scholarly journals Recapitulating Evolutionary Divergence in a Single Cis-Regulatory Element Is Sufficient to Cause Expression Changes of the Lens Gene Tdrd7

2020 ◽  
Author(s):  
Juliana G Roscito ◽  
Kaushikaram Subramanian ◽  
Ronald Naumann ◽  
Mihail Sarov ◽  
Anna Shevchenko ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Mrna Level ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Phenotypic Differences ◽  
Evolutionary Changes ◽  
Mole Rat ◽  
Regulatory Mutations ◽  
Subterranean Mammals ◽  
And Function

Abstract Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR; Nannospalax galili) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved noncoding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated evolutionary changes in this element by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR–Cas9. Strikingly, this repressor replacement caused a more than 2-fold upregulation of Tdrd7 in the developing lens; however, increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, possibly explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

scholarly journals Recapitulating evolutionary divergence in a single cis-regulatory element is sufficient to cause expression changes of the lens gene Tdrd7

2020 ◽  
Author(s):  
Juliana G. Roscito ◽  
Kaushikaram Subramanian ◽  
Ronald Naumann ◽  
Mihail Sarov ◽  
Anna Shevchenko ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Mrna Level ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Phenotypic Differences ◽  
Evolutionary Changes ◽  
Mole Rat ◽  
Regulatory Mutations ◽  
Subterranean Mammals ◽  
And Function

ABSTRACTMutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated the evolutionary changes by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor element has a large effect, causing a more than two-fold up-regulation of Tdrd7 in developing lens. Interestingly, the increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, likely explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

scuteexpression inCalliphora vicinareveals an ancestral pattern of longitudinal stripes on the thorax of higher Diptera

Development ◽  
2002 ◽  
Vol 129 (3) ◽  
pp. 563-572 ◽  
Author(s):  
Daniela Pistillo ◽  
Nick Skaer ◽  
Pat Simpson
Keyword(s):  
Expression Pattern ◽  
Regulatory Elements ◽  
Calliphora Vicina ◽  
Transcriptional Activators ◽  
Gene Complex ◽  
Secondary Loss ◽  
Evolutionary Changes ◽  
Sensory Bristles ◽  
And Function ◽  
Bristle Patterns

In Drosophila the stereotyped arrangement of sensory bristles on the notum is determined by the tightly regulated control of transcription of the achaete-scute (ac-sc) genes which are expressed in small proneural clusters of cells at the sites of each future bristle. Expression relies on a series of discrete cis-regulatory elements present in the ac-sc gene complex that are the target of the transcriptional activators pannier (pnr) and the genes of the iroquois complex. Stereotyped bristle patterns are common among species of acalyptrate Schizophora such as Drosophila, and are thought to have derived from an ancestral pattern of four longitudinal rows extending the length of the scutum, through secondary loss of bristles. To investigate evolutionary changes in bristle patterns and ac-sc regulation by pnr, we have isolated homologues of these genes from Calliphora vicina, a species of calyptrate Schizophora separated from Drosophila by at least 100 million years. Calliphora vicina displays a pattern of four rows of bristles on the scutum resembling the postulated ancestral one. We find that sc in Calliphora is expressed in two longitudinal stripes on the medial scutum that prefigure the development of the rows of acrostichal and dorsocentral bristles. This result suggests that a stripe-like expression pattern of sc may be an ancestral feature and may have preceded the evolution of proneural clusters. The implications for the evolution of the cis-regulatory elements responsible for sc expression in the proneural clusters of Drosophila, and function of Pnr are discussed.

scholarly journals Phylogenetic modeling of regulatory element turnover based on epigenomic data

2019 ◽  
Author(s):  
Noah Dukler ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Dna Sequence ◽  
Target Genes ◽  
Evolutionary Dynamics ◽  
Regulatory Element ◽  
Probabilistic Modeling ◽  
Regulatory Elements ◽  
Turnover Rates ◽  
Modeling Framework ◽  
Model Free ◽  
Evolutionary Changes

AbstractEvolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multi-species epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.

scholarly journals Genomic organization, expression, and phylogenetic analysis of Ca2+ channel β4 genes in 13 vertebrate species

2008 ◽  
Vol 35 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Alicia M. Ebert ◽  
Catherine A. McAnelly ◽  
Anne V. Handschy ◽  
Rachel Lockridge Mueller ◽  
William A. Horne ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Alternative Splicing ◽  
Membrane Trafficking ◽  
Sequence Divergence ◽  
Tissue Expression ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Voltage Dependent ◽  
Intron Structure ◽  
And Function

The Ca2+ channel β-subunits, encoded by CACNB genes 1–4, are membrane-associated guanylate kinase (MAGUK) proteins. As auxiliary subunits of voltage-gated Ca2+ channels, the β-subunits facilitate membrane trafficking of the pore-forming α1 subunits and regulate voltage-dependent channel gating. In this report, we investigate whether two zebrafish β4 genes, β4.1 and β4.2, have diverged in structure and function over time. Comparative expression analyses indicated that β4.1 and β4.2 were expressed in separable domains within the developing brain and other tissues. Alternative splicing in both genes was subject to differential temporal and spatial regulation, with some organs expressing different subsets of β4.1 and β4.2 transcript variants. We used several genomic tools to identify and compare predicted cDNAs for eight teleost and five tetrapod β4 genes. Teleost species had either one or two β4 paralogs, whereas each tetrapod species contained only one. Teleost β4.1 and β4.2 genes had regions of sequence divergence, but compared with tetrapod β4s, they exhibited similar exon/intron structure, strong conservation of residues involved in α1 subunit binding, and similar 5′ alternative splicing. Phylogenetic results are consistent with the duplicate teleost β4 genes resulting from the teleost whole genome duplication. Following duplication, the β4.1 genes have evolved faster than β4.2 genes. We identified disproportionately large second and third introns in several β4 genes, which we propose may provide regulatory elements contributing to their differential tissue expression. In sum, both mRNA expression data and phylogenetic analysis support the evolutionary divergence of β4.1 and β4.2 subunit function.

scholarly journals Evolutionary changes in transcription factor coding sequence quantitatively alter sensory organ development and function

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Simon Weinberger ◽  
Matthew P Topping ◽  
Jiekun Yan ◽  
Annelies Claeys ◽  
Natalie De Geest ◽  
...  
Keyword(s):  
Morphological Evolution ◽  
Regulatory Elements ◽  
Sensory Organ ◽  
Sequence Evolution ◽  
Mrna Levels ◽  
Proneural Genes ◽  
Coding Sequence ◽  
Evolutionary Changes ◽  
And Function

Animals are characterized by a set of highly conserved developmental regulators. Changes in the cis-regulatory elements of these regulators are thought to constitute the major driver of morphological evolution. However, the role of coding sequence evolution remains unresolved. To address this question, we used the Atonal family of proneural transcription factors as a model. Drosophila atonal coding sequence was endogenously replaced with that of atonal homologues (ATHs) at key phylogenetic positions, non-ATH proneural genes, and the closest homologue to ancestral proneural genes. ATHs and the ancestral-like coding sequences rescued sensory organ fate in atonal mutants, in contrast to non-ATHs. Surprisingly, different ATH factors displayed different levels of proneural activity as reflected by the number and functionality of sense organs. This proneural potency gradient correlated directly with ATH protein stability, including in response to Notch signaling, independently of mRNA levels or codon usage. This establishes a distinct and ancient function for ATHs and demonstrates that coding sequence evolution can underlie quantitative variation in sensory development and function.

scholarly journals Phenotype loss is associated with widespread divergence of the gene regulatory landscape in evolution

