Chapter 1 - Use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for multiplex genotyping

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Abstract

After completion of the human genome project, the focus of geneticists has shifted to elucidation of gene function and genetic diversity to understand the mechanisms of complex diseases or variation of patient response in drug treatment. In the past decade, many different genotyping techniques have been described for the detection of single-nucleotide polymorphisms (SNPs) and other common polymorphic variants. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Genotyping Using Mass Spectrometry

A characteristic feature of mass spectrometry is that the detection is based on an intrinsic physical property (mass to charge ratio), which contributes to highly accurate data. Traditional methods use indirect methods like fluorescence or radioactive reporter tags, which have to be labeled to the target molecule. While the number of different tags is limited and thus only supports low-level multiplex applications per reaction, MS provides multiple data points per experiment and enables

Principle

The MALDI process can be separated into three fundamental steps of analyte/matrix preparation, desorption of the upper matrix monolayers, and ionization of the analyte molecules. Successful MALDI involves incorporation of analyte molecules between the matrix molecules, either in the bulk or within the crystal surface, and separation of the analyte molecules from each other. There is no single MALDI matrix or protocol that is suited to all analytical questions, and a proper choice of both is

SNP-Genotyping Using Primer Extension Assays

Due to its robustness, flexibility, and easy design, primer extension has become the most widely used format for SNP-genotyping—not only in mass spectrometry [67], [68]. Several MALDI-based primer extension formats have been published using single- or multibase extension; they differ by speed, cost, complexity of sample preparation, quality of allele separation, and level of multiplexing. These methods usually begin with the amplification of a target region by PCR. A primer for detection of the

Conclusions

During the past years, MALDI-TOF-MS has been proven to be a versatile tool for rapid multiplex genotyping in different field of applications from pharmacogenetic and genomics [138], [139], [140], [141], disease association studies [125], [142], [143], [144], [145], [146], [147], clinical diagnostic testing [14], [15], [140], [148], controlling in agriculture [149], [150] and breeding [151], [152], [153], [154], and bacterial and viral typing [155], [156]. Determination of the molecular mass

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