1. BMC Genomics. 2014;15 Suppl 12:S3. doi: 10.1186/1471-2164-15-S12-S3. Epub 2014
Dec 19.
Application of quantitative trait locus mapping and transcriptomics to studies of
the senescence-accelerated phenotype in rats.
Korbolina EE, Ershov NI, Bryzgalov LO, Kolosova NG.
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.
PMCID: PMC4303943
PMID: 25563673 [PubMed - in process]
PUBMED: 25563673
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