Identification of candidate disease genes by EST alignments, synteny, and expression and verification of Ensembl genes on rat chromosome 1q43-54.
We aligned Incyte ESTs and publicly available sequences to the rat genome and analyzed rat chromosome 1q43-54, a region in which several quantitative trait loci (QTLs) have been identified, including renal disease, diabetes, hypertension, body weight, and encephalomyelitis. Within this region, which contains 255 Ensembl gene predictions, the aligned sequences clustered into 568 Incyte genes and gene fragments. Of the Incyte genes, 261 (46%) overlapped 184 (72%) of the Ensembl gene predictions, whereas 307 were unique to Incyte. The rat-to-human syntenic map displays rearrangement of this region on rat chr. 1 onto human chromosomes 9 and 10. The mapping of corresponding human disease phenotypes to either one of these chromosomes has allowed us to focus in on genes associated with disease phenotypes. As an example, we have used the syntenic information for the rat Rf-1 disease region and the orthologous human ESRD disease region to reduce the size of the original rat QTL to only 11.5 Mb. Using the syntenic information in combination with expression data from ESTs and microarrays, we have selected a set of 66 candidate disease genes for Rf-1. The combination of the results from these different analyses represents a powerful approach for narrowing the number of genes that could play a role in the development of complex diseases.
Vitt
Ursula
U
Incyte Corporation, Palo Alto, California 94304, USA. uvitt@incyte.com
Gietzen
Darryl
D
Stevens
Kristian
K
Wingrove
Jim
J
Becha
Shanya
S
Bulloch
Sean
S
Burrill
John
J
Chawla
Narinder
N
Chien
Jennifer
J
Crawford
Matthew
M
Ison
Craig
C
Kearney
Liam
L
Kwong
Mary
M
Park
Joe
J
Policky
Jennifer
J
Weiler
Mark
M
White
Renee
R
Xu
Yuming
Y
Daniels
Sue
S
Jacob
Howard
H
Jensen-Seaman
Michael I
MI
Lazar
Jozef
J
Stuve
Laura
L
Schmidt
Jeanette
J
D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D002875:Chromosomes / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D003920:Diabetes Mellitus / Q000235:genetics*; D004679:Encephalomyelitis / Q000235:genetics*; D020224:Expressed Sequence Tags; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics; D005807:Genes, Overlapping / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D005810:Multigene Family / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D020161:Physical Chromosome Mapping / Q000379:methods; D011237:Predictive Value of Tests; D040641:Quantitative Trait Loci / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment / Q000379:methods*; D012689:Sequence Homology, Nucleic Acid; D012986:Software Validation; D026801:Synteny / Q000235:genetics*