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Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome

Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation a...

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Detalles Bibliográficos
Autores principales: Li, Cai, Lenhard, Boris, Luscombe, Nicholas M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932608/
https://www.ncbi.nlm.nih.gov/pubmed/29618487
http://dx.doi.org/10.1101/gr.231449.117
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author Li, Cai
Lenhard, Boris
Luscombe, Nicholas M.
author_facet Li, Cai
Lenhard, Boris
Luscombe, Nicholas M.
author_sort Li, Cai
collection PubMed
description Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes.
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spelling pubmed-59326082018-05-31 Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome Li, Cai Lenhard, Boris Luscombe, Nicholas M. Genome Res Research Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes. Cold Spring Harbor Laboratory Press 2018-05 /pmc/articles/PMC5932608/ /pubmed/29618487 http://dx.doi.org/10.1101/gr.231449.117 Text en © 2018 Li et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Li, Cai
Lenhard, Boris
Luscombe, Nicholas M.
Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title_full Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title_fullStr Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title_full_unstemmed Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title_short Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
title_sort integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932608/
https://www.ncbi.nlm.nih.gov/pubmed/29618487
http://dx.doi.org/10.1101/gr.231449.117
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