Genetic basis of transcriptome differences between the founder strains of the rat HXB/BXH recombinant inbred panel

Abstract

BackgroundWith the advent of next generation sequencing it has become possible to detect genomic variation on a large scale. However, predicting which genomic variants are damaging to gene function remains a challenge, as knowledge of the effects of genomic variation on gene expression is still limited. Recombinant inbred panels are powerful tools to study the cis and trans effects of genetic variation on molecular phenotypes such as gene expression.ResultsWe generated a comprehensive inventory of genomic differences between the two founder strains of the rat HXB/BXH recombinant inbred panel: SHR/OlaIpcv and BN-Lx/Cub. We identified 3.2 million single nucleotide variants, 425,924 small insertions and deletions, 907 copy number changes and 1,094 large structural genetic variants. RNA-sequencing analyses on liver tissue of the two strains identified 532 differentially expressed genes and 40 alterations in transcript structure. We identified both coding and non-coding variants that correlate with differential expression and alternative splicing. Furthermore, structural variants, in particular gene duplications, show a strong correlation with transcriptome alterations.ConclusionsWe show that the panel is a good model for assessing the genetic basis of phenotypic heterogeneity and for providing insights into possible underlying molecular mechanisms. Our results reveal a high diversity and complexity underlying quantitative and qualitative transcriptional differences.

Identification of candidate risk gene variations by whole-genome sequence analysis of four rat strains commonly used in inflammation research

“…Therefore we excluded approximately 0.9 M positions per strain where 25-75% of the reads supported the variant allele. Almost 10% of these variants are detected in regions with high coverage (>30X), compared to <1% for homozygous SNVs, and may be due to duplications, as suggested previously [40]. Further, we found that 7% of the heterozygous SNVs in DA/O (coverage 9-25X) were called as homozygous SNVs in DA/K, whereas 1% were called as reference.…”

Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

“…The resulting libraries were sequenced on an Illumina HiSeq2000 following the manufacturer’s instructions. We also sequenced the genome of BN/Mcwi, the rat strain from which the reference BN rat genome was derived, on the SOLiD sequencing platform, using protocols previously described (Simonis et al., 2012), to identify and exclude potential sequencing errors in the reference genome.…”

Genomic variability and protein species — Improving sequence coverage for proteogenomics

“…Previous genomic and physiological studies generated large lists of candidate genes [86][87][88]. The inherited hypertension phenotype in this model suggests that disease is caused by a genetic defect that should manifest itself at the transcriptome and proteome levels.…”