DYNAMIC BALANCE OF SEGREGATION DISTORTION AND SELECTION MAINTAINS NORMAL ALLELE SIZES AT THE MYOTONIC-DYSTROPHY LOCUS

Myotonic dystrophy (DM), an autosomal dominant neurological disorder, is caused by CTG-repeat expansions at the DMPK locus, with affected in dividuals having greater than or equal to 50 repeats of this trinucleo tide. Reduced reproductive fitness of affected individuals and decreas ed viability of congenital DM have been noted. Expanded CTG-repeat all eles are highly unstable, predominantly yielding even higher repeat si zes. Preferential transmission of longer alleles from heterozygous mot hers within the normal size range of alleles also is observed. In view of these observations, it is worth examining how DM has been maintain ed in human populations for hundreds of generations. We present an ana lysis of the dynamic properties of a model of joint effects of segrega tion distortion and selection (intensity of which increases with allel e sizes of an individual's genotype). Our mathematical formulation and numerical analyses demonstrate that a weak segregation distortion dur ing female meiosis, together with selection of comparable intensity (w ithin the normal allele size range), can maintain an equilibrium distr ibution of allele frequencies. Genetic drift, acting in conjunction wi th the occasional contraction of alleles by mutation, can contribute t o the balance of segregation distortion and mutation, in the sense tha t even weaker selection can explain the observed allele frequencies. T he model is applied to CTG-repeat size distributions at the DMPK locus , observed in normal individuals from world populations. (C) 1998 Else vier Science Inc.