Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic [correction of amitotic] mutation mechanism [published erratum appears in Hum Mol Genet 1999 Apr;8(4):717]

Trinucleotide repeat disease alleles can undergo 'dynamic' mutations inwhich repeat number may change when a gene is transmitted from parent tooffspring. By typing >3500 sperm, we determined the size distribution ofHuntington's disease (HD) germline mutations produced by 26 individualsfrom the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to62. Both the mutation frequency and mean change in allele size increasedwith increasing somatic repeat number. The mutation frequencies averaged82% and, for individuals with at least 50 repeats, 98%. The extraordinarilyhigh mutation frequency levels are most consistent with a mutation processthat occurs throughout germline mitotic divisions, rather than resultingfrom a single meiotic event. In several cases, the mean change in repeatnumber differed significantly among individuals with similar somatic allelesizes. This individual variation could not be attributed to age in a simpleway or to ' cis ' sequences, suggesting the influence of genetic backgroundor other factors. A familial effect is suggested in one family where boththe father and son gave highly unusual spectra compared with otherindividuals matched for age and repeat number. A statistical model based onincomplete processing of Okazaki fragments during DNA replication was foundto provide an excellent fit to the data but variation in parameter valuesamong individuals suggests that the molecular mechanism might be morecomplex.