title: Extensive loss of heterozygosity accounts for differential mutation rate on chromosome 17q in human lymphoblasts.
abstract: In order to investigate the influence of loss of heterozygosity (LOH) events on mutation rate, we studied two closely related human lymphoblastoid cell lines, AHH-1 (h2E1.v2) and MCL-5, which are heterozygous at the tk locus (chromosome 17q23-25). Although they have similar mutant 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- mutants 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 microsatellite polymorphism loci was used to map the extent of LOH along chromosome 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 events observed in MCL-5 are very restricted in extent; only one LOH tract extended as far as 4 cM from tk. The higher mutation rate at tk in AHH-1 can, therefore, be entirely attributed to the recovery of chromosomal scale LOH in viable, normal growth TK- mutants. Furthermore, these data demonstrate that the regional potential for LOH is likely to be an important determinant of mutation rate for loci within that chromosomal segment.
authors.affiliation: Environmental Toxicology Graduate Program, University of California, Riverside 92521, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Dobo
authors.forename: C R
authors.initials: CR
authors.lastname: Giver
authors.forename: D A
authors.initials: DA
authors.lastname: Eastmond
authors.forename: H S
authors.initials: HS
authors.lastname: Rumbos
authors.forename: A J
authors.initials: AJ
authors.lastname: Grosovsky
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D004276:DNA, Satellite / Q000235:genetics; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008214:Lymphocytes / Q000648:ultrastructure*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009153:Mutagens; D009154:Mutation; D009588:Nitrogen Mustard Compounds; D011110:Polymorphism, Genetic; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
chemical_list: D004276:DNA, Satellite; D009153:Mutagens; D009588:Nitrogen Mustard Compounds; D000585:Aminacrine; C004294:acridine half-mustard; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase