scholarly journals Measurement of selective constraint on human gene expression

2018 ◽  
Author(s):  
Emily C Glassberg ◽  
Ziyue Gao ◽  
Arbel Harpak ◽  
Xun Lant ◽  
Jonathan K Pritchard
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Complex Traits ◽  
Stabilizing Selection ◽  
Common Variants ◽  
Loss Of Function ◽  
Specific Expression ◽  
Expression Levels ◽  
Expression Variation ◽  
Regulatory Variants

Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression levels. Here, we explore the effects of stabilizing selection on cis-regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have approximately 2.5 × greater effects on expression variance than common variants. Despite their increased effect sizes relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation.

scholarly journals Cis- and Trans-Regulatory Variations in the Domestication of the Chili Pepper Fruit

2020 ◽  
Vol 37 (6) ◽  
pp. 1593-1603 ◽  
Author(s):  
Erik Díaz-Valenzuela ◽  
Ruairidh H Sawers ◽  
Angélica Cibrián-Jaramillo
Keyword(s):  
Gene Expression ◽  
Chili Pepper ◽  
Loss Of Function ◽  
Morphological Transformation ◽  
Specific Expression ◽  
Network Analyses ◽  
Regulatory Variants ◽  
Regulatory Cascades ◽  
In The Wild ◽  
Cis And Trans

Abstract The process of domestication requires the rapid transformation of the wild morphology into the cultivated forms that humans select for. This process often takes place through changes in the regulation of genes, yet, there is no definite pattern on the role of cis- and trans-acting regulatory variations in the domestication of the fruit among crops. Using allele-specific expression and network analyses, we characterized the regulatory patterns and the inheritance of gene expression in wild and cultivated accessions of chili pepper, a crop with remarkable fruit morphological variation. We propose that gene expression differences associated to the cultivated form are best explained by cis-regulatory hubs acting through trans-regulatory cascades. We show that in cultivated chili, the expression of genes associated with fruit morphology is partially recessive with respect to those in the wild relative, consistent with the hybrid fruit phenotype. Decreased expression of fruit maturation and growth genes in cultivated chili suggest that selection for loss-of-function took place in its domestication. Trans-regulatory changes underlie the majority of the genes showing regulatory divergence and had larger effect sizes on gene expression than cis-regulatory variants. Network analysis of selected cis-regulated genes, including ARP9 and MED25, indicated their interaction with many transcription factors involved in organ growth and fruit ripening. Differentially expressed genes linked to cis-regulatory variants and their interactions with downstream trans-acting genes have the potential to drive the morphological differences observed between wild and cultivated fruits and provide an attractive mechanism of morphological transformation during the domestication of the chili pepper.

scholarly journals Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

2018 ◽  
Author(s):  
Min Wang ◽  
Timothy P Hancock ◽  
Amanda J. Chamberlain ◽  
Christy J. Vander Jagt ◽  
Jennie E Pryce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Bovine Genome ◽  
Search Space ◽  
Ctcf Binding ◽  
P Value ◽  
Trna Genes ◽  
Specific Expression ◽  
Binding Motifs ◽  
Regulatory Variants

AbstractBackgroundTopological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants.ResultsWe used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping gene, tRNA genes, CTCF binding motifs, SINEs, H3K4me3 and H3K27ac. Then we showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows’ white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The most significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value ≤ 0.001).ConclusionsOur results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.

scholarly journals Extensive tissue-specific expression variation and novel regulators underlying circadian behavior

2021 ◽  
Vol 7 (5) ◽  
pp. eabc3781
Author(s):  
Maria Litovchenko ◽  
Antonio C. A. Meireles-Filho ◽  
Michael V. Frochaux ◽  
Roel P. J. Bevers ◽  
Alessio Prunotto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Circadian Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Expression Variation ◽  
Circadian Expression

Natural genetic variation affects circadian rhythms across the evolutionary tree, but the underlying molecular mechanisms are poorly understood. We investigated population-level, molecular circadian clock variation by generating >700 tissue-specific transcriptomes of Drosophila melanogaster (w1118) and 141 Drosophila Genetic Reference Panel (DGRP) lines. This comprehensive circadian gene expression atlas contains >1700 cycling genes including previously unknown central circadian clock components and tissue-specific regulators. Furthermore, >30% of DGRP lines exhibited aberrant circadian gene expression, revealing abundant genetic variation–mediated, intertissue circadian expression desynchrony. Genetic analysis of one line with the strongest deviating circadian expression uncovered a novel cry mutation that, as shown by protein structural modeling and brain immunohistochemistry, disrupts the light-driven flavin adenine dinucleotide cofactor photoreduction, providing in vivo support for the importance of this conserved photoentrainment mechanism. Together, our study revealed pervasive tissue-specific circadian expression variation with genetic variants acting upon tissue-specific regulatory networks to generate local gene expression oscillations.

