Mutation at minisatellite locus DYF155S1: allele length mutation rate is affected by age of progenitor.

Abstract

A father/son material consisting of 1071 pairs was screened for de novo allele length mutation in locus DYF155S1. Six hundred of these pairs were also analyzed in locus DYF155S1 to detect de novo mutations in the minisatellite variant repeat (MVR)-code not resulting in a length change ("boundary switch" mutations). A modified MVR-polymerase chain reaction (PCR) method was used for this purpose. Twenty-seven de novo allele length mutations and eight "boundary switch" mutations were detected indicating mutation frequencies of approximately 2.5% and 1.3%, respectively. The combined mutation rate for MVR-code mutation is approximately 3.8%. There is a significant increase in mutation rate with paternal age (p = 0.049) in allele length mutations. In the present material, the mutation rate in the oldest age group is three times that of the youngest age group. A similar age relationship is not observed in "boundary switch" mutations. A comparison between progenitors and the other fathers in the material revealed no obvious association between mutation rate and allele length or modular structure (variation in repeat sequence). More than 75% of the length mutations involved the gain or loss of one repeat only. This finding as well as the observed paternal age influence on mutation rate, suggests replication slippage to be the major mutation mechanism in length mutations. However, in one particular case, an allele length mutant revealed rearrangements with direct duplication of repeats at distant sites within the repeat array, and with both loss and gain of repeats. Such complex structural changes could indicate that some of the mutants might arise from sister chromatide exchange. The mutation rate of "boundary switch" mutations is by far higher than would be expected if these mutations are two independent one-step allele length mutations. A different age distribution of "boundary switch" mutations than of allele length mutations also argue against such a hypothesis. Together this could indicate that "boundary switches" are products of another mutation mechanism than the one-step allele length mutations.