Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans.
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 genetics. 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 variation. 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.
Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, UK. t.aitman@csc.mrc.ac.uk
Timothy J
TJ
Aitman
Rong
R
Dong
Timothy J
TJ
Vyse
Penny J
PJ
Norsworthy
Michelle D
MD
Johnson
Jennifer
J
Smith
Jonathan
J
Mangion
Cheri
C
Roberton-Lowe
Amy J
AJ
Marshall
Enrico
E
Petretto
Matthew D
MD
Hodges
Gurjeet
G
Bhangal
Sheetal G
SG
Patel
Kelly
K
Sheehan-Rooney
Mark
M
Duda
Paul R
PR
Cook
David J
DJ
Evans
Jan
J
Domin
Jonathan
J
Flint
Joseph J
JJ
Boyle
Charles D
CD
Pusey
H Terence
HT
Cook
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D058851:GPI-Linked Proteins; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D011921:Rats, Inbred WKY; D017452:Receptors, IgG / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
D015703:Antigens, CD; C428200:FCGR3B protein, human; C508636:Fcgr2a protein, rat; D058851:GPI-Linked Proteins; D017452:Receptors, IgG