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REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species
Elucidating the genomic determinants of morphological differences between species is key to understanding how morphological diversity evolved. While differences in cis-regulatory elements are an important genetic source for morphological evolution, it remains challenging to identify regulatory eleme...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278867/ https://www.ncbi.nlm.nih.gov/pubmed/30256993 http://dx.doi.org/10.1093/molbev/msy187 |
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author | Langer, Björn E Roscito, Juliana G Hiller, Michael |
author_facet | Langer, Björn E Roscito, Juliana G Hiller, Michael |
author_sort | Langer, Björn E |
collection | PubMed |
description | Elucidating the genomic determinants of morphological differences between species is key to understanding how morphological diversity evolved. While differences in cis-regulatory elements are an important genetic source for morphological evolution, it remains challenging to identify regulatory elements involved in phenotypic differences. Here, we present Regulatory Element forward genomics (REforge), a computational approach that detects associations between transcription factor binding site divergence in putative regulatory elements and phenotypic differences between species. By simulating regulatory element evolution in silico, we show that this approach has substantial power to detect such associations. To validate REforge on real data, we used known binding motifs for eye-related transcription factors and identified significant binding site divergence in vision-impaired subterranean mammals in 1% of all conserved noncoding elements. We show that these genomic regions are significantly enriched in regulatory elements that are specifically active in mouse eye tissues, and that several of them are located near genes, which are required for eye development and photoreceptor function and are implicated in human eye disorders. Thus, our genome-wide screen detects widespread divergence of eye-regulatory elements and highlights regulatory regions that likely contributed to eye degeneration in subterranean mammals. REforge has broad applicability to detect regulatory elements that could be involved in many other phenotypes, which will help to reveal the genomic basis of morphological diversity. |
format | Online Article Text |
id | pubmed-6278867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62788672018-12-06 REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species Langer, Björn E Roscito, Juliana G Hiller, Michael Mol Biol Evol Methods Elucidating the genomic determinants of morphological differences between species is key to understanding how morphological diversity evolved. While differences in cis-regulatory elements are an important genetic source for morphological evolution, it remains challenging to identify regulatory elements involved in phenotypic differences. Here, we present Regulatory Element forward genomics (REforge), a computational approach that detects associations between transcription factor binding site divergence in putative regulatory elements and phenotypic differences between species. By simulating regulatory element evolution in silico, we show that this approach has substantial power to detect such associations. To validate REforge on real data, we used known binding motifs for eye-related transcription factors and identified significant binding site divergence in vision-impaired subterranean mammals in 1% of all conserved noncoding elements. We show that these genomic regions are significantly enriched in regulatory elements that are specifically active in mouse eye tissues, and that several of them are located near genes, which are required for eye development and photoreceptor function and are implicated in human eye disorders. Thus, our genome-wide screen detects widespread divergence of eye-regulatory elements and highlights regulatory regions that likely contributed to eye degeneration in subterranean mammals. REforge has broad applicability to detect regulatory elements that could be involved in many other phenotypes, which will help to reveal the genomic basis of morphological diversity. Oxford University Press 2018-12 2018-09-26 /pmc/articles/PMC6278867/ /pubmed/30256993 http://dx.doi.org/10.1093/molbev/msy187 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Methods Langer, Björn E Roscito, Juliana G Hiller, Michael REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title | REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title_full | REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title_fullStr | REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title_full_unstemmed | REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title_short | REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences between Species |
title_sort | reforge associates transcription factor binding site divergence in regulatory elements with phenotypic differences between species |
topic | Methods |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278867/ https://www.ncbi.nlm.nih.gov/pubmed/30256993 http://dx.doi.org/10.1093/molbev/msy187 |
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