Evolutionary mechanisms: Modularity, morphogenetic fields of gene expression, genetic regulation

Task allocation among social insect workers is an ideal framework for studying the molecular mechanisms underlying behavioural plasticity because workers of similar genotype adopt different behavioural phenotypes. Elegant laboratory studies have pioneered this effort, but field studies involving the genetic regulation of task allocation are rare. Here, we investigate the expression of the foraging gene in harvester ant workers from five age- and task-related groups in a natural population, and we experimentally test how exposure to light affects foraging expression in brood workers and foragers. Results from our field study show that the regulation of the foraging gene in harvester ants occurs at two time scales: levels of foraging mRNA are associated with ontogenetic changes over weeks in worker age, location and task, and there are significant daily oscillations in foraging expression in foragers. The temporal dissection of foraging expression reveals that gene expression changes in foragers occur across a scale of hours and the level of expression is predicted by activity rhythms: foragers have high levels of foraging mRNA during daylight hours when they are most active outside the nests. In the experimental study, we find complex interactions in foraging expression between task behaviour and light exposure. Oscillations occur in foragers following experimental exposure to 13 L : 11 D (LD) conditions, but not in brood workers under similar conditions. No significant differences were seen in foraging expression over time in either task in 24 h dark (DD) conditions. Interestingly, the expression of foraging in both undisturbed field and experimentally treated foragers is also significantly correlated with the expression of the circadian clock gene, cycle . Our results provide evidence that the regulation of this gene is context-dependent and associated with both ontogenetic and daily behavioural plasticity in field colonies of harvester ants. Our results underscore the importance of assaying temporal patterns in behavioural gene expression and suggest that gene regulation is an integral mechanism associated with behavioural plasticity in harvester ants.

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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

10.1101/483107 ◽

2018 ◽

Cited By ~ 1

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.

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Nuclear genetic regulation of the human mitochondrial transcriptome

eLife ◽

10.7554/elife.41927 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Aminah T Ali ◽

Lena Boehme ◽

Guillermo Carbajosa ◽

Vlad C Seitan ◽

Kerrin S Small ◽

...

Keyword(s):

Gene Expression ◽

Mitochondrial Genome ◽

Complex Disease ◽

Genetic Regulation ◽

Cell Types ◽

Tissue Cell ◽

Cellular Processes ◽

Genetic Mechanisms ◽

Cell Type Specific ◽

Nuclear Loci

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.

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Faculty Opinions recommendation of Dynamic genetic regulation of gene expression during cellular differentiation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736057096.793563104 ◽

2019 ◽

Author(s):

Robert Copeland

Keyword(s):

Gene Expression ◽

Cellular Differentiation ◽

Genetic Regulation ◽

Regulation Of Gene Expression

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

Cells ◽

10.3390/cells10102611 ◽

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.

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MOSTWAS: Multi-Omic Strategies for Transcriptome-Wide Association Studies

10.1101/2020.04.17.047225 ◽

2020 ◽

Cited By ~ 2

Author(s):

Arjun Bhattacharya ◽

Yun Li ◽

Michael I. Love

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Brain Tissue ◽

Predictive Models ◽

Association Studies ◽

Genetic Regulation ◽

Breast Tumors ◽

Risk Genes ◽

Complex Interactions ◽

Trait Associations

ABSTRACTTraditional predictive models for transcriptome-wide association studies (TWAS) consider only single nucleotide polymorphisms (SNPs) local to genes of interest and perform parameter shrinkage with a regularization process. These approaches ignore the effect of distal-SNPs or other molecular effects underlying the SNP-gene association. Here, we outline multi-omics strategies for transcriptome imputation from germline genetics to allow more powerful testing of gene-trait associations by prioritizing distal-SNPs to the gene of interest. In one extension, we identify mediating biomarkers (CpG sites, microRNAs, and transcription factors) highly associated with gene expression and train predictive models for these mediators using their local SNPs. Imputed values for mediators are then incorporated into the final predictive model of gene expression, along with local SNPs. In the second extension, we assess distal-eQTLs (SNPs associated with genes not in a local window around it) for their mediation effect through mediating biomarkers local to these distal-eSNPs. Distal-eSNPs with large indirect mediation effects are then included in the transcriptomic prediction model with the local SNPs around the gene of interest. Using simulations and real data from ROS/MAP brain tissue and TCGA breast tumors, we show considerable gains of percent variance explained (1-2% additive increase) of gene expression and TWAS power to detect gene-trait associations. This integrative approach to transcriptome-wide imputation and association studies aids in identifying the complex interactions underlying genetic regulation within a tissue and important risk genes for various traits and disorders.AUTHOR SUMMARYTranscriptome-wide association studies (TWAS) are a powerful strategy to study gene-trait associations by integrating genome-wide association studies (GWAS) with gene expression datasets. TWAS increases study power and interpretability by mapping genetic variants to genes. However, traditional TWAS consider only variants that are close to a gene and thus ignores important variants far away from the gene that may be involved in complex regulatory mechanisms. Here, we present MOSTWAS (Multi-Omic Strategies for TWAS), a suite of tools that extends the TWAS framework to include these distal variants. MOSTWAS leverages multi-omic data of regulatory biomarkers (transcription factors, microRNAs, epigenetics) and borrows from techniques in mediation analysis to prioritize distal variants that are around these regulatory biomarkers. Using simulations and real public data from brain tissue and breast tumors, we show that MOSTWAS improves upon traditional TWAS in both predictive performance and power to detect gene-trait associations. MOSTWAS also aids in identifying possible mechanisms for gene regulation using a novel added-last test that assesses the added information gained from the distal variants beyond the local association. In conclusion, our method aids in detecting important risk genes for traits and disorders and the possible complex interactions underlying genetic regulation within a tissue.

