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Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits

BACKGROUND: Enhancers are non-coding DNA sequences, which when they are bound by specific proteins increase the level of gene transcription. Enhancers activate unique gene expression patterns within cells of different types or under different conditions. Enhancers are key contributors to gene regula...

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Autores principales: Wang, Min, Hancock, Timothy P., MacLeod, Iona M., Pryce, Jennie E., Cocks, Benjamin G., Hayes, Benjamin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499214/
https://www.ncbi.nlm.nih.gov/pubmed/28683716
http://dx.doi.org/10.1186/s12711-017-0331-4
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author Wang, Min
Hancock, Timothy P.
MacLeod, Iona M.
Pryce, Jennie E.
Cocks, Benjamin G.
Hayes, Benjamin J.
author_facet Wang, Min
Hancock, Timothy P.
MacLeod, Iona M.
Pryce, Jennie E.
Cocks, Benjamin G.
Hayes, Benjamin J.
author_sort Wang, Min
collection PubMed
description BACKGROUND: Enhancers are non-coding DNA sequences, which when they are bound by specific proteins increase the level of gene transcription. Enhancers activate unique gene expression patterns within cells of different types or under different conditions. Enhancers are key contributors to gene regulation, and causative variants that affect quantitative traits in humans and mice have been located in enhancer regions. However, in the bovine genome, enhancers as well as other regulatory elements are not yet well defined. In this paper, we sought to improve the annotation of bovine enhancer regions by using publicly available mammalian enhancer information. To test if the identified putative bovine enhancer regions are enriched with functional variants that affect milk production traits, we performed genome-wide association studies using imputed whole-genome sequence data followed by meta-analysis and enrichment analysis. RESULTS: We produced a library of candidate bovine enhancer regions by using publicly available bovine ChIP-Seq enhancer data in combination with enhancer data that were identified based on sequence homology with human and mouse enhancer databases. We found that imputed whole-genome sequence variants associated with milk production traits in 16,581 dairy cattle were enriched with enhancer regions that were marked by bovine-liver H3K4me3 and H3K27ac histone modifications from both permutation tests and gene set enrichment analysis. Enhancer regions that were identified based on sequence homology with human and mouse enhancer regions were not as strongly enriched with trait-associated sequence variants as the bovine ChIP-Seq candidate enhancer regions. The bovine ChIP-Seq enriched enhancer regions were located near genes and quantitative trait loci that are associated with pregnancy, growth, disease resistance, meat quality and quantity, and milk quality and quantity traits in dairy and beef cattle. CONCLUSIONS: Our results suggest that sequence variants within enhancer regions that are located in bovine non-coding genomic regions contribute to the variation in complex traits. The level of enrichment was higher in bovine-specific enhancer regions that were identified by detecting histone modifications H3K4me3 and H3K27ac in bovine liver tissues than in enhancer regions identified by sequence homology with human and mouse data. These results highlight the need to use bovine-specific experimental data for the identification of enhancer regions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12711-017-0331-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-54992142017-07-10 Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits Wang, Min Hancock, Timothy P. MacLeod, Iona M. Pryce, Jennie E. Cocks, Benjamin G. Hayes, Benjamin J. Genet Sel Evol Research Article BACKGROUND: Enhancers are non-coding DNA sequences, which when they are bound by specific proteins increase the level of gene transcription. Enhancers activate unique gene expression patterns within cells of different types or under different conditions. Enhancers are key contributors to gene regulation, and causative variants that affect quantitative traits in humans and mice have been located in enhancer regions. However, in the bovine genome, enhancers as well as other regulatory elements are not yet well defined. In this paper, we sought to improve the annotation of bovine enhancer regions by using publicly available mammalian enhancer information. To test if the identified putative bovine enhancer regions are enriched with functional variants that affect milk production traits, we performed genome-wide association studies using imputed whole-genome sequence data followed by meta-analysis and enrichment analysis. RESULTS: We produced a library of candidate bovine enhancer regions by using publicly available bovine ChIP-Seq enhancer data in combination with enhancer data that were identified based on sequence homology with human and mouse enhancer databases. We found that imputed whole-genome sequence variants associated with milk production traits in 16,581 dairy cattle were enriched with enhancer regions that were marked by bovine-liver H3K4me3 and H3K27ac histone modifications from both permutation tests and gene set enrichment analysis. Enhancer regions that were identified based on sequence homology with human and mouse enhancer regions were not as strongly enriched with trait-associated sequence variants as the bovine ChIP-Seq candidate enhancer regions. The bovine ChIP-Seq enriched enhancer regions were located near genes and quantitative trait loci that are associated with pregnancy, growth, disease resistance, meat quality and quantity, and milk quality and quantity traits in dairy and beef cattle. CONCLUSIONS: Our results suggest that sequence variants within enhancer regions that are located in bovine non-coding genomic regions contribute to the variation in complex traits. The level of enrichment was higher in bovine-specific enhancer regions that were identified by detecting histone modifications H3K4me3 and H3K27ac in bovine liver tissues than in enhancer regions identified by sequence homology with human and mouse data. These results highlight the need to use bovine-specific experimental data for the identification of enhancer regions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12711-017-0331-4) contains supplementary material, which is available to authorized users. BioMed Central 2017-07-06 /pmc/articles/PMC5499214/ /pubmed/28683716 http://dx.doi.org/10.1186/s12711-017-0331-4 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Wang, Min
Hancock, Timothy P.
MacLeod, Iona M.
Pryce, Jennie E.
Cocks, Benjamin G.
Hayes, Benjamin J.
Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title_full Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title_fullStr Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title_full_unstemmed Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title_short Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
title_sort putative enhancer sites in the bovine genome are enriched with variants affecting complex traits
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499214/
https://www.ncbi.nlm.nih.gov/pubmed/28683716
http://dx.doi.org/10.1186/s12711-017-0331-4
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