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Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Abstract

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics1,2,3. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation3,4,5. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

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Figure 1: Genome screen for NTN susceptibility loci, and duplication and loss of Fcgr3 exon 5.
Figure 2: Macrophage activity and haplotype analysis.
Figure 3: Identification and functional characterization of Fcgr3-rs.
Figure 4: Copy number polymorphism in human FCGR3 and association with lupus nephritis.

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Acknowledgements

We acknowledge intramural funding from the CSC, and support from the Wellcome Trust Cardiovascular Functional Genomics award, the British Heart Foundation and the Medical Research Council. P.R.C. is a Medical Research Council Clinical Fellow. We thank E. Sodergren and G. Weinstock for BAC clone DNA; H. Hedrich, A. Dominiczak and J. Rapp for rat genomic DNA; T. Serikawa and the National Bio Resource Project in Japan for rat strains and genomic DNA; B. Foxwell for bicistronic vector; and M. Botto, B. Morley, P. Froguel, C. Shoulders and S. Cook for constructive criticism of the manuscript. We acknowledge the CSC Genomics Laboratory for DNA sequencing, and bioinformatics support from M. Müller, N. J. Dickens and the Imperial College Bioinformatics Support Service. Author Contributions The study was conceived and funded by T.J.A., H.T.C. and C.D.P. H.T.C., J.S., P.R.C. and D.J.E. carried out the rodent phenotyping. T.J.A., M.D., P.J.N., P.R.C. and J.F. carried out the rodent linkage studies. T.J.A., R.D., M.D.J., J.M., A.J.M., M.D.H., S.G.P. and K.S.-R. carried out the genomic analysis of rat and human Fcgr3. Cellular immunology studies were carried out by R.D., J.J.B., M.D.J., G.B., M.D., J.D., C.D.P. and H.T.C. Human genetics was carried out by P.J.N., A.J.M., C.R.-L., T.J.V., E.P. and T.J.A., and the manuscript was written by T.J.A., H.T.C., T.J.V. and J.M.

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Correspondence to Timothy J. Aitman or H. Terence Cook.

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The sequence of Fcgr3-rs exon 5 has been deposited in GenBank under accession number AY561710. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Supplementary Figures and Legends

This file contains Supplementary Figures 1–4. Supplementary Figure 1 details the distribution of phenotypes in rat parental strains, and in F1 and F2 animals. Supplementary Figure 2 details the results of the rat Fcgr3 clonotype analysis. Supplementary Figure 3 details the surface expression analysis of Fcgr3 isoforms. Supplementary Figure 4 details the copy number quantification data for human FCGR3B and the control gene CD36. (DOC 640 kb)

Supplementary Table

This contains the results from the logistic regression analysis carried out in patients with lupus nephritis. (DOC 50 kb)

Supplementary Methods

This contains detailed methods and resources used in the rodent and human studies to complement the brief Methods section of the main text. (DOC 61 kb)

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Aitman, T., Dong, R., Vyse, T. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006). https://doi.org/10.1038/nature04489

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