Dense encoding of developmental regulatory information may constrain evolvability

AbstractGene regulatory changes underlie much of phenotypic evolution. However, the evolutionary potential of regulatory evolution is unknown, because most evidence comes from either natural variation or limited experimental perturbations. Surveying an unbiased mutation library for a developmental enhancer in Drosophila melanogaster using an automated robotics pipeline, we found that most mutations alter gene expression. Our results suggest that regulatory information is distributed throughout most of a developmental enhancer and that parameters of gene expression—levels, location, and state—are convolved. The widespread pleiotropic effects of most mutations and the codependency of outputs may constrain the evolvability of developmental enhancers. Consistent with these observations, comparisons of diverse drosophilids reveal mainly stasis and apparent biases in the phenotypes influenced by this enhancer. Developmental enhancers may encode a much higher density of regulatory information than has been appreciated previously, which may impose constraints on regulatory evolution.Quote“Rock, robot rockRock, robot rockRock, robot rock”Daft Punk (2005)

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Gene-regulatory elements may change the amount, timing, or location of gene expression, cis-Regulation therapy platforms might become a gene therapy to treat many genetic diseases

10.31219/osf.io/xc5a2 ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Expression ◽

Genetic Diseases ◽

Regulatory Elements ◽

Tissue Type ◽

Gene Promoters ◽

Expression Levels ◽

Cis Regulation ◽

Gene Regulatory Elements ◽

Gene Regulatory ◽

Gene Expression Levels

Changes in gene expression levels above or below a particular threshold may have a dramatic impact on phenotypes, leading to a wide spectrum of human illnesses. Gene-regulatory elements, also known as cis-regulatory elements (CREs), may change the amount, timing, or location (cell/tissue type) of gene expression, whereas mutations in a gene's coding sequence may result in lower or higher gene expression levels resulting in protein loss or gain. Loss-of-function mutations in both genes produce recessive human illness, while haploinsufficient mutations in 65 genes are also known to be deleterious due to function gain, according to the ClinVar1 and ClinGen3 databases. CREs are promoters living near to a gene's transcription start site and switching it on at predefined times, places, and levels. Other distal CREs, like enhancers and silencers, are temporal and tissue-specific control promoters. Enhancers activate promoters, commonly referred to as "promoters," whereas silencers turn them off. Insulators also restrict promiscuous interactions between enhancers and gene promoters. Systematic genomic approaches can help understand the cis-regulatory circuitry of gene expression by highly detecting and functionally defining these CREs. This includes the new use of CRISPR–CRISPR-associated protein 9 (CRISPR–Cas9) and other editing approaches to discover CREs. Cis-Regulation therapy (CRT) provides many promises to heal human ailments. CRT may be used to upregulate or downregulate disease-causing genes due to lower or higher levels of expression, and it may also be used to precisely adjust the expression of genes that assist in alleviating disease features. CRT may employ proteins that generate epigenetic modifications like methylation, histone modification, or gene expression regulation looping. Weighing CRT's advantages and downsides against alternative treatment methods is crucial. CRT platforms might become a practical technique to treat many genetic diseases that now lack treatment alternatives if academics, patient communities, clinicians, regulators and industry work together.

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Characterization of the genetic architecture underlying eye size variation within Drosophila melanogaster and Drosophila simulans

10.1101/555698 ◽

2019 ◽

Author(s):

Pedro Gaspar ◽

Saad Arif ◽

Lauren Sumner-Rooney ◽

Maike Kittelmann ◽

Andrew J. Bodey ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Natural Variation ◽

