Investigation of mutant frequency at the HPRT locus and changes in microsatellite sequences in healthy young adults

In an attempt to understand the inter-individual variation that occurs in i n vivo mutant frequency at the HPRT locus, we have examined the effect of p olymorphisms in genes for metabolic enzymes on the mutation rate. In the sa me population of human volunteers, the background variant frequency in a nu mber of microsatellite sequences was studied to determine individual variat ion in the capacity to repair mismatches in these sequences. The HPRT mutan t frequency of T-cells isolated from a group of 49 healthy, non-smoking adu lts varied from 0.25 to 9.64 X 10(-6). The frequency of polymorphisms in CY P1A1, GSTM1 and NAT2 among these individuals was similar to those published , and when subjected to univariate analysis these polymorphisms showed no i nfluence on the HPRT mutant frequency. However, there was a significant int eraction between the GSTM1 null genotype and the slow acetylator status in NAT2 (P < 0.05) which was associated with higher mutant frequency. Analysis of 30 microsatellite sequences in 20 HPRT proficient clones per individual showed only six alterations in total, giving an overall mutation rate per allele of 0.01%, whilst three alterations were found in five HPRT deficient clones per individual examined for changes in 10 microsatellites, giving a n overall mutation rate per allele of 0.3%. Thus, the alterations detected are probably due to background mutations and not to differences in mismatch repair capacity. (C) 1999 Elsevier Science B.V. All rights reserved.