Cis-acting modifiers of expanded CAG CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands

An increasing number of human genetic disorders are associated with the exp ansion of trinucleotide repeats. The majority of these diseases are associa ted with CAG/CTG expansions, including Huntington's disease, myotonic dystr ophy and many of the spinocerebellar ataxias, Recently, two new expanded CA G/CTG repeats have been identified that are not associated with a phenotype . Expanded alleles at all of these loci are unstable, with frequent length changes during intergenerational transmission, However, variation in the re lative levels of instability, and the size and direction of the length chan ge mutations observed, between the CAG/CTG loci is apparent. We have quanti fied these differences, taking into account effects of progenitor allele le ngth, by calculating the relative expandability of each repeat. Since the r epeat motifs are the same, these differences must be a result of flanking s equence modifiers. We present data that indicate a strong correlation betwe en the relative expandability of these repeats and the flanking QC content. Moreover, we demonstrate that the most expandable loci are all located wit hin CpG islands. These data provide the first insights into the molecular b ases of cis-acting flanking sequences modifying the relative mutability of dispersed expanded human triplet repeats.