Size Variation ◽

Eye Size ◽

Specific Variation ◽

Gene Regulatory ◽

Morphological Differences ◽

Genomic Regions ◽

Insect Eye

AbstractThe compound eyes of insects exhibit striking variation in size, reflecting adaptation to different lifestyles and habitats. However, the genetic and developmental bases of variation in insect eye size is poorly understood, which limits our understanding of how these important morphological differences evolve. To address this, we further explored natural variation in eye size within and between four species of the Drosophila melanogaster species subgroup. We found extensive variation in eye size among these species, and flies with larger eyes generally had a shorter inter-ocular distance and vice versa. We then carried out quantitative trait loci (QTL) mapping of intra-specific variation in eye size and inter-ocular distance in both D. melanogaster and D. simulans. This revealed that different genomic regions underlie variation in eye size and inter-ocular distance in both species, which we corroborated by introgression mapping in D. simulans. This suggests that although there is a trade-off between eye size and inter-ocular distance, variation in these two traits is likely to be caused by different genes and so can be genetically decoupled. Finally, although we detected QTL for intra-specific variation in eye size at similar positions in D. melanogaster and D. simulans, we observed differences in eye fate commitment between strains of these two species. This indicates that different developmental mechanisms and therefore, most likely, different genes contribute to eye size variation in these species. Taken together with the results of previous studies, our findings suggest that the gene regulatory network that specifies eye size has evolved at multiple genetic nodes to give rise to natural variation in this trait within and among species.

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Evolution of Gene Expression and Splicing in Parallel Cold-Adapted Fly Populations

10.1101/795716 ◽

2019 ◽

Author(s):

Yuheng Huang ◽

Justin B. Lack ◽

Grant T. Hoppel ◽

John E. Pool

Keyword(s):

Gene Expression ◽

Adaptive Evolution ◽

Parallel Evolution ◽

Population Variation ◽

Regulatory Evolution ◽

Cold Adapted ◽

Mitochondrial Functions ◽

Expression Evolution ◽

Gene Regulatory ◽

Trans Regulation

AbstractChanges in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have assayed within- and between-population variation in gene regulatory traits at a transcriptomic scale, and therefore inferences about the characteristics of adaptive regulatory changes have been elusive. Here, we assess quantitative trait differentiation in gene expression levels and alternative splicing (intron usage) between three closely-related pairs of natural populations of Drosophila melanogaster from contrasting thermal environments that reflect three separate instances of cold tolerance evolution. The cold-adapted populations were known to show population genetic evidence for parallel evolution at the SNP level, and here we find significant although somewhat limited evidence for parallel expression evolution between them, and less evidence for parallel splicing evolution. We find that genes with mitochondrial functions are particularly enriched among candidates for adaptive expression evolution. We also develop a method to estimate cis-versus trans-encoded contributions to expression or splicing differences that does not rely on the presence of fixed differences between parental strains. Applying this method, we infer important roles of both cis-and trans-regulation among our putatively adaptive expression and splicing differences. The apparent contributions of cis-versus trans-regulation to adaptive evolution vary substantially among population pairs, with an Ethiopian pair showing pervasive trans-effects, suggesting that basic characteristics of regulatory evolution may depend on biological context. These findings expand our knowledge of adaptive gene regulatory evolution and our ability to make inferences about this important and widespread process.

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Redundant and cryptic enhancer activities of the Drosophila yellow gene

10.1101/419226 ◽

2018 ◽

Author(s):

Gizem Kalay ◽

Jennifer Lachowiec ◽

Ulises Rosas ◽

Mackenzie R. Dome ◽

Patricia Wittkopp

Keyword(s):

Gene Expression ◽

Drosophila Melanogaster ◽

Dna Sequences ◽

Model System ◽

Drosophila Species ◽

Drosophila Pseudoobscura ◽

Regulatory Sequences ◽

Phenotypic Evolution ◽

Evolutionary Changes ◽

And Function

Abstractcis-regulatory sequences known as enhancers play a key role in regulating gene expression. Evolutionary changes in these DNA sequences contribute to phenotypic evolution. The Drosophila yellow gene, which is required for pigmentation, has emerged as a model system for understanding how cis-regulatory sequences evolve, providing some of the most detailed insights available into how activities of orthologous enhancers have diverged between species. Here, we examine the evolution of yellow cis-regulatory sequences on a broader scale by comparing the distribution and function of yellow enhancer activities throughout the 5’ intergenic and intronic sequences of Drosophila melanogaster, Drosophila pseudoobscura, and Drosophila willistoni. We find that cis-regulatory sequences driving expression in a particular tissue are not as modular as previously described, but rather have many redundant and cryptic enhancer activities distributed throughout the regions surveyed. Interestingly, cryptic enhancer activities of sequences from one species often drove patterns of expression observed in other species, suggesting that the frequent evolutionary changes in yellow expression observed among Drosophila species may be facilitated by gaining and losing repression of pre-existing cis-regulatory sequences.

