The comparative genomics of polyglutamine repeats: Extreme difference in the codon organization of repeat-encoding regions between mammals and

Abstract. Polyglutamine repeats within proteins are common in eukaryotes and are associated with neuro-logical diseases in humans. Many are encoded by tandem repeats of the codon CAG that are likely to mutate pri-marily by replication slippage. However, a recent study in the yeast Saccharomyces cerevisiae has indicated that many others are encoded by mixtures of CAG and CAA which are less likely to undergo slippage. Here we at-tempt to estimate the proportions of polyglutamine re-peats encoded by slippage-prone structures in species currently the subject of genome sequencing projects. We find a general excess over random expectation of poly-glutamine repeats encoded by tandem repeats of codons. We nevertheless find many repeats encoded by nontan-dem codon structures. Mammals and Drosophila display extreme opposite patterns. Drosophila contains many proteins with polyglutamine tracts but these are generally encoded by interrupted structures. These structures may have been selected to be resistant to slippage. In contrast, mammals (humans and mice) have a high proportion of proteins in which repeats are encoded by tandem codon structures. In humans, these include most of the triplet expansion disease genes. Key words: Glutamine repeats — Replication slip-page — Comparative genome analysis — Repeat evolu-tion — Triplet expansion diseases — Triplet repeats — Genome evolutio