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Many human accelerated regions are developmental enhancers
The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826498/ https://www.ncbi.nlm.nih.gov/pubmed/24218637 http://dx.doi.org/10.1098/rstb.2013.0025 |
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author | Capra, John A. Erwin, Genevieve D. McKinsey, Gabriel Rubenstein, John L. R. Pollard, Katherine S. |
author_facet | Capra, John A. Erwin, Genevieve D. McKinsey, Gabriel Rubenstein, John L. R. Pollard, Katherine S. |
author_sort | Capra, John A. |
collection | PubMed |
description | The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used comparative genomics to find non-coding regions conserved across mammals that have acquired many sequence changes in humans since divergence from chimpanzees. These regions are good candidates for performing human-specific regulatory functions. Here, we analysed the DNA sequence, evolutionary history, histone modifications, chromatin state and transcription factor (TF) binding sites of a combined set of 2649 non-coding human accelerated regions (ncHARs) and predicted that at least 30% of them function as developmental enhancers. We prioritized the predicted ncHAR enhancers using analysis of TF binding site gain and loss, along with the functional annotations and expression patterns of nearby genes. We then tested both the human and chimpanzee sequence for 29 ncHARs in transgenic mice, and found 24 novel developmental enhancers active in both species, 17 of which had very consistent patterns of activity in specific embryonic tissues. Of these ncHAR enhancers, five drove expression patterns suggestive of different activity for the human and chimpanzee sequence at embryonic day 11.5. The changes to human non-coding DNA in these ncHAR enhancers may modify the complex patterns of gene expression necessary for proper development in a human-specific manner and are thus promising candidates for understanding the genetic basis of human-specific biology. |
format | Online Article Text |
id | pubmed-3826498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Royal Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-38264982013-12-19 Many human accelerated regions are developmental enhancers Capra, John A. Erwin, Genevieve D. McKinsey, Gabriel Rubenstein, John L. R. Pollard, Katherine S. Philos Trans R Soc Lond B Biol Sci Articles The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used comparative genomics to find non-coding regions conserved across mammals that have acquired many sequence changes in humans since divergence from chimpanzees. These regions are good candidates for performing human-specific regulatory functions. Here, we analysed the DNA sequence, evolutionary history, histone modifications, chromatin state and transcription factor (TF) binding sites of a combined set of 2649 non-coding human accelerated regions (ncHARs) and predicted that at least 30% of them function as developmental enhancers. We prioritized the predicted ncHAR enhancers using analysis of TF binding site gain and loss, along with the functional annotations and expression patterns of nearby genes. We then tested both the human and chimpanzee sequence for 29 ncHARs in transgenic mice, and found 24 novel developmental enhancers active in both species, 17 of which had very consistent patterns of activity in specific embryonic tissues. Of these ncHAR enhancers, five drove expression patterns suggestive of different activity for the human and chimpanzee sequence at embryonic day 11.5. The changes to human non-coding DNA in these ncHAR enhancers may modify the complex patterns of gene expression necessary for proper development in a human-specific manner and are thus promising candidates for understanding the genetic basis of human-specific biology. The Royal Society 2013-12-19 /pmc/articles/PMC3826498/ /pubmed/24218637 http://dx.doi.org/10.1098/rstb.2013.0025 Text en http://creativecommons.org/licenses/by/3.0/ © 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited. |
spellingShingle | Articles Capra, John A. Erwin, Genevieve D. McKinsey, Gabriel Rubenstein, John L. R. Pollard, Katherine S. Many human accelerated regions are developmental enhancers |
title | Many human accelerated regions are developmental enhancers |
title_full | Many human accelerated regions are developmental enhancers |
title_fullStr | Many human accelerated regions are developmental enhancers |
title_full_unstemmed | Many human accelerated regions are developmental enhancers |
title_short | Many human accelerated regions are developmental enhancers |
title_sort | many human accelerated regions are developmental enhancers |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826498/ https://www.ncbi.nlm.nih.gov/pubmed/24218637 http://dx.doi.org/10.1098/rstb.2013.0025 |
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