Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection
Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differ...
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| Format: | Online |
| Language: | English |
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Public Library of Science
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386175/ |
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pubmed-3386175 |
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pubmed-33861752012-07-03 Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection Shibata, Yoichiro Sheffield, Nathan C. Fedrigo, Olivier Babbitt, Courtney C. Wortham, Matthew Tewari, Alok K. London, Darin Song, Lingyun Lee, Bum-Kyu Iyer, Vishwanath R. Parker, Stephen C. J. Margulies, Elliott H. Wray, Gregory A. Furey, Terrence S. Crawford, Gregory E. Research Article Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS) sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species. Public Library of Science 2012-06-28 /pmc/articles/PMC3386175/ /pubmed/22761590 http://dx.doi.org/10.1371/journal.pgen.1002789 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Shibata, Yoichiro Sheffield, Nathan C. Fedrigo, Olivier Babbitt, Courtney C. Wortham, Matthew Tewari, Alok K. London, Darin Song, Lingyun Lee, Bum-Kyu Iyer, Vishwanath R. Parker, Stephen C. J. Margulies, Elliott H. Wray, Gregory A. Furey, Terrence S. Crawford, Gregory E. |
| spellingShingle |
Shibata, Yoichiro Sheffield, Nathan C. Fedrigo, Olivier Babbitt, Courtney C. Wortham, Matthew Tewari, Alok K. London, Darin Song, Lingyun Lee, Bum-Kyu Iyer, Vishwanath R. Parker, Stephen C. J. Margulies, Elliott H. Wray, Gregory A. Furey, Terrence S. Crawford, Gregory E. Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| author_facet |
Shibata, Yoichiro Sheffield, Nathan C. Fedrigo, Olivier Babbitt, Courtney C. Wortham, Matthew Tewari, Alok K. London, Darin Song, Lingyun Lee, Bum-Kyu Iyer, Vishwanath R. Parker, Stephen C. J. Margulies, Elliott H. Wray, Gregory A. Furey, Terrence S. Crawford, Gregory E. |
| author_sort |
Shibata, Yoichiro |
| title |
Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| title_short |
Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| title_full |
Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| title_fullStr |
Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| title_full_unstemmed |
Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection |
| title_sort |
extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection |
| description |
Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS) sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species. |
| publisher |
Public Library of Science |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386175/ |
| _version_ |
1611540011219419136 |