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

Abstract

BackgroundThe DA rat strain is particularly susceptible to the induction of a number of chronic inflammatory diseases, such as models for rheumatoid arthritis and multiple sclerosis. Here we sequenced the genomes of two DA sub-strains and two disease resistant strains, E3 and PVG, previously used together with DA strains in genetically segregating crosses.ResultsThe data uncovers genomic variations, such as single nucleotide variations (SNVs) and copy number variations that underlie phenotypic differences between the strains. Comparisons of regional differences between the two DA sub-strains identified 8 genomic regions that discriminate between the strains that together cover 38 Mbp and harbor 302 genes. We analyzed 10 fine-mapped quantitative trait loci and our data implicate strong candidates for genetic variations that mediate their effects. For example we could identify a single SNV candidate in a regulatory region of the gene Il21r, which has been associated to differential expression in both rats and human MS patients. In the APLEC complex we identified two SNVs in a highly conserved region, which could affect the regulation of all APLEC encoded genes and explain the polygenic differential expression seen in the complex. Furthermore, the non-synonymous SNV modifying aa153 of the Ncf1 protein was confirmed as the sole causative factor.ConclusionThis complete map of genetic differences between the most commonly used rat strains in inflammation research constitutes an important reference in understanding how genetic variations contribute to the traits of importance for inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-391) contains supplementary material, which is available to authorized users.

Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles

“…Furthermore, our study highlights the genetic divergence regarding MCh-induced AHR, where DA rats were more reactive, both in central and peripheral airways, compared to BN rats. In addition to this genetically determined susceptibility, DA rats has previously been identified as being prone to developing chronic inflammatory diseases (Bäckdahl et al, 2014;Carlson et al, 2000), involving macrophage activation and neutrophil recruitment to injured tissues (Gustafsson et al, 2011(Gustafsson et al, , 2014Zhang et al, 2011), while BN rats are susceptible to developing a prominent humoral immune response with IgE production and eosinophil inflammation (Granum and Løvik, 2002;Martin and Tamaoka, 2006). These results indicate that these strains are useful for further investigations of genetic influence of asthma pathology due to their different responses in terms of immune activation, AHR, and inflammatory profile.…”

‘Candidatus Phytoplasma phoenicium’ associated with almond witches’-broom disease: from draft genome to genetic diversity among strain populations

“…An estimation of the covered gene content of ‘ Ca. P. phoenicium’ draft genome was performed by comparison to the phytoplasmas protein coding gene core set [ 49 ]. Even obtained data evidenced that ‘ Ca.…”

“…Even obtained data evidenced that ‘ Ca. P. phoenicium’ draft genome is far away from being complete [ 49 ], it can be shown that 81 % (238 protein coding genes) of the core set protein coding genes are also included in the ‘ Ca. P. phoenicium’ draft sequence (Additional file 2 : Table S2).…”

“…P. phoenicium’ draft genome, the percentage of AlmWB phytoplasma proteins included in the core-genome of ‘ Ca . Phytoplasma’ [ 49 ] was calculated. Therefore, the ‘ Ca .…”

C-type lectin receptors Mcl and Mincle control development of multiple sclerosis–like neuroinflammation

“…Inbred DA and PVG.1AV1 rats were originally obtained from the Zentralinstitut für Versuchstierzucht (Hannover, Germany) and Harlan UK Ltd, respectively. Separate lines have been established at Karolinska Institutet (DA/Kini and PVG.1AV1/Kini) (52). The CLRc strain stems from a natural recombination event between the DA strain and the APLEC strain, encompassing a larger congenic fragment from the PVG background (19,53).…”