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The vasopressin mRNA poly(A) tract is unusually long and increases during stimulation of vasopressin gene expression in vivo.

Molecular and Cellular Biology ◽

10.1128/mcb.8.6.2267 ◽

1988 ◽

Vol 8 (6) ◽

pp. 2267-2274 ◽

Cited By ~ 96

Author(s):

E J Carrazana ◽

K B Pasieka ◽

J A Majzoub

Keyword(s):

Gene Expression ◽

Osmotic Stress ◽

Genetic Regulation ◽

Tail Length ◽

Rnase H ◽

The Body ◽

Base Line ◽

Tract Length ◽

Stimulation Of

We developed a method, termed an H-blot, by which the poly(A) tract of any specific mRNA may be detected by RNA filter hybridization after its removal from the body of the mRNA by a RNase H-catalyzed endonucleolytic cleavage in the 3' untranslated region. Using this method, we studied the modulation of the length of the poly(A) tract of rat vasopressin mRNA in vivo during changes in the levels of this mRNA resulting from a physiologic stimulus, osmotic stress. The poly(A) tract of hypothalamic vasopressin mRNA in hydrated rats was, quite remarkably, approximately 250 nucleotides in length, in contrast to that of somatostatin mRNA, which was approximately 30 nucleotides long. Vasopressin mRNA poly(A) tail length increased progressively from approximately 250 to approximately 400 nucleotides with the application of the hyperosmotic stimulus and declined to base line after its removal; somatostatin mRNA poly(A) tail length did not change during osmotic stress. The poly(A) tract length of total hypothalamic mRNA was between 35 and 140 nucleotides and also did not change with osmotic stress. Modulation of poly(A) tract length of specific mRNAs during stimulation of gene expression may provide an additional level of genetic regulation.

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Endopeptidase PepO Regulates the SpeB Cysteine Protease and Is Essential for the Virulence of Invasive M1T1Streptococcus pyogenes

Journal of Bacteriology ◽

10.1128/jb.00654-17 ◽

2018 ◽

Vol 200 (8) ◽

Cited By ~ 7

Author(s):

Stephan Brouwer ◽

Amanda J. Cork ◽

Cheryl-Lynn Y. Ong ◽

Timothy C. Barnett ◽

Nicholas P. West ◽

...

Keyword(s):

Gene Expression ◽

Growth Phase ◽

Cysteine Protease ◽

Genetic Regulation ◽

Bacterial Pathogen ◽

Targeted Mutagenesis ◽

Human Neutrophils ◽

Content Type ◽

Wide Range ◽

Human Infections

ABSTRACTStreptococcus pyogenes(group AStreptococcus[GAS]) causes a wide range of human infections. The pathogenesis of GAS infections is dependent on the temporal expression of numerous secreted and surface-associated virulence factors that interact with host proteins. Streptococcal pyrogenic exotoxin B (SpeB) is one of the most extensively studied toxins produced by GAS, and the coordinate growth phase-dependent regulation ofspeBexpression is linked to disease severity phenotypes. Here, we identified the endopeptidase PepO as a novel growth phase-dependent regulator of SpeB in the invasive GAS M1 serotype strain 5448. By using transcriptomics followed by quantitative reverse transcriptase PCR and Western blot analyses, we demonstrate through targeted mutagenesis that PepO influences growth phase-dependent induction ofspeBgene expression. Compared to wild-type and complemented mutant strains, we demonstrate that the 5448ΔpepOmutant strain is more susceptible to killing by human neutrophils and is attenuated in virulence in a murine model of invasive GAS infection. Our results expand the complex regulatory network that is operating in GAS to control SpeB production and suggest that PepO is a virulence requirement during GAS M1T1 strain 5448 infections.IMPORTANCEDespite the continuing susceptibility ofS. pyogenesto penicillin, this bacterial pathogen remains a leading infectious cause of global morbidity and mortality. A particular subclone of the M1 serotype (M1T1) has persisted globally for decades as the most frequently isolated serotype from patients with invasive and noninvasive diseases in Western countries. One of the key GAS pathogenicity factors is the potent broad-spectrum cysteine protease SpeB. Although there has been extensive research interest on the regulatory mechanisms that controlspeBgene expression, its genetic regulation is not fully understood. Here, we identify the endopeptidase PepO as a new regulator ofspeBgene expression in the globally disseminated M1T1 clone and as being essential for virulence.

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