2017 ◽  
Author(s):  
Juliana G. Roscito ◽  
Katrin Sameith ◽  
Genis Parra ◽  
Bjoern E. Langer ◽  
Andreas Petzold ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Morphological Traits ◽  
Morphological Changes ◽  
Sequence Divergence ◽  
Regulatory Elements ◽  
Genomic Changes ◽  
Genome Wide ◽  
Subterranean Mammals ◽  
And Function ◽  
Regulatory Landscape

AbstractDetecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Evolutionary theory predicts that changes in cis-regulatory elements are important for morphological changes. Here, we combine genome sequencing and functional genomics with genome-wide comparative analyses to investigate the fate of regulatory elements in lineages that lost morphological traits. We first show that limb loss in snakes is associated with widespread divergence of limb regulatory elements. We next show that eye degeneration in subterranean mammals is associated with widespread divergence of eye regulatory elements. In both cases, sequence divergence results in an extensive loss of relevant transcription factor binding sites. Importantly, diverged regulatory elements are associated with key genes required for normal limb patterning or normal eye development and function, suggesting that regulatory divergence contributed to the loss of these phenotypes. Together, our results provide the first evidence that genome-wide decay of the phenotype-specific cis-regulatory landscape is a hallmark of lost morphological traits.

scholarly journals Phylogenetic Modeling of Regulatory Element Turnover Based on Epigenomic Data

2020 ◽  
Vol 37 (7) ◽  
pp. 2137-2152
Author(s):  
Noah Dukler ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Dna Sequence ◽  
Target Genes ◽  
Evolutionary Dynamics ◽  
Regulatory Element ◽  
Probabilistic Modeling ◽  
Regulatory Elements ◽  
Turnover Rates ◽  
Modeling Framework ◽  
Model Free ◽  
Evolutionary Changes

Abstract Evolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multispecies epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.

Transvection and Silencing of the Scr Homeotic Gene of Drosophila melanogaster

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 733-746
Author(s):  
Jeffrey W Southworth ◽  
James A Kennison
Keyword(s):  
Drosophila Melanogaster ◽  
Chromosomal Aberrations ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Anomalous Behavior ◽  
Polycomb Group ◽  
Homeotic Gene ◽  
Polycomb Group Proteins ◽  
Sex Combs Reduced ◽  
In Cis

Abstract The Sex combs reduced (Scr) gene specifies the identities of the labial and first thoracic segments in Drosophila melanogaster. In imaginal cells, some Scr mutations allow cis-regulatory elements on one chromosome to stimulate expression of the promoter on the homolog, a phenomenon that was named transvection by Ed Lewis in 1954. Transvection at the Scr gene is blocked by rearrangements that disrupt pairing, but is zeste independent. Silencing of the Scr gene in the second and third thoracic segments, which requires the Polycomb group proteins, is disrupted by most chromosomal aberrations within the Scr gene. Some chromosomal aberrations completely derepress Scr even in the presence of normal levels of all Polycomb group proteins. On the basis of the pattern of chromosomal aberrations that disrupt Scr gene silencing, we propose a model in which two cis-regulatory elements interact to stabilize silencing of any promoter or cis-regulatory element physically between them. This model also explains the anomalous behavior of the Scx allele of the flanking homeotic gene, Antennapedia. This allele, which is associated with an insertion near the Antennapedia P1 promoter, inactivates the Antennapedia P1 and P2 promoters in cis and derepresses the Scr promoters both in cis and on the homologous chromosome.

scholarly journals Genomic basis of striking fin shapes and colours in the fighting fish

2021 ◽  
Author(s):  
Le Wang ◽  
Fei Sun ◽  
Zi Yi Wan ◽  
Baoqing Ye ◽  
Yanfei Wen ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Association Studies ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Major Effect ◽  
Betta Splendens ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Phenotypic Variations ◽  
Genomic Basis

Abstract Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole genome sequencing, QTL mapping, genome-wide association studies and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double tail mutant was suggested to be caused by a deletion in a zic1/zic4 co-enhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

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