Practical Informatics Approaches to Microsatellite and Variable Number Tandem Repeat Analysis

The second most common source of genetic variation after SNPs is polymorphic tandem repeats, the alleles of which consist of a variable number of repeated units that can be either small (e.g., CA) or large (to >100 nucleotides in length). There are perhaps over half a million of these in the human genome. They have been implicated as functional promoter polymorphisms acting as common genetic risk factors for complex disorders (in diabetes and depression), as pathogenic mutations (Spinocerebellar Ataxias, Huntington’s Disease) and in association mapping, linkage and forensics, but while they enjoyed much success and use in early genetic linkage and association studies, they have recently been neglected. While SNPs are markers of great utility in genetic studies, different alleles of a polymorphic tandem repeat represent a very large physical and chemical change to a stretch of DNA sequence. They can act variously as: (a) functional elements binding transcription factors and other proteins that inhibit or promote expression; (b) motif elements affecting the efficiency of mRNA splicing; and (c) elements having physical effects, such as varying the spacing between functional motifs or in altering the structure and melting properties of DNA in their proximity. For these reasons, they are very good a priori functional candidates. Geneticists wishing to work with these polymorphisms need to know how to find them in sequence, use their annotation in genome browsers and online databases, use specialist bioinformatics web-tools for their analysis, and how to go about analyzing them in the lab and for genetic association.