scholarly journals Effects of reference databases' refinements on the validity of molecular definitions of 15,371 candidate human-specific regulatory sequences

2015 ◽  
Author(s):  
Gennadi Glinsky
Keyword(s):  
Regulatory Networks ◽  
Regulatory Elements ◽  
Regulatory Sequences ◽  
Accurate Definition ◽  
Reference Databases ◽  
Definition Of ◽  
Regulatory Dna ◽  
Sequence Quality ◽  
Human Specific

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the idea that unique to human phenotypes result from human-specific changes to genomic regulatory networks (GRNs). The sequence quality of reference genome databases is essential for the accurate definition of regulatory DNA segments as candidate HSRS. It is unclear how database improvements would affect the validity of the HSRS' definition. Sequence conservation analysis of 15,371 candidate HSRS was carried out using the most recent releases of reference genomes' databases of humans and nonhuman primates (NHP) defining the conservation threshold as the minimum ratio of bases that must remap of 1.00. This analysis identifies 3,793 regulatory DNA segments that lack evidence of human-specific mutations and represent regulatory sequences highly conserved in humans, Bonobo, and Chimpanzee. Present analysis revealed a major database refinement's effect on the validity of HSRS' definition and suggests that human-specific phenotypes may evolve as a results of integration into human-specific GRNs of both conserved in NHP and human-specific genomic regulatory elements.

scholarly journals Conservation patterns’ analysis of 18,364 candidate human-specific regulatory sequences revealed two distinct pathways of the human regulatory DNA divergence

2015 ◽  
Author(s):  
Gennadi Glinsky
Keyword(s):  
Transposable Elements ◽  
Regulatory Networks ◽  
Homo Sapiens ◽  
Functional Divergence ◽  
Regulatory Sequences ◽  
Conservation Patterns ◽  
Genomic Regulatory Networks ◽  
Species Specific ◽  
Regulatory Dna ◽  
Human Specific

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the idea that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Here, conservation patterns analysis of 18,364 regulatory DNA segments comprising candidate HSRS was carried out using the most recent releases of the reference genomes’ databases of humans and nonhuman primates (NHP) and defining the sequence conservation threshold as the minimum ratio of bases that must remap of 1.00. Present analyses identified 5,535 candidate HSRS defined by either the acceleration of mutation rates on the human lineage or the functional divergence from chimpanzee that are highly conserved in NHP and appear to evolve by the exaptation of ancestral DNA pathway. This pathway seems mechanistically distinct from the evolution of regulatory DNA driven by the species-specific expansion of transposable elements. It is proposed that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: i) exaptation of the highly conserved ancestral regulatory DNA segments; ii) human-specific insertions of transposable elements.

scholarly journals Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190347 ◽  
Author(s):  
Vasavi Sundaram ◽  
Joanna Wysocka
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Regulatory Function ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Unique Contribution ◽  
Regulatory Potential

Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals Methylation-mediated retuning on the enhancer-to-silencer activity scale of networked regulatory elements guides driver-gene misregulation

2021 ◽  
Author(s):  
Y. Edrei ◽  
R. levy ◽  
A. Marom ◽  
B. Radlwimmer ◽  
A. Hellman
Keyword(s):  
Regulatory Networks ◽  
Driving Forces ◽  
Regulatory Elements ◽  
Driver Gene ◽  
Regulatory Sequence ◽  
Regulatory Sequences ◽  
Cancer Genes ◽  
Transformation Mechanism ◽  
Driver Genes ◽  
Regulatory Effects

AbstractCancers arise when particular disease-driving genes adopt abnormal functions, but analyses of coding and regulatory sequences leave many of these abnormalities unexplained. We developed a strategy to explore alternations in the regulatory effects of silencers and enhancers in cancer tumors. Applying the method to 177 gene regulatory domains in human glioblastomas, we produced a driver-gene wide dataset of gene-associated, functional regulatory elements. Many genes were controlled by cis-regulatory networks composed of multiple regulatory elements, each of them providing a defined positive or negative input to the overall regulatory output of the network. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints within wide ranges of potential regulatory effects, varying between strong transcriptional enhancing to strong silencing. Extensive analysis of methylation-expression associations reveals the organization of domain-wide cis-regulatory networks, and highlighted key regulatory sites which provide pivotal contributions to the network outputs. Consideration of these effects through mathematical models of gene expression variations signified prime molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Of the observed gene-malfunctioning events, gene misregulation due to epigenetic retuning of networked enhancers and silencers dominated driver-genes mutagenesis, compared with other types of mutation including coding or regulatory sequence alterations. Elucidation of this gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases.

