Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAGrepeat expansion in the first exon of the androgen receptor (AR) gene.Disease-associated alleles (37-66 CAGs) change in length when transmittedfrom parents to offspring, with a significantly greater tendency to shiftsize when inherited paternally. As transgenic mice carrying human AR cDNAswith 45 and 66 CAG repeats do not display repeat instability, we attemptedto model trinucleotide repeat instability by generating transgenic micewith yeast artificial chromosomes (YACs) carrying AR CAG repeat expansionsin their genomic context. Studies of independent lines of AR YAC transgenicmice with CAG 45 alleles reveal intergenerational instability at an overallrate of approximately 10%. We also find that the 45 CAG repeat tracts aresignificantly more unstable with maternal transmission and as thetransmitting mother ages. Of all the CAG/CTG repeat transgenic miceproduced to date the AR YAC CAG 45 mice are unstable with the smallesttrinucleotide repeat mutations, suggesting that the length threshold forrepeat instability in the mouse may be lowered by including the appropriateflanking human DNA sequences. By sequence-tagged site content analysis andlong range mapping we determined that one unstable transgenic line hasintegrated an approximately 70 kb segment of the AR locus due tofragmentation of the AR YAC. Identification of the cis - acting elementsthat permit CAG tract instability and the trans -acting factors thatmodulate repeat instability in the AR YAC CAG 45 mice may provide insightsinto the molecular basis of trinucleotide repeat instability in humans.