title: Systematic investigation of genetic variability in 111 human genes-implications for studying variable drug response.
abstract: In order to identify single-nucleotide polymorphisms (SNPs) and analyze their characteristics in a set of 111 genes, we resequenced exons and flanking regions in an average of 170 chromosomes from individuals of European origin. Genetic variability was decreased in noncoding regions highly conserved between human and rodents, indicating functional relevance of these regions. Furthermore, diversity of coding nonsynonymous SNPs was found lower in regions encoding a known protein sequence motif. SNPs predicted to be of functional significance were more common amongst rare variants. Despite the significant recent growth of SNP numbers in public SNP databases, only a small fraction of these rare variants is represented. This may be relevant in the investigation of the genetic causes of severe side effects, for which rare variants are plausible candidates. Estimation of htSNPs reduces the genotyping effort required in capturing common haplotypes, for certain genes, however, this accounts for only a small fraction of haplotype diversity.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Freudenberg-Hua
authors.forename: J
authors.initials: J
authors.lastname: Freudenberg
authors.forename: J
authors.initials: J
authors.lastname: Winantea
authors.forename: N
authors.initials: N
authors.lastname: Kluck
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.forename: M
authors.initials: M
authors.lastname: Brüss
authors.forename: P
authors.initials: P
authors.lastname: Propping
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
mesh_terms: D000483:Alleles; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics; D002491:Central Nervous System Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D003627:Data Interpretation, Statistical; D030541:Databases, Genetic; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012984:Software
chemical_list: D002491:Central Nervous System Agents; D043562:Receptors, G-Protein-Coupled; D004247:DNA