TRPing up the genome: Tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease

Repetitive DNA sequences constitute a large fraction of the genomes of humans and other animal species. Tandem repeats are a major class of repetitive DNA and the extent of their polymorphic distributions and functions within the human genome are only beginning to be explored. Tandem repeat polymorphisms (TRPs) provide a unique source of genomic variability and recent evidence suggests they can modulate a range of biological processes, in developing and mature organisms. Tandem repeats can change length during meiosis and mitosis, providing a dynamic source of genetic variation which may not only influence evolutionary processes, but also somatic cellular selection. Furthermore, recent evidence for post-mitotic instability of specific tandem repeats in neurons supports their additional possible roles in neuronal function and dysfunction. The mutation rate of TRPs is higher and the extent of polymorphism is far more diverse than that of single nucleotide polymorphisms (SNPs). Whereas SNPs are invariably binary in nature, TRPs generally exhibit extended digital (multiallelic) distributions, which provide a much richer range of polymorphic variants, and thus a wider possible range of genetic contribution to disease susceptibility. Expansions in tandem repeats are known to cause many monogenic disorders, which mainly affect the nervous system, including Huntington's disease, various spinocerebellar ataxias, other polyglutamine diseases, Friedreich ataxia, fragile X syndrome, myoclonic epilepsy, polyalanine disorders, and myotonic dystrophy. Furthermore, it has recently been proposed that TRPs could help solve the conundrum of "missing heritability" produced by SNP-based genome-wide association studies of various polygenic complex diseases. There are hundreds of thousands of unique tandem repeats in the human genome and their polymorphic distributions have the potential to greatly influence functional diversity and disease susceptibility. Recent discoveries in this expanding field are discussed, with a focus on the role of TRPs in brain development, function, and dysfunction.