scholarly journals Similar evolutionary trajectories for retrotransposon accumulation in mammals

2016 ◽  
Author(s):  
Reuben M Buckley ◽  
R Daniel Kortschak ◽  
Joy M Raison ◽  
David L Adelson
Keyword(s):  
Large Scale ◽  
Regulatory Element ◽  
Insertion Site ◽  
Regulatory Elements ◽  
Site Preference ◽  
Open Chromatin ◽  
Short Interspersed Elements ◽  
Evolutionary Trajectories ◽  
Mammalian Genomes ◽  
Retrotransposon Activity

AbstractThe factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their non-autonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analysed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalise retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organisation, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.

scholarly journals SnapATAC: A Comprehensive Analysis Package for Single Cell ATAC-seq

2019 ◽  
Author(s):  
Rongxin Fang ◽  
Sebastian Preissl ◽  
Yang Li ◽  
Xiaomeng Hou ◽  
Jacinta Lucero ◽  
...  
Keyword(s):  
Single Cell ◽  
Large Scale ◽  
Expression Patterns ◽  
Sampling Technique ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Low Rank ◽  
Specific Gene ◽  
Open Chromatin ◽  
Process Data

AbstractIdentification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by heterogeneity of the samples. Single cell analysis of transposase-accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volumes of data could pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC can efficiently dissect cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, a sampling technique that generates the low rank embedding for large-scale dataset, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC was applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis revealed ∼370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate transcriptional regulators in each of the cell types.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
pp. gr.275901.121
Author(s):  
Alexandre Laverre ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is significantly associated with gene expression evolution.

scholarly journals The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

2020 ◽  
Author(s):  
Amanda K Tilot ◽  
Ekaterina A Khramtsova ◽  
Dan Liang ◽  
Katrina L Grasby ◽  
Neda Jahanshad ◽  
...  
Keyword(s):  
Human Brain ◽  
Surface Area ◽  
Brain Structure ◽  
Visual Processing ◽  
Large Scale ◽  
Structural Changes ◽  
Homo Sapiens ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Common Genetic Variants

Abstract Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
Author(s):  
Alexandre Laverré ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

AbstractGene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve regulatory element sequences and their interactions with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory interactions constrains large-scale genome evolution. Notably, we show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is tightly linked to gene expression evolution.

scholarly journals RNA polymerase mapping in plants identifies intergenic regulatory elements enriched in causal variants

2021 ◽  
Author(s):  
Roberto Lozano ◽  
Gregory T Booth ◽  
Bilan Yonis Omar ◽  
Bo Li ◽  
Edward S Buckler ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Cell Function ◽  
Regulatory Element ◽  
Crop Improvement ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Control Of Gene Expression ◽  
Causal Variants ◽  
Divergent Transcription ◽  
Genomic Regions

Abstract Control of gene expression is fundamental at every level of cell function. Promoter-proximal pausing and divergent transcription at promoters and enhancers, which are prominent features in animals, have only been studied in a handful of research experiments in plants. PRO-Seq analysis in cassava (Manihot esculenta) identified peaks of transcriptionally engaged RNA polymerase at both the 5′ and 3′ end of genes, consistent with paused or slowly moving Polymerase. In addition, we identified divergent transcription at intergenic sites. A full genome search for bi-directional transcription using an algorithm for enhancer detection developed in mammals (dREG) identified many intergenic regulatory element (IRE) candidates. These sites showed distinct patterns of methylation and nucleotide conservation based on genomic evolutionary rate profiling (GERP). SNPs within these IRE candidates explained significantly more variation in fitness and root composition than SNPs in chromosomal segments randomly ascertained from the same intergenic distribution, strongly suggesting a functional importance of these sites. Maize GRO-Seq data showed RNA polymerase occupancy at IREs consistent with patterns in cassava. Furthermore, these IREs in maize significantly overlapped with sites previously identified on the basis of open chromatin, histone marks, and methylation, and were enriched for reported eQTL. Our results suggest that bidirectional transcription can identify intergenic genomic regions in plants that play an important role in transcription regulation and whose identification has the potential to aid crop improvement.

scholarly journals De novo assembly, delivery and expression of a 101 kb human gene in mouse cells

2018 ◽  
Author(s):  
Leslie A. Mitchell ◽  
Laura H. McCulloch ◽  
Sudarshan Pinglay ◽  
Henri Berger ◽  
Nazario Bosco ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Large Scale ◽  
De Novo ◽  
Regulatory Elements ◽  
Functional Study ◽  
Regulatory Sequences ◽  
Dna Assembly ◽  
Functional Evaluation ◽  
Mammalian Genomes ◽  
Mammalian Genes

