Tandem repeat polymorphisms: Mediators of genetic plasticity, modulators of biological diversity and dynamic sources of disease susceptibility

Abstract

Tandem repetitive DNA elements (tandem repeats), including microsatellites and simple sequence repeats, are extremely common throughout the genomes of a wide range of species. Tandem repeat expansions have been found to cause a range of monogenic diseases, such as Huntington's disease, various ataxias and other neurological diseases. The human genome contains hundreds ofthousands of distinct tandem repeats, many of which appear to have evolved to regulate specific aspects of gene expression, RNA function and protein function. Tandem repeat polymorphisms (TRPs) provide a unique source of genetic variability that has an extended digital distribution, as opposed to the usual binary nature of single nucleotide polymorphisms. In this chapter I will review studies in which tandem repeats have been implicated in a multitude of molecular and cellular processes associated with the development, behavior and evolution of a variety of animal species, including mammals. Recent data suggesting that these repetitive sequences can increase the 'evolvability' of genomes provides further evidence that TRPs not only have functional consequences but also provide a rich source of genetic diversity that can facilitate evolutionary processes. I propose that a readily mutable subclass of tandem repeats may provide an important template for stochastic genetic variation, which could in turn generate diversity in epigenetics, development and organismal function, thus impacting upon evolution. Furthermore, the distinctive characteristics ofTRPs also uniquely position them as contributors to complex polygenic disorders. Ultimately, there is much to be gained from systematic analysis of the 'repeatome', defined as the entire set of tandem repeats and other repetitive DNA in a genome, as well as their transcribed and translated expression products. Applying such approaches not only to the human genome but to other species will yield new insights into the genetic regulation of a wide range of biological processes in healthy and diseased states.