scholarly journals Genomic and Molecular Maps of Stemness and Malignant Regulatory Signatures

2020 ◽  
Author(s):  
Gennadi Glinsky
Keyword(s):  
Dna Sequences ◽  
Regulatory Networks ◽  
Pathological Condition ◽  
Clinical Manifestations ◽  
Diagnostic Tools ◽  
Regulatory Sequences ◽  
Related Family ◽  
Increased Risk ◽  
Organ Specific ◽  
Definition Of

<p>Repetitive DNA sequences (repeats) colonized two-third of human genomes and a majority of repeats comprised of transposable genetic elements (TE). Evolutionary distinct categories of TE represent nucleic acid sequences that are repeatedly copied from and pasted into chromosomes at multiple genomic locations and acquired a multitude of regulatory functions. Here, genomics-guided maps of stemness regulatory signatures were drawn to dissect the contribution of TE to clinical manifestations of malignant phenotypes of human cancers. From patients’ and physicians’ perspectives, the clinical definition of a tumor’s malignant phenotype could be restricted to the early diagnosis of sub-types of malignancies with the increased risk of existing therapy failure and high likelihood of death from cancer. It is the viewpoint from which the understanding of stemness and malignant regulatory signatures is considered in this contribution. Analyses from this perspective of experimental and clinical observations revealed the pivotal role of human stem cell-associated retroviral sequences (SCARS) in the origin and pathophysiology of clinically-lethal malignancies. SCARS were defined as the evolutionary- and biologically-related family of genomic regulatory sequences, the principal physiological function of which is to create and maintain the stemness phenotype during human preimplantation embryogenesis. For cell differentiation to occur, SCARS expression must be silenced and SCARS activity remains repressed in most terminally-differentiated human cells performing specialized functions in the human body. De-repression and sustained activity of SCARS results in various differentiation-defective phenotypes. One of the most prominent tissue- and organ-specific clinical manifestations of sustained SCARS activities is diagnosed as a pathological condition defined by a consensus of morphological, molecular, and genetic examinations as the malignant growth. Contemporary evidence are acquired, analyzed, and reported defining both reliable diagnostic tools and druggable molecular targets readily amenable for diagnosis and efficient therapeutic management of clinically-lethal malignancies: detection of high-fidelity molecular signals of continuing SCARS activities in association with genomic regulatory networks of thousands’ functionally-active enhancers triggering engagements of down-stream phenotype-altering genetic loci. </p>

Democracy

2008 ◽  
Vol 41 (1) ◽  
pp. 233-234
Author(s):  
Kristen Parris
Keyword(s):  
New York ◽  
Cambridge University ◽  
Contemporary World ◽  
Working Definition ◽  
Charles Tilly ◽  
Accurate Definition ◽  
The Social ◽  
Essentially Contested Concepts ◽  
Definition Of

Democracy, Charles Tilly, New York: Cambridge University Press, 2007, pp. xi, 227.The ideal of democracy is rarely challenged openly in the contemporary world, yet it remains one of the social science's essentially contested concepts. Despite a large and growing literature on the topic, there is little consensus on how we are to decide when a particular regime qualifies as a democracy or not. In his ambitious and forceful new book, Charles Tilly argues that this lack of a clear and accurate definition of democracy is of considerable consequence. Lucid explanations of democratization, political standing of regimes, related foreign policy decisions and the quality of people's lives are all at stake. Tilly devotes his first chapter to building a working definition of democracy before putting forward a cogent explanatory framework for understanding how and why democracies emerge and why they sometimes disappear and to demonstrate what difference it makes.

