Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans
AU - Aitman, Timothy J.
AU - Dong, Rong
AU - Vyse, Timothy J.
AU - Norsworthy, Penny J.
AU - Johnson, Michelle D.
AU - Smith, Jennifer
AU - Mangion, Jonathan
AU - Roberton-Lowe, Cheri
AU - Marshall, Amy J.
AU - Petretto, Enrico
AU - Hodges, Matt
AU - Bhangal, Gurjeet
AU - Patel, Sheetal G.
AU - Sheehan-Rooney, Kelly
AU - Duda, Mark
AU - Cook, Paul R.
AU - Evans, David J.
AU - Domin, Jan
AU - Flint, Jonathan
AU - Boyle, Joseph J.
AU - Pusey, Charles D.
AU - Cook, H. Terence
PY - 2006/2/16
Y1 - 2006/2/16
N2 - 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.
AB - 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.
KW - copy number polymorphism
KW - Fcgr3
KW - glomerulonephritis
U2 - 10.1038/nature04489
DO - 10.1038/nature04489
M3 - Journal article
VL - 439
SP - 851
EP - 855
JO - Nature
JF - Nature
SN - 0028-0836
ER -