Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA

• DOI: 10.1038/332278a0
• Publication Date: 2003-06-12T21:55:17Z
• Authors: Alec J. Jeffreys; Nicola J. Royle; Victoria Wilson; Zilla Wong
• Keywords: Male; 0301 basic medicine; Heterozygote; DNA, Recombinant; 612; DNA, Satellite; Repetitive Sequences; 03 medical and health sciences; Genetic; Humans; Alleles; Repetitive Sequences, Nucleic Acid; Recombination, Genetic; 0303 health sciences; Recombinant; Nucleic Acid; Mosaicism; Nucleic Acid Hybridization; DNA; Spermatozoa; Recombination; Pedigree; Meiosis; Satellite; Mutation; Oocytes; Female

Tandem-repetitive minisatellite regions in vertebrate DNA frequently show substantial allelic variation in the number of repeat units. This variation is thought to arise through processes such as unequal crossover or replication slippage. We show here that the spontaneous mutation rate to new length alleles at extremely variable human minisatellites is sufficiently high to be directly measurable in human pedigrees. The mutation rate at different loci increases with variability in accord with the neutral mutation/random drift hypothesis, and rises to 5% per gamete for the most unstable human minisatellite isolated. Mutations are sporadic, occur with similar frequencies in sperm and oocytes, and can involve the gain or loss of substantial numbers of repeat units, consistent with length changes arising primarily by unequal exchange at meiosis. Germline instability must therefore be taken into account when using hypervariable loci as genetic markers, particularly in pedigree analysis and parenthood testing.