Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies

The creation of single nucleotide polymorphism (SNP) databases (such as NCBI dbSNP) has facilitated scientific research in many fields. SNP discovery and detection has improved to the extent that there are over 17 million human reference (rs) SNPs reported to date (Build 129 of dbSNP). SNP databases are unfortunately not always complete and/or accurate. In fact, half of the reported SNPs are still only candidate SNPs and are not validated in a population. We describe the identification of SNDs (single nucleotide differences) in humans, that may contaminate the dbSNP database. These SNDs, reported as real SNPs in the database, do not exist as such, but are merely artifacts due to the presence of a paralogue (highly similar duplicated) sequence in the genome. Using sequencing we showed how SNDs could originate in two paralogous genes and evaluated samples from a population of 100 individuals for the presence/absence of SNPs. Moreover, using bioinformatics, we predicted as many as 8.32% of the biallelic, coding SNPs in the dbSNP database to be SNDs. Our identification of SNDs in the database will allow researchers to not only select truly informative SNPs for association studies, but also aid in determining accurate SNP genotypes and haplotypes. Hum Mutat 31:67–73, 2010. © 2009 Wiley‐Liss, Inc.

[1]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[2]  Jin-Sung Lee,et al.  MedRefSNP: A database of medically investigated SNPs , 2009, Human mutation.

[3]  Alan F. Scott,et al.  McKusick's Online Mendelian Inheritance in Man (OMIM®) , 2008, Nucleic Acids Res..

[4]  Chris Mungall,et al.  Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins , 2008, PLoS Comput. Biol..

[5]  Leonid Kruglyak,et al.  The road to genome-wide association studies , 2008, Nature Reviews Genetics.

[6]  R. Britten Almost all human genes resulted from ancient duplication , 2006, Proceedings of the National Academy of Sciences.

[7]  S. Gabriel,et al.  Efficiency and power in genetic association studies , 2005, Nature Genetics.

[8]  J. Jurka,et al.  Repbase Update, a database of eukaryotic repetitive elements , 2005, Cytogenetic and Genome Research.

[9]  J. Vijg,et al.  SNP discovery in associating genetic variation with human disease phenotypes. , 2005, Mutation research.

[10]  J. Reichardt,et al.  A renaissance of "biochemical genetics"? SNPs, haplotypes, function, and complex diseases. , 2004, Molecular genetics and metabolism.

[11]  Anthony J Brookes,et al.  Complex SNP-related sequence variation in segmental genome duplications , 2004, Nature Genetics.

[12]  David J. Cutler,et al.  Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns , 2004, Bioinform..

[13]  J. Long,et al.  Current limitations of SNP data from the public domain for studies of complex disorders: a test for ten candidate genes for obesity and osteoporosis , 2004, BMC Genetics.

[14]  S. Gabriel,et al.  Quality and completeness of SNP databases , 2003, Nature Genetics.

[15]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[16]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[17]  Gapped BLAST and PSI-BLAST: A new , 1997 .