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.
Highlights
The DA rat strain is susceptible to the induction of a number of chronic inflammatory diseases, such as models for rheumatoid arthritis and multiple sclerosis
Single nucleotide variation (SNV) and short indels were identified using a strategy developed by Guryev et al [36]
DA rats are susceptible to the induction of a number of chronic inflammatory diseases
Summary
The DA rat strain is susceptible to the induction of a number of chronic inflammatory diseases, such as models for rheumatoid arthritis and multiple sclerosis. Inbred rat strains and genetically segregating crosses are important tools in functionally proving disease mechanisms and represents a controlled setting where molecular interactions between different genetic factors as well as environmental factors can be tested [1]. There are many common characteristics between chronic inflammatory diseases like Rheumatoid Arthritis (RA) [2], and Multiple Sclerosis (MS) [3]: these diseases are both consequences of dys-regulated immune responses that has initially been triggered by a combination of genetic and environmental factors. Despite recent progress in identifying loci that associate with complex diseases in human [5], the identification of the causative genetic polymorphisms, (both within and outside MHC), and the understanding of their pathophysiological roles, still represents a significant challenge. The complexity of chronic inflammatory diseases lies in intricate interactions between genes and environment, and in elaborate genetic phenomena such as gene-gene interactions, synergistic effects and epigenetic mechanisms
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