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Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat
BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strai...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741965/ https://www.ncbi.nlm.nih.gov/pubmed/29272997 http://dx.doi.org/10.1186/s12864-017-4351-9 |
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author | Martín-Gálvez, David Dunoyer de Segonzac, Denis Ma, Man Chun John Kwitek, Anne E. Thybert, David Flicek, Paul |
author_facet | Martín-Gálvez, David Dunoyer de Segonzac, Denis Ma, Man Chun John Kwitek, Anne E. Thybert, David Flicek, Paul |
author_sort | Martín-Gálvez, David |
collection | PubMed |
description | BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems. RESULTS: We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver-associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain-specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity—one of the metabolic symptoms shown by the Lyon strains—amongst the genes assigned to promoters with strain-specific variation. CONCLUSIONS: Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-017-4351-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5741965 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57419652018-01-03 Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat Martín-Gálvez, David Dunoyer de Segonzac, Denis Ma, Man Chun John Kwitek, Anne E. Thybert, David Flicek, Paul BMC Genomics Research Article BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems. RESULTS: We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver-associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain-specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity—one of the metabolic symptoms shown by the Lyon strains—amongst the genes assigned to promoters with strain-specific variation. CONCLUSIONS: Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-017-4351-9) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-22 /pmc/articles/PMC5741965/ /pubmed/29272997 http://dx.doi.org/10.1186/s12864-017-4351-9 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 Martín-Gálvez, David Dunoyer de Segonzac, Denis Ma, Man Chun John Kwitek, Anne E. Thybert, David Flicek, Paul Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title | Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title_full | Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title_fullStr | Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title_full_unstemmed | Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title_short | Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
title_sort | genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741965/ https://www.ncbi.nlm.nih.gov/pubmed/29272997 http://dx.doi.org/10.1186/s12864-017-4351-9 |
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