in Cardiac Tissue of Experimentally Induced Diabetic Rats

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 498
Author(s):  
Mojdeh Khajehlandi ◽  
Lotfali Bolboli ◽  
Marefat Siahkuhian ◽  
Mohammad Rami ◽  
Mohammadreza Tabandeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endurance Training ◽  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Diabetic Rats ◽  
Moderate Intensity ◽  
Pcr Analysis ◽  
Cardiac Tissues ◽  
The Impact

Exercise can ameliorate cardiovascular dysfunctions in the diabetes condition, but its precise molecular mechanisms have not been entirely understood. The aim of the present study was to determine the impact of endurance training on expression of angiogenesis-related genes in cardiac tissue of diabetic rats. Thirty adults male Wistar rats were randomly divided into three groups (N = 10) including diabetic training (DT), sedentary diabetes (SD), and sedentary healthy (SH), in which diabetes was induced by a single dose of streptozotocin (50 mg/kg). Endurance training (ET) with moderate-intensity was performed on a motorized treadmill for six weeks. Training duration and treadmill speed were increased during five weeks, but they were kept constant at the final week, and slope was zero at all stages. Real-time polymerase chain reaction (RT-PCR) analysis was used to measure the expression of myocyte enhancer factor-2C (MEF2C), histone deacetylase-4 (HDAC4) and Calmodulin-dependent protein kinase II (CaMKII) in cardiac tissues of the rats. Our results demonstrated that six weeks of ET increased gene expression of MEF2C significantly (p < 0.05), and caused a significant reduction in HDAC4 and CaMKII gene expression in the DT rats compared to the SD rats (p < 0.05). We concluded that moderate-intensity ET could play a critical role in ameliorating cardiovascular dysfunction in a diabetes condition by regulating the expression of some angiogenesis-related genes in cardiac tissues.

Speciation and changes in male gene expression in Drosophila

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Bahar Patlar ◽  
Alberto Civetta
Keyword(s):  
Gene Expression ◽  
Reproductive Isolation ◽  
Potential Role ◽  
Regulation Of Gene Expression ◽  
Drosophila Model ◽  
Depth Analysis ◽  
The Impact ◽  
Plastic Responses ◽  
Male Gene

It has long been acknowledged that changes in the regulation of gene expression may account for major organismal differences. However, we still do not fully understand how changes in gene expression evolve and how do such changes influence organisms’ differences. We are even less aware of the impact such changes might have in restricting gene flow between species. Here, we focus on studies of gene expression and speciation in the Drosophila model. We review studies that have identified gene interactions in post-mating reproductive isolation and speciation, particularly those that modulate male gene expression. We also address studies that have experimentally manipulated changes in gene expression to test their effect in post-mating reproductive isolation. We highlight the need for a more in-depth analysis of the role of selection causing disrupted gene expression of such candidate genes in sterile/inviable hybrids. Moreover, we discuss the relevance to incorporate more routinely assays that simultaneously evaluate the potential effects of environmental factors and genetic background in modulating plastic responses in male genes and their potential role in speciation.

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