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

Mapping Intimacies ◽

10.1101/029975 ◽

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.

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Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence ofHomo sapiens

Genome Biology and Evolution ◽

10.1093/gbe/evw185 ◽

2016 ◽

Vol 8 (9) ◽

pp. 2774-2788 ◽

Cited By ~ 12

Author(s):

Gennadi V. Glinsky

Keyword(s):

Regulatory Networks ◽

Phenotypic Divergence ◽

Genomic Regulatory Networks ◽

Regulatory Dna ◽

Human Specific

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

10.1101/026435 ◽

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.

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

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0347 ◽

2020 ◽

Vol 375 (1795) ◽

pp. 20190347 ◽

Cited By ~ 14

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’.

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Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs

Genome Biology and Evolution ◽

10.1093/gbe/evv081 ◽

2015 ◽

Vol 7 (6) ◽

pp. 1432-1454 ◽

Cited By ~ 36

Author(s):

Gennadi V. Glinsky

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Transposable Elements ◽

Embryonic Stem ◽

Noncoding Rnas ◽

Regulatory Sequences ◽

Human Specific

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

10.1101/432625 ◽

2018 ◽

Cited By ~ 1

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.

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Species-specific recruitment of transcription factors dictates toxin expression

Nucleic Acids Research ◽

10.1093/nar/gkz1232 ◽

2020 ◽

Vol 48 (5) ◽

pp. 2388-2400 ◽

Cited By ~ 4

Author(s):

Julian Trouillon ◽

Erwin Sentausa ◽

Michel Ragno ◽

Mylène Robert-Genthon ◽

Stephen Lory ◽

...

Keyword(s):

Regulatory Networks ◽

Regulatory Sequences ◽

Virulence Determinants ◽

Transcriptional Regulatory Networks ◽

Coordinate Regulation ◽

Promoter Sequences ◽

Transcriptional Regulatory ◽

Pseudomonas Species ◽

Species Specific

Abstract Tight and coordinate regulation of virulence determinants is essential for bacterial biology and involves dynamic shaping of transcriptional regulatory networks during evolution. The horizontally transferred two-partner secretion system ExlB–ExlA is instrumental in the virulence of different Pseudomonas species, ranging from soil- and plant-dwelling biocontrol agents to the major human pathogen Pseudomonas aeruginosa. Here, we identify a Cro/CI-like repressor, named ErfA, which together with Vfr, a CRP-like activator, controls exlBA expression in P. aeruginosa. The characterization of ErfA regulon across P. aeruginosa subfamilies revealed a second conserved target, the ergAB operon, with functions unrelated to virulence. To gain insights into this functional dichotomy, we defined the pan-regulon of ErfA in several Pseudomonas species and found ergAB as the sole conserved target of ErfA. The analysis of 446 exlBA promoter sequences from all exlBA+ genomes revealed a wide variety of regulatory sequences, as ErfA- and Vfr-binding sites were found to have evolved specifically in P. aeruginosa and nearly each species carries different regulatory sequences for this operon. We propose that the emergence of different regulatory cis-elements in the promoters of horizontally transferred genes is an example of plasticity of regulatory networks evolving to provide an adapted response in each individual niche.

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Genome-wide analysis of the association of transposable elements with gene regulation suggests that Alu elements have the largest overall regulatory impact

10.1101/142018 ◽

2017 ◽

Author(s):

Lu Zeng ◽

Stephen M. Pederson ◽

Danfeng Cao ◽

Zhipeng Qu ◽

Zhiqiang Hu ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transposable Elements ◽

Regulatory Sequences ◽

Alu Elements ◽

Genome Wide ◽

A Genome ◽

Regulatory Impact ◽

Species Specific ◽

Regulated Gene Expression

ABSTRACTNearly half of the human genome is made up of transposable elements (TEs) and there is evidence that TEs are involved in gene regulation. Here, we have integrated publicly available genomic, epigenetic and transcriptomic data to investigate this in a genome-wide manner. A bootstrapping statistical method was applied to minimize the confounder effects from different repeat types. Our results show that although most TE classes are primarily associated with reduced gene expression, Alu elements are associated with up regulated gene expression. Furthermore, Alu elements had the highest probability of any TE class of contributing to regulatory regions of any type defined by chromatin state. This suggests a general model where clade specific SINEs may contribute more to gene regulation than ancient/ancestral TEs. Finally, non-coding regions were found to have a high probability of TE content within regulatory sequences, most notably in repressors. Our exhaustive analysis has extended and updated our understanding of TEs in terms of their global impact on gene regulation, and suggests that the most recently derived types of TEs, i.e. clade or species specific SINES, have the greatest overall impact on gene regulation.

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