ATAC-pipe: general analysis of genome-wide chromatin accessibility

2019 ◽  
Vol 20 (5) ◽  
pp. 1934-1943 ◽  
Author(s):  
Zuqi Zuo ◽  
Yonghao Jin ◽  
Wen Zhang ◽  
Yichen Lu ◽  
Bin Li ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Length Distribution ◽  
Original Data ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
General Analysis ◽  
Read Length ◽  
Genome Wide ◽  
Cell Type Specific

Abstract Assay of Transposase-Accessible Chromatin by deep sequencing (ATAC-seq) has been widely used to profile the chromatin accessibility genome-wide. For the absence of an integrated scheme for deep data mining of specific biological issues, here we present ATAC-pipe, an efficient pipeline for general analysis of chromatin accessibility data obtained from ATAC-seq experiments. ATAC-pipe captures information includes not only the quality of original data and genome-wide chromatin accessibility but also signatures of significant differential peaks, transcription factor (TF) occupancy and nucleosome positions around regulatory sites. In addition, ATAC-pipe automatically converts statistic results into intuitive plots at publication quality, such as the read length distribution, heatmaps of sample clustering and cell-type-specific regulatory elements, enriched TF occupancy with motifs footprints and TF-driven regulatory networks. ATAC-pipe provides convenient workflow for researchers to study chromatin accessibility and gene regulation. Availability https://github.com/QuKunLab/ATAC-pipe

scholarly journals Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19

2021 ◽  
Author(s):  
Michael Tun Yin Lam ◽  
Sascha H Duttke ◽  
Mazen Faris Odish ◽  
Hiep D Le ◽  
Emily A Hansen ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Regulatory Networks ◽  
Severe Disease ◽  
Cell Types ◽  
Regulatory Elements ◽  
Global Changes ◽  
Genome Wide ◽  
Dna Elements ◽  
Peripheral Leukocytes ◽  
Regulatory Dna

The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the 'active cistrome,' offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID-19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

scholarly journals Analysis of genomic loci harboring 59,732 human-specific regulatory sequences reveals unique to human regulatory patterns associated with brain development

2018 ◽  
Author(s):  
Gennadi V. Glinsky
Keyword(s):  
Gene Expression ◽  
Brain Development ◽  
Regulatory Networks ◽  
Radial Glia ◽  
De Novo ◽  
Incomplete Lineage Sorting ◽  
Preimplantation Embryos ◽  
Regulatory Sequences ◽  
Genes Encoding ◽  
Human Specific

AbstractExtensive searches for genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) identified thousands’ HSRS using high-resolution next-generation sequencing technologies and methodologically diverse comparative analyses of human and non-human primates’ reference genomes. Here, a comprehensive catalogue of 59,732 genomic loci harboring candidate HSRS has been assembled to facilitate the systematic analyses of genomic sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes. Present analyses identified thousands of HSRS that appear inherited from ECAs yet absent in genomes of our closest evolutionary relatives, Chimpanzee and Bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. This pattern is particularly prominent for HSRS that have been putatively associated with human-specific (HS) gene expression changes in cerebral organoid models. Significant fractions of retrotransposon-derived loci transcriptionally-active in human dorsolateral prefrontal cortex (DLPFC) are highly conserved in genomes of Gorilla, Orangutan, Gibbon, and Rhesus (1,688; 1,371; 1,148; and 1,045 loci, respectively), yet they are absent in genomes of both Chimpanzee and Bonobo. A prominent majority of regions harboring HS mutations associated with HS expression changes during brain development is highly conserved in Chimpanzee, Bonobo, and Gorilla genomes. Among non-human primates (NHP), dominant fractions of HSRS associated with HS gene expression in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the Gorilla genome. Analysis of 4,433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of HS regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult DLPFC. Present analyses demonstrate that Modern Humans captured unique combinations of regulatory sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Present analyses of HSRS support the model of complex continuous speciation process during evolution of the human lineage that is not likely to occur as an instantaneous event. Genes encoding VIPs may represent a principal genomic target of HS regulatory networks, thus affecting a functionally diverse spectrum of biological processes controlled by VIP-containing liquid-liquid phase separated condensates.

