Increased trinucleotide repeat instability with advanced maternal age

Nucleotide repeat instability is associated with an increasing number ofcancers and neurological disorders. The mechanisms that govern repeatinstability in these biological disorders are not well understood. Toexamine genetic aspects of repeat instability we have introduced anexpanded CAG trinucleotide repeat into transgenic mice. We have detectedintergenerational CAG repeat instability in transgenic mice only when thetransgene was maternally transmitted. These intergenerational instabilitiesincreased in frequency and magnitude as the transgenic mother aged.Furthermore, triplet repeat variations were detected in unfertilizedoocytes and were comparable with those in the offspring. These data showthat maternal repeat instability in the transgenic mice occurs aftermeiotic DNA replication and prior to oocyte fertilization. Thus, thesefindings demonstrate that advanced maternal age is an important factor forinstability of nucleotide repeats in mammalian DNA.