Transcriptome Sequencing Reveals Widespread Gene-Gene and Gene-Environment Interactions

Understanding the genetic architecture of gene expression is an intermediate step to understand the genetic architecture of complex diseases. RNA-seq technologies have improved the quantification of gene expression and allow to measure allelic specific expression (ASE)1-3. ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed to date. In this study we take advantage of a sample of twins to measure the relative contribution of genetic and environmental effects on ASE and we found substantial effects of gene x gene (GxG) and gene x environment (GxE) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants. We uncover large GxG and GxE effects on gene expression and likely complex phenotypes that currently remain elusive.

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How Nonshared Environmental Factors Come to Correlate with Heredity

10.31234/osf.io/6fdbe ◽

2020 ◽

Author(s):

Christopher Beam ◽

Patrizia Pezzoli ◽

Jane Mendle ◽

S. Alexandra Burt ◽

Michael C. Neale ◽

...

Keyword(s):

Environmental Factors ◽

Genetic Models ◽

Future Research ◽

Longitudinal Models ◽

Behavioral Genetic ◽

Relative Contribution ◽

Environment Effects ◽

Gene Environment ◽

Genetic And Environmental Factors ◽

Over Time

Conventional longitudinal behavioral genetic models estimate the relative contribution of genetic and environmental factors to stability and change of traits and behaviors. Longitudinal models rarely explain the processes that generate observed differences between genetically and socially related individuals. We propose that exchanges between people and their environments (i.e., phenotype-environment effects) can explain the emergence of observed differences over time. Such models, however, require violation of the independence assumption of standard behavioral genetic models, that is, uncorrelated genetic and environmental factors (Beam & Turkheimer, 2013; de Kort, Dolan, & Boomsma, 2012; Dolan, De Kort, Van Beijsterveldt, Bartels, & Boomsma, 2014). We review how specification of phenotype-environment effects contributes to understanding observed changes in genetic variability over time and longitudinal correlations among nonshared environmental factors. We then provide an example using 30 days of positive and negative affect scores from an all-female sample of twins. Results demonstrate that the phenotype-environment effects explain how heritability estimates fluctuate as well as how nonshared environmental factors persist over time. We discuss possible mechanisms underlying change in gene-environment correlation over time, the advantages and challenges of including gene-environment correlation in longitudinal twin models, and recommendations for future research.

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Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106554 ◽

2020 ◽

Vol 57 (8) ◽

pp. 519-527 ◽

Cited By ~ 1

Author(s):

Daniel Forrest Comiskey Jr. ◽

Huiling He ◽

Sandya Liyanarachchi ◽

Mehek S Sheikh ◽

Luke K Genutis ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Transcriptional Control ◽

Genome Wide Association Study ◽

Transcriptome Profiling ◽

Missense Variant ◽

Papillary Thyroid ◽

Specific Expression ◽

Relative Contribution ◽

Regulatory Variants

BackgroundPapillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34).MethodsWe report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis.ResultsWe observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis.ConclusionsOur study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

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

Molecular Biology and Evolution ◽

10.1093/molbev/msaa027 ◽

2020 ◽

Vol 37 (6) ◽

pp. 1593-1603 ◽

Cited By ~ 1

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.

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Mechanisms and modifiers of methylmercury-induced neurotoxicity

Toxicology Research ◽

10.1039/c2tx20010d ◽

2012 ◽

Vol 1 (1) ◽

pp. 32-38 ◽

Cited By ~ 23

Author(s):

Stephanie J. B. Fretham ◽

Samuel Caito ◽

Ebany J. Martinez-Finley ◽

Michael Aschner

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Environmental Factors ◽

Genetic Polymorphisms ◽

Experimental Studies ◽

Mehg Exposure ◽

Complete Understanding ◽

Cellular Processes ◽

Gene Environment ◽

Genetic And Environmental Factors

Abstract The neurotoxic consequences of methylmercury (MeHg) exposure have long been known, however a complete understanding of the mechanisms underlying this toxicity is elusive. Recent epidemiological and experimental studies have provided mechanistic insights into the contribution of genetic and environmental factors that interact with MeHg to modify toxicity. This review will outline cellular processes directly and indirectly affected by MeHg, including oxidative stress, cellular signaling and gene expression, and discuss epigenetic modifications, genetic polymorphisms and gene–environment interactions capable of modifying MeHg neurotoxicity.

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

10.1101/242792 ◽

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.

