A major effort in discovery and characterization of genetic variation will require innovative, low-cost, high throughput methods for highly accurate comparative sequencing of DNA. We propose to develop a novel combinatorial array to enable ultralow cost, sensitive and high throughput discovery of single nucleotide polymorphisms. This will be accelerated by the development of technology to resequence PCR products from multiple individuals. We will develop a low complexity array based on 4mer DNA sequences for use in a high throughput 96-array microplate format (one array per well) to screen candidate cSNPs. This SNP discovery system, including software analysis tools, will facilitate greatly the discovery and characterization of new SNPs and will be amenable to adaptation in large and small-scale laboratory settings.