ABSTRACT
In recent years, a new mechanism of genetic disease has been discovered: the expansion of the triplet DNA sequences [tri-nucleotides] that either interrupt or compromise a gene. The presence of these expansions, sometimes containing thousands of tri-nucleotide repeats lead to processing of DNA and RNA that result in specific diseases. It remains mysterious that how this expansion in a single allele may exert a dominant effect and how the extent of the expansion increases the severity of the disease remain mysteries. This article describes a novel type of genome instability, expansion of tri-nucleotide repeats, originally discovered in 1991 upon cloning the gene responsible for fragile X syndrome. It has proved to be a general phenomenon responsible for a growing number of human neurological disorders. Besides apparent medical importance, the discovery of tri-nucleotide repeat expansion unraveled a fundamental problem in classical view of human genetics: a non-Mendelian type of inheritance called anticipation. Understanding the mechanisms of repeat expansion and the molecular pathways originally from these expansions expression to human diseases became a formidable task for modern biology. Here we discuss the major breakthroughs made in this field during the last decade, with an emphasis on molecular models of repeat expansion