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Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats
BACKGROUND: Etiology of complex disorders, such as cataract and neurodegenerative diseases including age-related macular degeneration (AMD), remains poorly understood due to the paucity of animal models, fully replicating the human disease. Previously, two quantitative trait loci (QTLs) associated w...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303943/ https://www.ncbi.nlm.nih.gov/pubmed/25563673 http://dx.doi.org/10.1186/1471-2164-15-S12-S3 |
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author | Korbolina, Elena E Ershov, Nikita I Bryzgalov, Leonid O Kolosova, Natalia G |
author_facet | Korbolina, Elena E Ershov, Nikita I Bryzgalov, Leonid O Kolosova, Natalia G |
author_sort | Korbolina, Elena E |
collection | PubMed |
description | BACKGROUND: Etiology of complex disorders, such as cataract and neurodegenerative diseases including age-related macular degeneration (AMD), remains poorly understood due to the paucity of animal models, fully replicating the human disease. Previously, two quantitative trait loci (QTLs) associated with early cataract, AMD-like retinopathy, and some behavioral aberrations in senescence-accelerated OXYS rats were uncovered on chromosome 1 in a cross between OXYS and WAG rats. To confirm the findings, we generated interval-specific congenic strains, WAG/OXYS-1.1 and WAG/OXYS-1.2, carrying OXYS-derived loci of chromosome 1 in the WAG strain. Both congenic strains displayed early cataract and retinopathy but differed clinically from OXYS rats. Here we applied a high-throughput RNA sequencing (RNA-Seq) strategy to facilitate nomination of the candidate genes and functional pathways that may be responsible for these differences and can contribute to the development of the senescence-accelerated phenotype of OXYS rats. RESULTS: First, the size and map position of QTL-derived congenic segments were determined by comparative analysis of coding single-nucleotide polymorphisms (SNPs), which were identified for OXYS, WAG, and congenic retinal RNAs after sequencing. The transferred locus was not what we expected in WAG/OXYS-1.1 rats. In rat retina, 15442 genes were expressed. Coherent sets of differentially expressed genes were identified when we compared RNA-Seq retinal profiles of 20-day-old WAG/OXYS-1.1, WAG/OXYS-1.2, and OXYS rats. The genes most different in the average expression level between the congenic strains included those generally associated with the Wnt, integrin, and TGF-β signaling pathways, widely involved in neurodegenerative processes. Several candidate genes (including Arhgap33, Cebpg, Gtf3c1, Snurf, Tnfaip3, Yme1l1, Cbs, Car9 and Fn1) were found to be either polymorphic in the congenic loci or differentially expressed between the strains. These genes may contribute to the development of cataract and retinopathy. CONCLUSIONS: This study is the first RNA-Seq analysis of the rat retinal transcriptome generated with 40 mln sequencing read depth. The integration of QTL and transcriptomic analyses in our study forms the basis of future research into the relationship between the candidate genes within the congenic regions and specific changes in the retinal transcriptome as possible causal mechanisms that underlie age-associated disorders. |
format | Online Article Text |
id | pubmed-4303943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43039432015-02-09 Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats Korbolina, Elena E Ershov, Nikita I Bryzgalov, Leonid O Kolosova, Natalia G BMC Genomics Research BACKGROUND: Etiology of complex disorders, such as cataract and neurodegenerative diseases including age-related macular degeneration (AMD), remains poorly understood due to the paucity of animal models, fully replicating the human disease. Previously, two quantitative trait loci (QTLs) associated with early cataract, AMD-like retinopathy, and some behavioral aberrations in senescence-accelerated OXYS rats were uncovered on chromosome 1 in a cross between OXYS and WAG rats. To confirm the findings, we generated interval-specific congenic strains, WAG/OXYS-1.1 and WAG/OXYS-1.2, carrying OXYS-derived loci of chromosome 1 in the WAG strain. Both congenic strains displayed early cataract and retinopathy but differed clinically from OXYS rats. Here we applied a high-throughput RNA sequencing (RNA-Seq) strategy to facilitate nomination of the candidate genes and functional pathways that may be responsible for these differences and can contribute to the development of the senescence-accelerated phenotype of OXYS rats. RESULTS: First, the size and map position of QTL-derived congenic segments were determined by comparative analysis of coding single-nucleotide polymorphisms (SNPs), which were identified for OXYS, WAG, and congenic retinal RNAs after sequencing. The transferred locus was not what we expected in WAG/OXYS-1.1 rats. In rat retina, 15442 genes were expressed. Coherent sets of differentially expressed genes were identified when we compared RNA-Seq retinal profiles of 20-day-old WAG/OXYS-1.1, WAG/OXYS-1.2, and OXYS rats. The genes most different in the average expression level between the congenic strains included those generally associated with the Wnt, integrin, and TGF-β signaling pathways, widely involved in neurodegenerative processes. Several candidate genes (including Arhgap33, Cebpg, Gtf3c1, Snurf, Tnfaip3, Yme1l1, Cbs, Car9 and Fn1) were found to be either polymorphic in the congenic loci or differentially expressed between the strains. These genes may contribute to the development of cataract and retinopathy. CONCLUSIONS: This study is the first RNA-Seq analysis of the rat retinal transcriptome generated with 40 mln sequencing read depth. The integration of QTL and transcriptomic analyses in our study forms the basis of future research into the relationship between the candidate genes within the congenic regions and specific changes in the retinal transcriptome as possible causal mechanisms that underlie age-associated disorders. BioMed Central 2014-12-19 /pmc/articles/PMC4303943/ /pubmed/25563673 http://dx.doi.org/10.1186/1471-2164-15-S12-S3 Text en Copyright © 2014 Korbolina et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 Korbolina, Elena E Ershov, Nikita I Bryzgalov, Leonid O Kolosova, Natalia G Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title | Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title_full | Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title_fullStr | Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title_full_unstemmed | Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title_short | Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
title_sort | application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303943/ https://www.ncbi.nlm.nih.gov/pubmed/25563673 http://dx.doi.org/10.1186/1471-2164-15-S12-S3 |
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