Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep
[EN] In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neo...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | España |
| Institución: | Universidad de León |
| Repositorio: | BULERIA. Repositorio Institucional de la Universidad de León |
| OAI Identifier: | oai:buleria.unileon.es:10612/24346 |
| Acceso en línea: | https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126416 https://hdl.handle.net/10612/24346 |
| Access Level: | acceso abierto |
| Palabra clave: | Genética Producción animal Veterinaria GWAS RNA sequencing Sheep 3109 Ciencias Veterinarias 3104 Producción Animal |
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Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in SheepSuárez Vega, AroaGutiérrez Gil, BeatrizBenavides Silván, JulioPérez Pérez, ValentínTosser-Klopp, GwenolaKlopp, ChristopheKeennel, Stephen J.Arranz Santos, Juan JoséGenéticaProducción animalVeterinariaGWASRNA sequencingSheep3109 Ciencias Veterinarias3104 Producción Animal[EN] In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412-4415del). The c.4412-4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412-4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approachevidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforwardSIFunded by Spanish Ministry of Economy and Competitiveness (grant AGL2012-34437 to JJA); Aroa Suarez-Vega is funded by an FPU contract from Spanish Ministry of Education. Beatriz Guterrez-Gil is funded by an Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptPublic Library of ScienceProducción AnimalFacultad de Veterinaria2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126416https://hdl.handle.net/10612/24346reponame:BULERIA. Repositorio Institucional de la Universidad de Leóninstname:Universidad de LeónIngléshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:buleria.unileon.es:10612/243462026-06-24T12:43:27Z |
| dc.title.none.fl_str_mv |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| title |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| spellingShingle |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep Suárez Vega, Aroa Genética Producción animal Veterinaria GWAS RNA sequencing Sheep 3109 Ciencias Veterinarias 3104 Producción Animal |
| title_short |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| title_full |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| title_fullStr |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| title_full_unstemmed |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| title_sort |
Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep |
| dc.creator.none.fl_str_mv |
Suárez Vega, Aroa Gutiérrez Gil, Beatriz Benavides Silván, Julio Pérez Pérez, Valentín Tosser-Klopp, Gwenola Klopp, Christophe Keennel, Stephen J. Arranz Santos, Juan José |
| author |
Suárez Vega, Aroa |
| author_facet |
Suárez Vega, Aroa Gutiérrez Gil, Beatriz Benavides Silván, Julio Pérez Pérez, Valentín Tosser-Klopp, Gwenola Klopp, Christophe Keennel, Stephen J. Arranz Santos, Juan José |
| author_role |
author |
| author2 |
Gutiérrez Gil, Beatriz Benavides Silván, Julio Pérez Pérez, Valentín Tosser-Klopp, Gwenola Klopp, Christophe Keennel, Stephen J. Arranz Santos, Juan José |
| author2_role |
author author author author author author author |
| dc.contributor.none.fl_str_mv |
Producción Animal Facultad de Veterinaria |
| dc.subject.none.fl_str_mv |
Genética Producción animal Veterinaria GWAS RNA sequencing Sheep 3109 Ciencias Veterinarias 3104 Producción Animal |
| topic |
Genética Producción animal Veterinaria GWAS RNA sequencing Sheep 3109 Ciencias Veterinarias 3104 Producción Animal |
| description |
[EN] In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412-4415del). The c.4412-4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412-4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approachevidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforward |
| publishDate |
2015 |
| dc.date.none.fl_str_mv |
2015 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126416 https://hdl.handle.net/10612/24346 |
| url |
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126416 https://hdl.handle.net/10612/24346 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Public Library of Science |
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Public Library of Science |
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reponame:BULERIA. Repositorio Institucional de la Universidad de León instname:Universidad de León |
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Universidad de León |
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BULERIA. Repositorio Institucional de la Universidad de León |
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BULERIA. Repositorio Institucional de la Universidad de León |
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