scholarly journals Population-scale long-read sequencing uncovers transposable elements contributing to gene expression variation and associated with adaptive signatures in Drosophila melanogaster

2021 ◽  
Author(s):  
Gabriel Rech ◽  
Santiago Radio ◽  
Sara Guirao-Rico ◽  
Laura Aguilera ◽  
Vivien Horvath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transposable Elements ◽  
Natural Populations ◽  
Gene Expression Variation ◽  
High Quality ◽  
Expression Variation ◽  
Climatic Regions ◽  
Genomic Studies ◽  
Reference Genomes

High quality reference genomes are crucial to understanding genome function, structure and evolution. The availability of reference genomes has allowed us to start inferring the role of genetic variation in biology, disease, and biodiversity conservation. However, analyses across organisms demonstrate that a single reference genome is not enough to capture the global genetic diversity present in populations. In this work, we generated 32 high-quality reference genomes for the well-known model species D. melanogaster and focused on the identification and analysis of transposable element variation as they are the most common type of structural variant. We showed that integrating the genetic variation across natural populations from five climatic regions increases the number of detected insertions by 58%. Moreover, 26% to 57% of the insertions identified using long-reads were missed by short-reads methods. We also identified hundreds of transposable elements associated with gene expression variation and new TE variants likely to contribute to adaptive evolution in this species. Our results highlight the importance of incorporating the genetic variation present in natural populations to genomic studies, which is essential if we are to understand how genomes function and evolve.

scholarly journals Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

2018 ◽  
Author(s):  
Eilis Hannon ◽  
Tyler J Gorrie-Stone ◽  
Melissa C Smart ◽  
Joe Burrage ◽  
Amanda Hughes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genetic Variation ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Complex Traits ◽  
Common Genetic Variation ◽  
Online Data ◽  
The Relationship ◽  
Methylation Quantitative Trait Loci

ABSTRACTCharacterizing the complex relationship between genetic, epigenetic and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. In this study, we describe the most comprehensive analysis of common genetic variation on DNA methylation (DNAm) to date, using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (P < 6.52x10-14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified using previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits, using Summary data–based Mendelian Randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression, identifying 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database (http://www.epigenomicslab.com/online-data-resources/) as a resource to the research community.

scholarly journals Auxin methylation is required for differential growth inArabidopsis

2018 ◽  
Vol 115 (26) ◽  
pp. 6864-6869 ◽  
Author(s):  
Mohamad Abbas ◽  
Jorge Hernández-García ◽  
Stephan Pollmann ◽  
Sophia L. Samodelov ◽  
Martina Kolb ◽  
...  
Keyword(s):  
Gene Expression ◽  
Auxin Transport ◽  
Polar Auxin Transport ◽  
Asymmetric Distribution ◽  
Loss Of Function ◽  
Differential Growth ◽  
Specific Expression ◽  
Auxin Homeostasis ◽  
Auxin Distribution ◽  
Gene Expression Levels

Asymmetric auxin distribution is instrumental for the differential growth that causes organ bending on tropic stimuli and curvatures during plant development. Local differences in auxin concentrations are achieved mainly by polarized cellular distribution of PIN auxin transporters, but whether other mechanisms involving auxin homeostasis are also relevant for the formation of auxin gradients is not clear. Here we show that auxin methylation is required for asymmetric auxin distribution across the hypocotyl, particularly during its response to gravity. We found that loss-of-function mutants inArabidopsis IAA CARBOXYL METHYLTRANSFERASE1(IAMT1) prematurely unfold the apical hook, and that their hypocotyls are impaired in gravitropic reorientation. This defect is linked to an auxin-dependent increase inPINgene expression, leading to an increased polar auxin transport and lack of asymmetric distribution of PIN3 in theiamt1mutant. Gravitropic reorientation in theiamt1mutant could be restored with either endodermis-specific expression ofIAMT1or partial inhibition of polar auxin transport, which also results in normalPINgene expression levels. We propose that IAA methylation is necessary in gravity-sensing cells to restrict polar auxin transport within the range of auxin levels that allow for differential responses.

scholarly journals CoMM: A Collaborative Mixed Model That Integrates GWAS and eQTL Data Sets to Investigate the Genetic Architecture of Complex Traits

2019 ◽  
Vol 13 ◽  
pp. 117793221988143 ◽  
Author(s):  
Kar-Fu Yeung ◽  
Yi Yang ◽  
Can Yang ◽  
Jin Liu
Keyword(s):  
Gene Expression ◽  
Association Study ◽  
Genetic Variants ◽  
Complex Traits ◽  
Mixed Model ◽  
Genome Wide Association Study ◽  
Data Sets ◽  
Transcriptome Data ◽  
Data Set ◽  
Expression Levels

