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Fine Mapping of Collagen-Induced Arthritis Quantitative Trait Loci in an Advanced Intercross Line¹

Xinhua Yu^2,*, Kristin Bauer^2,*, Patrik Wernhoff^*, Dirk Koczan, Steffen Möller, Hans-Jürgen Thiesen and Saleh M. Ibrahim^3,*

^* Immunogenetics Group and Institute for Immunology, University of Rostock, Rostock, Germany

The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine mapping of quantitative trait loci (QTLs), because they accumulate much more recombination events compared with conventional F₂ intercross and N₂ backcross. However, the application of this approach is severely hampered by the requirements of excessive resources to maintain such crosses, i.e., in terms of animal care, space, and time. Therefore, in this study, we produced an AIL to fine map collagen-induced arthritis (CIA) QTLs using comparatively limited resources. We used only 308 (DBA/1 x FVB/N)F_11/12 AIL mice to refine QTLs controlling the severity and onset of arthritis as well as the Ab response and T cell subset in CIA, namely Cia2, Cia27, and Trmq3. These QTLs were originally identified in (DBA/1 x FVB/N)F₂ progeny. The confidence intervals of the three QTLs were refined from 40, 43, and 48 Mb to 12, 4.1, and 12 Mb, respectively. The data were complemented by the use of another QTL fine-mapping approach, haplotype analysis, to further refine Cia2 into a 2-Mb genomic region. To aid in the search for candidate genes for the QTLs, genome-wide expression profiling was performed to identify strain-specific differentially expressed genes within the confidence intervals. Of the 1396 strain-specific differentially expressed genes, 3, 3, and 12 genes were within the support intervals of the Cia2, Cia27, and Trmq3, respectively. In addition, this study revealed that Cia27 and Trmq3 controlling anti-CII IgG2a Ab and CD4:CD8 T cell ratio, respectively, also regulated CIA clinical phenotypes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Marie Curie Training Network Grant MCTN CT 2004-005693.

² X.Y. and K.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Saleh M. Ibrahim, Immunogenetics Group, University of Rostock, Schillingallee 70, 18055 Rostock, Germany. E-mail address: saleh.ibrahim{at}med.uni-rostock.de

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; AIL, advanced intercross line; AUC, area under the curve; SNP, single nucleotide polymorphism; CI, confidence interval; LOD, logarithm of the likelihood ratios; QTL, quantitative trait locus; LN, lymph node.

⁵ The online version of this article contains supplemental material.

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