Sequenom has developed technology to scan chip-based arrays of samples by Matrix Assisted Laser Desorption Ionization (MALDI) time of flight (TOF) Mass Spectrometry (MS). Current instrumentation analyses samples of about 6 fmol of DNA in 200 micron sized features. Sequenom's commercially available chips are 2 cm by 3cm and are provided in either 96 or 384 formats. Available spectrometers can process ten 384-sample chips simultaneously, with spectra acquired automatically at rates up to 1.8 seconds per sample. DNA analysis by Sequenom's technology covers a gamut of applications but allele determination is the most well developed application and the one that is currently enabling high-throughput whole genome scans. MS analysis of alleles offers several advantages over more conventional methods. The assays are so robust that assay development can be automated. Thus, the large number of single nucleotide polymorphisms (SNP's) required for a genomic study is not daunting. Assay development, SNP validation and the determination of allele frequencies in population pools can be carried out in a single experiment. If well-designed population pools are created, one can dramatically reduce the cost and time of associating alleles with diseases or other phenotypes by two to three orders of magnitude. The very high resolution of MS allows a number of different loci to be processed in a single spectrum. Such a procedure is called multiplexing. The high resolution also allows unequivocal detection of heterozygotes and in some cases even allows the phase of compound heterozygotes to be called. The overwhelming advantage of MS based genotyping is its accuracy. Errors are never made in known alleles. Sometimes, MS actually reveals the presence of alleles that were not previously known. While SNP scoring is the most mature application, array MS methods can also be used for efficient SNP discovery.
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