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The genetic architecture of gene expression levels in wild baboons

eLife ◽

10.7554/elife.04729 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 70

Author(s):

Jenny Tung ◽

Xiang Zhou ◽

Susan C Alberts ◽

Matthew Stephens ◽

Yoav Gilad

Keyword(s):

Gene Expression ◽

Genetic Architecture ◽

Eqtl Mapping ◽

Rna Seq ◽

Specific Expression ◽

Data Set ◽

Expression Levels ◽

Trait Locus ◽

Eqtl Data ◽

Gene Expression Levels

Primate evolution has been argued to result, in part, from changes in how genes are regulated. However, we still know little about gene regulation in natural primate populations. We conducted an RNA sequencing (RNA-seq)-based study of baboons from an intensively studied wild population. We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set. Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species. Further, they establish the feasibility of eQTL mapping using RNA-seq data alone, and represent an important step towards understanding the genetic architecture of gene expression in primates.

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Cis-regulatory variants affect gene expression dynamics in yeast

10.1101/2021.03.16.435665 ◽

2021 ◽

Author(s):

Ching-Hua Shih ◽

Justin C. Fay

Keyword(s):

Gene Expression ◽

Gene Activation ◽

Regulatory Sequences ◽

Diauxic Shift ◽

Promoter Regions ◽

Specific Expression ◽

Cis Acting ◽

Regulatory Variants ◽

Endogenous Expression ◽

Gene Expression Dynamics

Evolution of cis-regulatory sequences depends on how they effect gene expression and motivates both the identification and prediction of cis-regulatory variants responsible for expression differences within and between species. While much progress has been made in relating cis-regulatory variants to expression levels, the timing of gene activation and repression may also be important to the evolution of cis-regulatory sequences. We investigated allele-specific expression (ASE) dynamics within and between Saccharomyces species during the diauxic shift and found appreciable cis-acting variation in gene expression dynamics. Within species ASE is associated with intergenic variants, but ASE dynamics are more strongly associated with insertions and deletions than ASE levels. To refine these associations we used a high-throughput reporter assay to test promoter regions and individual variants. Within the subset of regions that recapitulated endogenous expression we identified and characterized cis-regulatory variants that affect expression dynamics. Between species, chimeric promoter regions generate novel patterns and indicate constraints on the evolution of gene expression dynamics. We conclude that changes in cis-regulatory sequences can tune gene expression dynamics and that the interplay between expression dynamics and other aspects expression are relevant to the evolution of cis-regulatory sequences.

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How nonshared environmental factors come to correlate with heredity

Development and Psychopathology ◽

10.1017/s0954579420001017 ◽

2020 ◽

pp. 1-13

Author(s):

Christopher R. Beam ◽

Patrizia Pezzoli ◽

Jane Mendle ◽

S. Alexandra Burt ◽

Michael C. Neale ◽

...

Keyword(s):

Environmental Factors ◽

Genetic Models ◽

Future Research ◽

Longitudinal Models ◽

Behavioral Genetic ◽

Relative Contribution ◽

Environment Effects ◽

Gene Environment ◽

Genetic And Environmental Factors ◽

Over Time

Abstract Conventional longitudinal behavioral genetic models estimate the relative contribution of genetic and environmental factors to stability and change of traits and behaviors. Longitudinal models rarely explain the processes that generate observed differences between genetically and socially related individuals. We propose that exchanges between individuals and their environments (i.e., phenotype–environment effects) can explain the emergence of observed differences over time. Phenotype–environment models, however, would require violation of the independence assumption of standard behavioral genetic models; that is, uncorrelated genetic and environmental factors. We review how specification of phenotype–environment effects contributes to understanding observed changes in genetic variability over time and longitudinal correlations among nonshared environmental factors. We then provide an example using 30 days of positive and negative affect scores from an all-female sample of twins. Results demonstrate that the phenotype–environment effects explain how heritability estimates fluctuate as well as how nonshared environmental factors persist over time. We discuss possible mechanisms underlying change in gene–environment correlation over time, the advantages and challenges of including gene–environment correlation in longitudinal twin models, and recommendations for future research.

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Monoallelic expression of the human FOXP2 speech gene

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1411270111 ◽

2014 ◽

Vol 112 (22) ◽

pp. 6848-6854 ◽

Cited By ~ 22

Author(s):

Abidemi A. Adegbola ◽

Gerald F. Cox ◽

Elizabeth M. Bradshaw ◽

David A. Hafler ◽

Alexander Gimelbrant ◽

...

Keyword(s):

Gene Expression ◽

Monoallelic Expression ◽

Language Deficits ◽

Specific Expression ◽

Mendelian Disorders ◽

Forkhead Box ◽

Number Of Genes ◽

Allele Specific ◽

In Cis ◽

The Relationship

The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations.

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Impact of the X chromosome and sex on regulatory variation

10.1101/024117 ◽

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.

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