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 CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmi tted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally, As transgenic mice carrying h uman AR cDNAs with 45 and 66 CAG repeats do not display repeat instabi lity, we attempted to model trinucleotide repeat instability by genera ting transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of indepen dent lines of AR YAC transgenic mice with CAG 45 alleles reveal interg enerational instability at an overall rate of similar to 10%, We also find that the 45 CAG repeat tracts are significantly more unstable wit h maternal transmission and as the transmitting mother ages. Of all th e CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mi ce are unstable with the smallest trinucleotide repeat mutations, sugg esting that the length threshold for repeat instability in the mouse m ay be lowered by including the appropriate flanking human DNA sequence s, By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an similar to 70 kb segment of the AR locus due to fragmentation of the AR YAC, Identification of the cis-acting elements that permit CAG tract instab ility and the trans-acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.