Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches.
Human chromosome 2q33 is an immunologically important region based on the linkage of numerous autoimmune diseases to the CTLA4 locus. Here, we sequenced and assembled 2q33 bacterial artificial chromosome (BAC) clones, resulting in 381,403 bp of contiguous sequence containing genes encoding a NADH: ubiquinone oxidoreductase, the costimulatory receptors CD28, CTLA4, and ICOS, and a HERV-H type endogenous retrovirus located 366 bp downstream of ICOS in the reverse orientation. Genomic microarray expression analysis using differentially activated T-cell RNA against a subcloned CTLA4/ICOS BAC library revealed upregulation of CTLA4 and ICOS sequences, plus antisense ICOS transcripts generated by the HERV-H, suggesting a potential mechanism for ICOS regulation. We identified four nonlinked, polymorphic, simple repetitive sequence elements in this region, which may be used to delineate genetic effects of ICOS and CTLA4 in disease populations. Comparative genomic analysis of mouse genomic Icos sequences revealed 60% sequence identity in the 5' UTR and regions between exon 2 and the 3' UTR, suggesting the importance of ICOS gene function.
Ling
V
V
Genetics Institute/Wyeth Research, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. VLing@genetics.com
Wu
P W
PW
Finnerty
H F
HF
Agostino
M J
MJ
Graham
J R
JR
Chen
S
S
Jussiff
J M
JM
Fisk
G J
GJ
Miller
C P
CP
Collins
M
M
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D022202:Chromosomes, Artificial, Bacterial; D002889:Chromosomes, Human, Pair 2; D006801:Humans; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D020161:Physical Chromosome Mapping; D011110:Polymorphism, Genetic; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556692:ICOS protein, human; C556694:Icos protein, mouse; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D000069594:Abatacept