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 in vivo mutant frequency at the HPRT locus, we have examined the effect of polymorphisms in genes for metabolic enzymes on the mutation rate. In the same population of human volunteers, the background variant frequency in a number of microsatellite sequences was studied to determine individual variation in the capacity to repair mismatches in these sequences. The HPRT mutant frequency of T-cells isolated from a group of 49 healthy, non-smoking adults varied from 0.25 to 9.64 x 10(-6). The frequency of polymorphisms in CYP1A1, GSTM1 and NAT2 among these individuals was similar to those published, and when subjected to univariate analysis these polymorphisms showed no influence on the HPRT mutant frequency. However, there was a significant interaction 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 an 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.
Davies
M J
MJ
Department of Molecular Biology, BIBRA International, Carshalton, Surrey, UK. mdavies@bibra.co.uk
Turner
J G
JG
Vives-Bauza
C
C
Rumsby
P C
PC
D000293:Adolescent; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D025542:Neurofibromin 1; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000502:physiology; D006113:United Kingdom
D001191:Arylamine N-Acetyltransferase; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D007041:Hypoxanthine Phosphoribosyltransferase; D025542:Neurofibromin 1; D011506:Proteins; C478900:NAT2 protein, human