Abstract
The use of genetically modified mice, i.e. transgenic as well as gene knockout (KO) and knock-in mice, has become an established tool to study gene function in many animal models for human diseases . However, a gene functions in a particular genomic context. This implies the importance of a well-defined homogenous genetic background for the analysis and interpretation of phenotypes associated with genetic mutations. By studying a Plasmodium chabaudi chabaudi AS (PcAS) malaria infection in mice bearing a TLR9 null mutation, we found an increased susceptibility to infection, i.e. higher parasitemia levels and increased mortality. However, this was not triggered by the deficient TLR9 gene itself. Instead, this disease phenotype was dependent on the heterogeneous genetic background of the mice, which appeared insufficiently defined as determined by single nucleotide polymorphism (SNP) analysis. Hence, it is of critical importance to study gene KO phenotypes on a homogenous genetic background identical to that of their wild type (WT) control counterparts. In particular, to avoid problems related to an insufficiently defined genetic background, we advocate that for each study involving genetically modified mice, at least a detailed description of the origin and genetic background of both the WT control and the altered strain of mice is essential.
Highlights
The major histocompatibility complex (MHC) on human chromosome 6 covers a large genomic region with a central role in determining the degree of disease susceptibility
The infection of C57Bl/6 wild type (WT) mice with Plasmodium chabaudi chabaudi AS (PcAS) is characterized by an acute primary peak of parasitemia around day 9–10, followed by a chronic phase marked by one or two small recrudescences around day 30 post infection
We compared the course of PcAS infection in the originally received B6.TLR92/2(OR) mice and commercial inbred B6.WT(Jv) mice and observed a phenotype in parasitemia
Summary
The major histocompatibility complex (MHC) on human chromosome 6 covers a large genomic region with a central role in determining the degree of disease susceptibility In this locus, small gene polymorphisms, typically located in alleles in charge of protein processing and presentation as well as immune regulation, are associated with several human autoimmune diseases, e.g. multiple sclerosis, type 1 diabetes and rheumatoid arthritis, and with infectious diseases, e.g. malaria [1,2,3,4,5,6]. Aside the MHC having a major impact on immune phenotypes, many genes outside this susceptibility locus contribute to immunomodulation This is increasingly recognized by genome-wide association studies (GWAS) in which genes encoding cytokines, cytokine receptors and pattern recognition receptors (PRRs, e.g. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs)) are identified to play small but definite effects that may synergize [7,8]. Our data demonstrate that phenotypic differences observed between mutant and control mice can result from the effect of background genes and this might lead to misinterpretation of results
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