Genome-wide association study (GWAS) analyses have identified thousands of associations between genetic variants and complex traits. However, it is still a challenge to uncover the mechanisms underlying the association. With the growing availability of transcriptome data sets, it has become possible to perform statistical analyses targeted at identifying influential genes whose expression levels correlate with the phenotype. Methods such as PrediXcan and transcriptome-wide association study (TWAS) use the transcriptome data set to fit a predictive model for gene expression, with genetic variants as covariates. The gene expression levels for the GWAS data set are then ‘imputed’ using the prediction model, and the imputed expression levels are tested for their association with the phenotype. These methods fail to account for the uncertainty in the GWAS imputation step, and we propose a collaborative mixed model (CoMM) that addresses this limitation by jointly modelling the multiple analysis steps. We illustrate CoMM’s ability to identify relevant genes in the Northern Finland Birth Cohort 1966 data set and extend the model to handle the more widely available GWAS summary statistics.

Expression profiles of metamorphosis-related genes during natural transformations in tadpoles of wild Wood Frogs (Lithobates sylvaticus)

2012 ◽  
Vol 90 (9) ◽  
pp. 1059-1071 ◽  
Author(s):  
Laia Navarro-Martín ◽  
Chantal Lanctôt ◽  
Christopher Edge ◽  
Jeff Houlahan ◽  
Vance L. Trudeau
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Rana Sylvatica ◽  
Fold Increase ◽  
Gonadal Development ◽  
Specific Expression ◽  
Wood Frogs ◽  
Lithobates Sylvaticus ◽  
Expression Levels ◽  
Gene Expression Levels

Numerous studies using laboratory-reared tadpoles have shown the importance of thyroid hormones (TH), thyroid receptors (TR), and deiodinase (Dio) enzymes during anuran metamorphosis. Our study focuses on the analysis of thyroid-related genes in tadpoles of wild Wood Frogs ( Lithobates sylvaticus (LeConte, 1825); also known as Rana sylvatica (Cope, 1889)) during metamorphosis. Results showed that, in concordance with laboratory-reared studies, thyroid receptor beta (trb) gene expression profiles presented the most marked changes. At climax and compared with premetamorphic stages, brains, tails, and gonad–mesonephros complex (GMC) tissues increased trb expression levels 5-, 21-, and 41-fold, respectively (p < 0.05). In addition, gene expression levels of brain deiodinase type II and III showed opposite trends, where 3-fold decrease and 10-fold increase were, respectively, found. This finding supports the idea that thyroid hormone, as it has been demonstrated in laboratory-reared tadpoles, is also involved in natural metamorphosis in wild tadpoles. Interestingly, and contrary to our predictions, we observed that whole brain corticotropin-releasing factor (crf) and crf receptor 1 (crfr1) gene expression levels significantly decrease through metamorphosis in wild L. sylvaticus tadpoles. Further analyses are required to determine if a role of TH in the timing of anuran gonadal development exists, as well as the importance of cell-specific and tissue-specific expression of crf and crfr1 to metamorphosis.

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.

scholarly journals Imputed gene associations identify replicable trans-acting genes enriched in transcription pathways and complex traits

2018 ◽  
Author(s):  
Heather E. Wheeler ◽  
Sally Ploch ◽  
Alvaro N. Barbeira ◽  
Rodrigo Bonazzola ◽  
Angela Andaleon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Complex Traits ◽  
Target Gene ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nucleic Acid Binding ◽  
Expression Of Genes ◽  
Gene Associations ◽  
Made In

AbstractRegulation of gene expression is an important mechanism through which genetic variation can affect complex traits. A substantial portion of gene expression variation can be explained by both local (cis) and distal (trans) genetic variation. Much progress has been made in uncovering cis-acting expression quantitative trait loci (cis-eQTL), but trans-eQTL have been more difficult to identify and replicate. Here we take advantage of our ability to predict the cis component of gene expression coupled with gene mapping methods such as PrediXcan to identify high confidence candidate trans-acting genes and their targets. That is, we correlate the cis component of gene expression with observed expression of genes in different chromosomes. Leveraging the shared cis-acting regulation across tissues, we combine the evidence of association across all available GTEx tissues and find 2356 trans-acting/target gene pairs with high mappability scores. Reassuringly, trans-acting genes are enriched in transcription and nucleic acid binding pathways and target genes are enriched in known transcription factor binding sites. Interestingly, trans-acting genes are more significantly associated with selected complex traits and diseases than target or background genes, consistent with percolating trans effects. Our scripts and summary statistics are publicly available for future studies of trans-acting gene regulation.

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