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Gene expression is encoded in all parts of a co-evolving interacting gene regulatory structure

10.1101/792531 ◽

2019 ◽

Author(s):

Jan Zrimec ◽

Filip Buric ◽

Azam Sheikh Muhammad ◽

Rhongzen Chen ◽

Vilhelm Verendel ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Regulation ◽

Model Organisms ◽

Regulatory Structure ◽

Expression Levels ◽

Coding Regions ◽

Dna Regulatory Motifs ◽

Gene Regulatory ◽

The Individual ◽

Gene Expression Levels

AbstractUnderstanding the genetic regulatory code that governs gene expression is a primary, yet challenging aspiration in molecular biology that opens up possibilities to cure human diseases and solve biotechnology problems. However, the fundamental question of how each of the individual coding and non-coding regions of the gene regulatory structure interact and contribute to the mRNA expression levels remains unanswered. Considering that all the information for gene expression regulation is already present in living cells, here we applied deep learning on over 20,000 mRNA datasets in 7 model organisms ranging from bacteria to Human. We show that in all organisms, mRNA abundance can be predicted directly from the DNA sequence with high accuracy, demonstrating that up to 82% of the variation of gene expression levels is encoded in the gene regulatory structure. Coding and non-coding regions carry both overlapping and orthogonal information and additively contribute to gene expression levels. By searching for DNA regulatory motifs present across the whole gene regulatory structure, we discover that motif interactions can regulate gene expression levels in a range of over three orders of magnitude. The uncovered co-evolution of coding and non-coding regions challenges the current paradigm that single motifs or regions are solely responsible for gene expression levels. Instead, we show that the correct combination of all regulatory regions must be established in order to accurately control gene expression levels. Therefore, the holistic system that spans the entire gene regulatory structure is required to analyse, understand, and design any future gene expression systems.

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Automated generation of context-specific gene regulatory networks with a weighted approach in Drosophila melanogaster

Interface Focus ◽

10.1098/rsfs.2020.0076 ◽

2021 ◽

Vol 11 (4) ◽

pp. 20200076 ◽

Cited By ~ 1

Author(s):

Leandro Murgas ◽

Sebastian Contreras-Riquelme ◽

J. Eduardo Martínez-Hernandez ◽

Camilo Villaman ◽

Rodrigo Santibáñez ◽

...

Keyword(s):

Gene Expression ◽

Drosophila Melanogaster ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Current Knowledge ◽

Regulation Of Gene Expression ◽

Reference Network ◽

Specific Gene ◽

Gene Regulatory ◽

Context Specific

The regulation of gene expression is a key factor in the development and maintenance of life in all organisms. Even so, little is known at whole genome scale for most genes and contexts. We propose a method, Tool for Weighted Epigenomic Networks in Drosophila melanogaster (Fly T-WEoN), to generate context-specific gene regulatory networks starting from a reference network that contains all known gene regulations in the fly. Unlikely regulations are removed by applying a series of knowledge-based filters. Each of these filters is implemented as an independent module that considers a type of experimental evidence, including DNA methylation, chromatin accessibility, histone modifications and gene expression. Fly T-WEoN is based on heuristic rules that reflect current knowledge on gene regulation in D. melanogaster obtained from the literature. Experimental data files can be generated with several standard procedures and used solely when and if available. Fly T-WEoN is available as a Cytoscape application that permits integration with other tools and facilitates downstream network analysis. In this work, we first demonstrate the reliability of our method to then provide a relevant application case of our tool: early development of D. melanogaster . Fly T-WEoN together with its step-by-step guide is available at https://weon.readthedocs.io .

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Structure and Evolution of Constitutive Bacterial Promoters

10.1101/2020.05.19.104232 ◽

2020 ◽

Author(s):

Mato Lagator ◽

Srdjan Sarikas ◽

Magdalena Steinrück ◽

David Toledo-Aparicio ◽

Jonathan P. Bollback ◽

...

Keyword(s):

Gene Expression ◽

Binding Sites ◽

Structural Features ◽

Biophysical Model ◽

Regulatory Evolution ◽

Random Sequences ◽

Expression Levels ◽

Constitutive Gene Expression ◽

Polymerase Binding ◽

Gene Expression Levels

AbstractPredicting gene expression levels from any DNA sequence is a major challenge in biology. Using libraries with >25,000 random mutants, we developed a biophysical model that accounts for major features of σ70-binding bacterial promoters to accurately predict constitutive gene expression levels of any sequence. We experimentally and theoretically estimated that 10-20% of random sequences lead to expression and 82% of non-expressing sequences are one point mutation away from a functional promoter. Generating expression from random sequences is pervasive, such that selection acts against σ70-RNA polymerase binding sites even within inter-genic, promoter-containing regions. The pervasiveness of σ70– binding sites, which arises from the structural features of promoters captured by our biophysical model, implies that their emergence is unlikely the limiting step in gene regulatory evolution.

