Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor...

Trinucleotide repeat mutations of normal alleles at the human androgen receptor locus were studied by typing approximately 4,300 sperm. Control experiments established that the mutation events were of germline origin. The mutation rate for 20-22 repeat alleles was similar to that shown by family analysis. Alleles with 28-31 repeats had a 4.4 times greater rate of mutation with contractions outnumbering expansions. Preliminary experiments on the trinucleotide repeat associated with myotonic dystrophy gave similar results although in one donor expansions were six times greater than contractions. Comparison of the sperm data to mutations of disease alleles in SBMA families suggests that expansions may have a different origin than contractions.