EXTENSIVE LOSS OF HETEROZYGOSITY ACCOUNTS FOR DIFFERENTIAL MUTATION-RATE ON CHROMOSOME 17Q IN HUMAN LYMPHOBLASTS

In order to investigate the influence of loss of heterozygosity (LOH) events on mutation rate, we studied two closely related human lymphobl astoid cell lines, AHH-1 (h2E1.v2) and MCL-5, which are heterozygous a t the tk locus (chromosome 17q23 -25). Although they have similar muta nt fractions at the hprt locus, the mutant fraction and rate at tk is four to five times higher in AHH-1. Analysis of 58 spontaneous TK- mut ants from AHH-1 and MCL-5 showed that the occurrence of LOH events was more frequent (23/24) in AHH-1 than MCL-5 (16/34). A set of five micr osatellite polymorphism loci was used to map the extent of LOH along c hromosome 17q. In AHH-1 cells, 15/23 of the LOH events encompassed at least 35% of the sex-averaged genetic length of chromosome 17q (98 cM) . Additionally, the next most extensive category of LOH accounted for 5/23 TK- mutants, and encompassed at least 17 cM. In contrast, LOH eve nts observed in MCL-5 are very restricted in extent; only one LOH trac t extended as far as 4 cM from tk. The higher mutation rate at tk in A HH-1 can, therefore, be entirely attributed to the recovery of chromos omal scale LOH in viable, normal growth TK- mutants. Furthermore, thes e data demonstrate that the regional potential for LOH is likely to be an important determinant of mutation rate for loci within that chromo somal segment.