scholarly journals Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

2017 ◽  
Author(s):  
Dennis Kostka ◽  
Alisha K. Holloway ◽  
Katherine S. Pollard
Keyword(s):  
Statistical Tests ◽  
Regulatory Elements ◽  
Altered Expression ◽  
Evolutionary Forces ◽  
Shared Set ◽  
Accelerated Evolution ◽  
Core Set ◽  
Regulatory Dna ◽  
Human Accelerated Regions ◽  
Human Specific

AbstractSome of the fastest evolving regions of the human genome are conserved non-coding elements with many human-specific DNA substitutions. These Human Accelerated Regions (HARs) are enriched nearby regulatory genes, and several HARs function as developmental enhancers. To investigate if this evolutionary signature is unique to humans, we quantified evidence of accelerated substitutions in conserved genomic elements across multiple lineages and applied this approach simultaneously to the genomes of five apes: human, chimpanzee, gorilla, orangutan, and gibbon. We find roughly similar numbers and genomic distributions of lineage-specific accelerated regions (linARs) in all five apes. In particular, apes share an enrichment of linARs in regulatory DNA nearby genes involved in development, especially transcription factors and other regulators. Many developmental loci harbor clusters of nonoverlapping linARs from multiple apes, suggesting that accelerated evolution in each species affected distinct regulatory elements that control a shared set of developmental pathways. Our statistical tests distinguish between GC-biased and unbiased accelerated substitution rates, allowing us to quantify the roles of different evolutionary forces in creating linARs. We find evidence of GC-biased gene conversion in each ape, but unbiased acceleration consistent with positive selection or loss of constraint is more common in all five lineages. It therefore appears that similar evolutionary processes created independent accelerated regions in the genomes of different apes, and that these lineage-specific changes to conserved non-coding sequences may have differentially altered expression of a core set of developmental genes across ape evolution.

scholarly journals Genomic and Molecular Maps of Stemness and Malignant Regulatory Signatures

2020 ◽  
Author(s):  
Gennadi Glinsky
Keyword(s):  
Dna Sequences ◽  
Regulatory Networks ◽  
Pathological Condition ◽  
Clinical Manifestations ◽  
Diagnostic Tools ◽  
Regulatory Sequences ◽  
Related Family ◽  
Increased Risk ◽  
Organ Specific ◽  
Definition Of

<p>Repetitive DNA sequences (repeats) colonized two-third of human genomes and a majority of repeats comprised of transposable genetic elements (TE). Evolutionary distinct categories of TE represent nucleic acid sequences that are repeatedly copied from and pasted into chromosomes at multiple genomic locations and acquired a multitude of regulatory functions. Here, genomics-guided maps of stemness regulatory signatures were drawn to dissect the contribution of TE to clinical manifestations of malignant phenotypes of human cancers. From patients’ and physicians’ perspectives, the clinical definition of a tumor’s malignant phenotype could be restricted to the early diagnosis of sub-types of malignancies with the increased risk of existing therapy failure and high likelihood of death from cancer. It is the viewpoint from which the understanding of stemness and malignant regulatory signatures is considered in this contribution. Analyses from this perspective of experimental and clinical observations revealed the pivotal role of human stem cell-associated retroviral sequences (SCARS) in the origin and pathophysiology of clinically-lethal malignancies. SCARS were defined as the evolutionary- and biologically-related family of genomic regulatory sequences, the principal physiological function of which is to create and maintain the stemness phenotype during human preimplantation embryogenesis. For cell differentiation to occur, SCARS expression must be silenced and SCARS activity remains repressed in most terminally-differentiated human cells performing specialized functions in the human body. De-repression and sustained activity of SCARS results in various differentiation-defective phenotypes. One of the most prominent tissue- and organ-specific clinical manifestations of sustained SCARS activities is diagnosed as a pathological condition defined by a consensus of morphological, molecular, and genetic examinations as the malignant growth. Contemporary evidence are acquired, analyzed, and reported defining both reliable diagnostic tools and druggable molecular targets readily amenable for diagnosis and efficient therapeutic management of clinically-lethal malignancies: detection of high-fidelity molecular signals of continuing SCARS activities in association with genomic regulatory networks of thousands’ functionally-active enhancers triggering engagements of down-stream phenotype-altering genetic loci. </p>

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