Human Molecular Genetics, Vol 8, 173-183, Copyright © 1999 by Oxford University Press
EP Leeflang, S Tavare, P Marjoram, CO Neal, J Srinidhi, H MacFarlane, ME MacDonald, JF Gusella, M de Young, NS Wexler and N Arnheim
Trinucleotide repeat disease alleles can undergo 'dynamic' mutations in
which repeat number may change when a gene is transmitted from parent to
offspring. By typing >3500 sperm, we determined the size distribution of
Huntington's disease (HD) germline mutations produced by 26 individuals
from the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to
62. Both the mutation frequency and mean change in allele size increased
with increasing somatic repeat number. The mutation frequencies averaged
82% and, for individuals with at least 50 repeats, 98%. The extraordinarily
high mutation frequency levels are most consistent with a mutation process
that occurs throughout germline mitotic divisions, rather than resulting
from a single meiotic event. In several cases, the mean change in repeat
number differed significantly among individuals with similar somatic allele
sizes. This individual variation could not be attributed to age in a simple
way or to ' cis ' sequences, suggesting the influence of genetic background
or other factors. A familial effect is suggested in one family where both
the father and son gave highly unusual spectra compared with other
individuals matched for age and repeat number. A statistical model based on
incomplete processing of Okazaki fragments during DNA replication was found
to provide an excellent fit to the data but variation in parameter values
among individuals suggests that the molecular mechanism might be more
complex.
ARTICLES
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]
Molecular Biology Program and Department of Mathematics, University of Southern California, Los Angeles, CA 90089-1340, USA.
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