Inconsistent susceptibility to autoimmunity in inbred LEW rats is due to genetic crossbreeding involving segregation of the arthritis-regulating gene Ncf1.
We recently identified a single-nucleotide polymorphism in the Ncf1 gene, a component of the NADPH oxidase complex, to be the cause of one of the strongest identified loci for arthritis severity in rats. This polymorphism was found to be naturally occurring in a collection of inbred rat strains as well as in wild rats. Among the inbred strains we found that different LEW substrains (LEW/Ztm and LEW/Mol), originating from different breeders, showed an allelic discrepancy in Ncf1, suggesting an impact on arthritis susceptibility between these substrains. In fact, the LEW/Mol strain was completely resistant to pristane-induced arthritis, in contrast to the LEW/Ztm strain, which was susceptible. Moreover, the LEW/Mol strain had higher production of radical oxygen species in peripheral blood leukocytes, a phenomenon most likely regulated by the polymorphisms in the Ncf1 gene. However, the phenotypic difference between LEW/Mol and LEW/Ztm is most likely a combination of several genes, of which Ncf1 is suggested to be the major regulating gene. This has also been confirmed by previous linkage analyses involving the LEW/Ztm strain which shows that a QTL on chromosome 12, most likely caused by polymorphism of Ncf1, is the major regulatory gene but that other loci are contributing. That more genes are likely to contribute was shown by a complete genome comparison of the LEW/Ztm and the LEW/Mol rat strains that uncovered an introduction of approximately 37% non-LEW genome into the LEW/Mol strain, which probably was caused by past crossbreeding. Therefore, the LEW/Mol should be regarded as a recombinant inbred strain.
Olofsson
Peter
P
Section for Medical Inflammation Research, Lund University, S-22184 Lund, Sweden.
Johansson
Asa
A
Wedekind
Dirk
D
Klöting
Ingrid
I
Klinga-Levan
Karin
K
Lu
Shemin
S
Holmdahl
Rikard
R
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006824:Hybridization, Genetic / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D019255:NADPH Oxidases; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology
D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D013729:Terpenes; C009042:pristane; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1