Improving Estimates of Compensatory cis-trans Regulatory Divergence.
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ABSTRACT:
SUBMITTER: Fraser HB
PROVIDER: S-EPMC6652221 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: Not available
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Project description:The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ~95% similar with that derived from human TF footprints. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity. We performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution.
2014-11-19 | E-GEOD-51341 | biostudies-arrayexpress
Project description:The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ~95% similar with that derived from human TF footprints. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
2014-11-19 | GSE51341 | GEO
Project description:Spatial patterning of gene expression is a key process in development, yet how it evolves is still poorly understood. Both cis- and trans-acting changes could participate in complex interactions, so to isolate the cis-regulatory component of patterning evolution, we measured allele-specific spatial gene expression patterns in D. melanogaster × simulans hybrid embryos. RNA-seq of cryo-sectioned slices revealed 66 genes with strong spatially varying allele-specific expression. We found that hunchback, a major regulator of developmental patterning, had reduced expression of the D. simulans allele specifically in the anterior tip of hybrid embryos. Mathematical modeling of hunchback cis-regulation suggested a candidate transcription factor binding site variant, which we verified as causal using CRISPR-Cas9 genome editing. In sum, even comparing morphologically near-identical species we identified surprisingly extensive spatial variation in gene expression, suggesting not only that development is robust to many such changes, but also that natural selection may have ample raw material for evolving new body plans via changes in spatial patterning.
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Project description:Gene regulation can evolve either by cis-acting local changes to regulatory element DNA sequences or by global changes to the trans-acting regulatory environment; however, the modes favored during recent human evolution are unknown. To date, studies investigating gene regulatory divergence between closely-related species have produced limited estimates on the relative contributions of cis and trans effects on DNA regulatory element activities at a global-scale. By leveraging a comparative ATAC-STARR-seq framework, we identified 10,779 regulatory regions with divergent activity in cis and 10,608 regulatory regions with divergent activity in trans between human and rhesus macaque lymphoblastoid cell lines (LCLs). This revealed substantially more trans effects than predicted and indicates trans-regulatory mechanisms play a larger role in human evolution than previously expected. We also discover that most species-specific regulatory elements (67%) diverge in both cis and trans, suggesting these two mechanisms jointly drive divergent regulatory activity in a single sequence.
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Project description:Transcriptional networks have been shown to evolve very rapidly, prompting questions as to how such changes arise and are tolerated. Recent comparisons of transcriptional networks across species have implicated variations in the cis-acting DNA sequences near genes as the main cause of divergence. What is less clear is how these changes interact with trans-acting changes occurring elsewhere in the genetic circuit. Here, we report the discovery of a system of compensatory trans and cis mutations in the yeast AP-1 transcriptional network that allows for conserved transcriptional regulation despite continued genetic change. We pinpoint a single species, the fungal pathogen Candida glabrata, in which a trans mutation has occurred very recently in a single AP-1 family member, distinguishing it from its Saccharomyces ortholog. Comparison of chromatin immunoprecipitation profiles between Candida and Saccharomyces shows that, despite their different DNA-binding domains, the AP-1 orthologs regulate a conserved block of genes. This conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene. Thus, both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another. This demonstrates an example of "coevolution" between a DNA-binding transcription factor and its cis-regulatory site, reminiscent of the coevolution of protein binding partners.
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Project description:Two inbred mouse strains, C57BL/6J and CAST/EiJ, were crossed to generate both initial and reciprocal F1 crosses. For each genetically distinct class of mice (F0 C57BL/6J, F0 CAST/EiJ, F1i - C57BL/6J x CAST/EiJ, F1r - CAST/EiJ x C57BL/6J, where the male parent is listed first), samples were collected from a single lobe of the liver from 6 male mice between the ages of 4 and 6 months. The 24 samples were then processed to generate strand-specific RNA-seq libraries, which were sequenced on the Illumina GAII platform using 72bp paired-end reads.
2012-09-07 | E-MTAB-1091 | biostudies-arrayexpress
Project description:Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expression in their F1 progeny. We identified 535 genes with parent-of-origin specific expression patterns, although few of these showed full allelic silencing. This suggests that the number of imprinted genes in a typical mouse somatic tissue is relatively small. In the set of nonimprinted genes, 32% showed evidence of divergent expression between the two strains. Of these, 2% could be attributed purely to variants acting in trans, while 43% were attributable only to variants acting in cis. The genes with expression divergence driven by changes in trans showed significantly higher sequence constraint than genes where the divergence was explained by variants acting in cis. The remaining genes with divergent patterns of expression (55%) were regulated by a combination of variants acting in cis and variants acting in trans. Intriguingly, the changes in expression induced by the cis and trans variants were in opposite directions more frequently than expected by chance, implying that compensatory regulation to stabilize gene expression levels is widespread. We propose that expression levels of genes regulated by this mechanism are fine-tuned by cis variants that arise following regulatory changes in trans, suggesting that many cis variants are not the primary targets of natural selection.
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Project description:Gene-expression divergence between species shapes morphological evolution, but the molecular basis is largely unknown. Here we show cis- and trans-regulatory elements and chromatin modifications on gene-expression diversity in genetically tractable Arabidopsis allotetraploids. In Arabidopsis thaliana and Arabidopsis arenosa, both cis and trans with predominant cis-regulatory effects mediate gene-expression divergence. The majority of genes with both cis- and trans-effects are subjected to compensating interactions and stabilizing selection. Interestingly, chromatin modifications correlate with cis - and trans -regulation. In F1 allotetraploids, Arabidopsis arenosa trans factors predominately affect allelic expression divergence. Arabidopsis arenosa trans factors tend to upregulate Arabidopsis thaliana alleles, whereas Arabidopsis thaliana trans factors up- or down-regulate Arabidopsis arenosa alleles. In resynthesized and natural allotetraploids, trans effects drive expression of both homoeologous loci into the same direction. We provide evidence for natural selection and chromatin regulation in shaping gene-expression diversity during plant evolution and speciation. Examination of gene expression in 5 tetraploid Arabidopsis using mRNA-seq
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