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Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity

10.1101/2020.07.02.184036 ◽

2020 ◽

Author(s):

F. He ◽

K. A. Steige ◽

V. Kovacova ◽

U. Göbel ◽

M. Bouzid ◽

...

Keyword(s):

Gene Expression ◽

Plastic Response ◽

Regulatory Evolution ◽

Individual Fitness ◽

Regulatory Variants ◽

Regulatory Changes ◽

Direction Of Effects ◽

Selective Forces ◽

Response To Stress ◽

New Mutations

AbstractPhenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response between A. thaliana and the sister species A. lyrata and A. halleri depends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response in A. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently in A. halleri. Our results demonstrate that pre-existing plasticity can be a stepping stone for adaptation, but its selective remodeling differs between lineages.

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Characterization of the Genetic Architecture Underlying Eye Size Variation Within Drosophila melanogaster and Drosophila simulans

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400877 ◽

2020 ◽

Vol 10 (3) ◽

pp. 1005-1018 ◽

Cited By ~ 5

Author(s):

Pedro Gaspar ◽

Saad Arif ◽

Lauren Sumner-Rooney ◽

Maike Kittelmann ◽

Andrew J. Bodey ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Natural Variation ◽

Size Variation ◽

Eye Size ◽

Specific Variation ◽

Gene Regulatory ◽

Morphological Differences ◽

Genomic Regions ◽

Insect Eye

The compound eyes of insects exhibit striking variation in size, reflecting adaptation to different lifestyles and habitats. However, the genetic and developmental bases of variation in insect eye size is poorly understood, which limits our understanding of how these important morphological differences evolve. To address this, we further explored natural variation in eye size within and between four species of the Drosophila melanogaster species subgroup. We found extensive variation in eye size among these species, and flies with larger eyes generally had a shorter inter-ocular distance and vice versa. We then carried out quantitative trait loci (QTL) mapping of intra-specific variation in eye size and inter-ocular distance in both D. melanogaster and D. simulans. This revealed that different genomic regions underlie variation in eye size and inter-ocular distance in both species, which we corroborated by introgression mapping in D. simulans. This suggests that although there is a trade-off between eye size and inter-ocular distance, variation in these two traits is likely to be caused by different genes and so can be genetically decoupled. Finally, although we detected QTL for intra-specific variation in eye size at similar positions in D. melanogaster and D. simulans, we observed differences in eye fate commitment between strains of these two species. This indicates that different developmental mechanisms and therefore, most likely, different genes contribute to eye size variation in these species. Taken together with the results of previous studies, our findings suggest that the gene regulatory network that specifies eye size has evolved at multiple genetic nodes to give rise to natural variation in this trait within and among species.

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Modulation and Evolution of Animal Development through microRNA Regulation of Gene Expression

Genes ◽

10.3390/genes10040321 ◽

2019 ◽

Vol 10 (4) ◽

pp. 321 ◽

Cited By ~ 12

Author(s):

Kittelmann ◽

McGregor

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Regulation Of Gene Expression ◽

Feedback Loops ◽

Phenotypic Evolution ◽

Regulate Gene Expression ◽

Microrna Regulation ◽

Animal Development ◽

Gene Regulatory ◽

Developmental Buffering

microRNAs regulate gene expression by blocking the translation of mRNAs and/or promoting their degradation. They, therefore, play important roles in gene regulatory networks (GRNs) by modulating the expression levels of specific genes and can tune GRN outputs more broadly as part of feedback loops. These roles for microRNAs provide developmental buffering on one hand but can facilitate evolution of development on the other. Here we review how microRNAs can modulate GRNs during animal development as part of feedback loops and through their individual or combinatorial targeting of multiple different genes in the same network. We then explore how changes in the expression of microRNAs and consequently targets can facilitate changes in GRNs that alter development and lead to phenotypic evolution. The reviewed studies exemplify the key roles played by microRNAs in the regulation and evolution of gene expression during developmental processes in animals.

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