A SCA7 CAG/CTG repeat expansion is stable in Drosophila melanogaster despite modulation of genomic context and gene dosage

• Published in: Gene 2005-02, Vol.347 (1), p.35-41
• Main Authors: Jackson, Stephen M., Whitworth, Alex J., Greene, Jessica C., Libby, Randell T., Baccam, Sandy L., Pallanck, Leo J., La Spada, Albert R.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Ataxin-7; Deficiency stock; Disease Models, Animal; DNA - genetics; DNA - metabolism; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Drosophila melanogaster; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Flap Endonucleases - genetics; Flap Endonucleases - metabolism; Gene Dosage; Genome; Genomic context; Genomic Instability - genetics; Genomic Instability - physiology; Modifier screen; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Quantitative Trait Loci - genetics; Quantitative Trait Loci - physiology; Repeat instability; Spinocerebellar ataxia type 7; Spinocerebellar Degenerations - genetics; Spinocerebellar Degenerations - physiopathology; Trans-acting factor; Trinucleotide; Trinucleotide Repeat Expansion - genetics; Trinucleotide Repeat Expansion - physiology
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2004.12.008

CAG and CTG repeat expansions are the cause of at least a dozen inherited neurological disorders. In these so-called “dynamic mutation” diseases, the expanded repeats display dramatic genetic instability, changing in size when transmitted through the germline and within somatic tissues. As the molecular basis of the repeat instability process remains poorly understood, modeling of repeat instability in model organisms has provided some insights into potentially involved factors, implicating especially replication and repair pathways. Studies in mice have also shown that the genomic context of the repeat sequence is required for CAG/CTG repeat instability in the case of spinocerebellar ataxia type 7 (SCA7), one of the most unstable of all CAG/CTG repeat disease loci. While most studies of repeat instability have taken a candidate gene approach, unbiased screens for factors involved in trinucleotide repeat instability have been lacking. We therefore attempted to use Drosophila melanogaster to model expanded CAG repeat instability by creating transgenic flies carrying trinucleotide repeat expansions, deriving flies with SCA7 CAG90 repeats in cDNA and genomic context. We found that SCA7 CAG90 repeats are stable in Drosophila, regardless of context. To screen for genes whose reduced function might destabilize expanded CAG repeat tracts in Drosophila, we crossed the SCA7 CAG90 repeat flies with various deficiency stocks, including lines lacking genes encoding the orthologues of flap endonuclease-1, PCNA, and MutS. In all cases, perfect repeat stability was preserved, suggesting that Drosophila may not be a suitable system for determining the molecular basis of SCA7 CAG repeat instability.