SEGREGATION DISTORTION OF THE CTG REPEATS AT THE MYOTONIC-DYSTROPHY LOCUS

Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having greater than or equal to 50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ab ility. Alleles in the normal range of CTG repeats are not as unstable as the (CTG)(greater than or equal to 50) alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are co nflicting. We present a maximum-likelihood model for examining segrega tion distortion of CTG-repeat alleles in normal families. Analyzing 72 6 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of s ize less than or equal to 29 repeats) from females (the probability of transmission of larger alleles is .565 +/- 0.03, different from .5 at P approximate to .028). There is no evidence of segregation distortio n during male meiosis. We propose a hypothesis that preferential trans mission of larger CTG-repeat alleles during female meiosis can compens ate for mutational contraction of repeats within the normal allelic si ze range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation st atus to give rise to DM.