SNPdetector: A software tool for sensitive accurate SNP detection

Abstract

Identification of single nudeotide poiymorphisms (SNPs) and mutations is important for the discovery of genetic predisposition to complex diseases. PCR resequerscmg is the method of choice for de novo SMP discovery. However, manua! curation of pmtative ShSPs has beers a major boîîîeneck art the application of this method to high-throughput screening, Therefore it is critical to deveSop a more sensitive and accurate computational method for automated SHP detection. We developed a software tool, S-4Pdetector, for automated identification of SMPs and mutations in fluorescence-based resetjuencing reads. SfJPdetector was designed to mode! the process of human visual inspection and has a very Sow faase positive and fa!se rsegatwe rate. We demonstrate the superior performance of SMPdetector m ShäP and mutation analysis by comparing its resets with those derived by human inspection, PoîyPhred (a popular S-4SP detection too!}, and independent genotype assays in three Sarge-scafe investigations. The first study identified arid vaudaîed inter- and mtra-sisbspeeses variations in 4,65o traces of 25 inbred mouse strains that belong to either the MMS mtfsctf/ws species or the M. sprstus species. Unexpected heterozgyosity in CASI/Ei strain was observed in two out of 1,167 mouse SMPs. The second stydy identified 11,241 candidate SMPs irs five ENCODE regions of the hyman genome covering 2.5 Mb of genomic sequence. Approssirrsateiy 50% of the candidate SNPs were selected for expérimenta! genotypirsg; the vaudation rate exceeded 95%. The third study detected ENU-indisced mutations (at 0.04% aHele frequency) in 64,896 traces of 1,236 zebra fish. Our arsaîysis of three Sarge and diverse test datasets demonstrated that SNPdetector is an effective tool for geraome-scaae research and for iarge-sample diraicaa studies. S-4Pdetector runs on Unix/Linus: platform and is avauabîe publicly {http://lpg.nci.nih.gov). Copyright: ©2005 Zhang et al.