AbstractDesign and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here we describe a pipeline for de novo DNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kb. The DNA assembly step is supported by an integrated robotic workcell. We assembled the 101 kb human HPRT1 gene in yeast, delivered it to mouse embryonic stem cells, and showed expression of the human protein from its full-length gene. This pipeline provides a framework for producing systematic, designer variants of any mammalian gene locus for functional evaluation in cells.Significance StatementMammalian genomes consist of a tiny proportion of relatively well-characterized coding regions and vast swaths of poorly characterized “dark matter” containing critical but much less well-defined regulatory sequences. Given the dominant role of noncoding DNA in common human diseases and traits, the interconnectivity of regulatory elements, and the importance of genomic context, de novo design, assembly, and delivery can enable large-scale manipulation of these elements on a locus scale. Here we outline a pipeline for de novo assembly, delivery and expression of mammalian genes replete with native regulatory sequences. We expect this pipeline will be useful for dissecting the function of non-coding sequence variation in mammalian genomes.

scholarly journals Evaluation of Chromatin Accessibility in Prefrontal Cortex of Schizophrenia Cases and Controls

2017 ◽  
Author(s):  
Julien Bryois ◽  
Melanie E Garrett ◽  
Lingyun Song ◽  
Alexias Safi ◽  
Paola Giusti-Rodriguez ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Disease Risk ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Brain Diseases ◽  
Open Chromatin ◽  
Regulatory Processes ◽  
Fold Enrichment ◽  
Genomic Studies

AbstractSchizophrenia genome-wide association (GWA) studies have identified over 150 regions of the genome that are associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in brain are highly enriched for SNP-heritability for schizophrenia (10.6 fold enrichment, P=2.4×10−4, second only to genomic regions conserved in Eutherian mammals) and replicated in an independent dataset (9.0 fold enrichment, P=2.7×10−4). This degree of enrichment of schizophrenia heritability was higher than in open chromatin found in 138 different cell and tissue types. Brain open chromatin regions that overlapped highly conserved regions exhibited an even higher degree of heritability enrichment, indicating that conservation can identify functional subsets within regulatory elements active in brain. However, we did not identify chromatin accessibility differences between schizophrenia cases and controls, nor did we find an interaction of chromatin QTLs with case-control status. This indicates that although causal variants map within regulatory elements, mechanisms other than differential chromatin may govern the contribution of regulatory element variation to schizophrenia risk. Our results strongly implicate gene regulatory processes involving open chromatin in the pathogenesis of schizophrenia, and suggest a strategy to understand the hundreds of common variants emerging from large genomic studies of complex brain diseases.

scholarly journals Creb5 establishes the competence for Prg4 expression in articular cartilage

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cheng-Hai Zhang ◽  
Yao Gao ◽  
Unmesh Jadhav ◽  
Han-Hwa Hung ◽  
Kristina M. Holton ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Articular Cartilage ◽  
Articular Chondrocytes ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Chromatin Conformation ◽  
Deep Zone ◽  
Egfr Signaling ◽  
Superficial Zone

AbstractA hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to induce Prg4 expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction of Prg4 by TGF-β. Our results indicate that Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage.

scholarly journals Genome-wide annotation of gene regulatory elements linked to cell fitness

2021 ◽  
Author(s):  
Tyler S. Klann ◽  
Alejandro Barrera ◽  
Adarsh R. Ettyreddy ◽  
Ryan A. Rickels ◽  
Julien Bryois ◽  
...  
Keyword(s):  
Target Genes ◽  
Disease Risk ◽  
Regulatory Element ◽  
Cancer Cell Line ◽  
K562 Cells ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Cell Type Specificity ◽  
Cellular Processes ◽  
Genome Wide

AbstractNoncoding regulatory elements control gene expression and govern all biological processes. Epigenomic profiling assays have identified millions of putative regulatory elements, but systematically determining the function of each of those regulatory elements remains a substantial challenge. Here we adapt CRISPR-dCas9-based epigenomic regulatory element screening (CERES) technology to screen all >100,000 putative non-coding regulatory elements defined by open chromatin sites in human K562 leukemia cells for their role in regulating essential cellular processes. In an initial screen containing more than 1 million gRNAs, we discovered approximately 12,000 regulatory elements with evidence of impact on cell fitness. We validated many of the screen hits in K562 cells, evaluated cell-type specificity in a second cancer cell line, and identified target genes of regulatory elements using CERES perturbations combined with single cell RNA-seq. This comprehensive and quantitative genome-wide map of essential regulatory elements represents a framework for extensive characterization of noncoding regulatory elements that drive complex cell phenotypes and for prioritizing non-coding genetic variants that likely contribute to common traits and disease risk.

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