Detection and characterization of DNA variants in the promoter regions of hundreds of human disease candidate genes.
Understanding genetic variation might reveal the cause of individual susceptibility to a variety of complex diseases such as asthma, diabetes, and cancer. Current efforts to identify functional DNA variants have essentially been oriented toward single nucleotide polymorphisms (SNPs) found in coding regions of candidate genes since they have direct impact on the structure and function of the affected proteins. Abnormal expression of finely regulated genes could also lead to disequilibria in different metabolic pathways and/or biological processes. Thus investigation of SNPs in the promoter regions (pSNPs) of genes should improve our knowledge of the etiology of complex diseases. Unfortunately, little is known about the nature and the prevalence of pSNPs. We have analyzed 197 genes targeting the promoter region, arbitrarily defined as a 2-kb genomic segment upstream of the transcription initiation site, by screening by dHPLC for the presence of SNPs in a worldwide panel of 40 individuals. As a result 1838 pSNPs were detected, 75% of which modify (by either gain or loss) putative binding sites of known transcription factors. We also examined the distribution of these pSNPs among features such as conserved regions, repeats, and dinucleotides as well as Gene Ontology terms. This report supports the functional relevance of several of the pSNPs investigated and suggests a putative impact on disease susceptibility.
Sinnett
Daniel
D
Division of Hematology-Oncology, Research Center, Sainte-Justine Hospital, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Canada QC H3T 1C5. daniel.sinnett@umontreal.ca
Beaulieu
Patrick
P
Bélanger
Hélène
H
Lefebvre
Jean-François
JF
Langlois
Sylvie
S
Théberge
Marie-Christine
MC
Drouin
Simon
S
Zotti
Corinne
C
Hudson
Thomas J
TJ
Labuda
Damian
D
D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors; D004247:DNA