Dobo K L, Giver C R, Eastmond D A, Rumbos H S, Grosovsky A J
Environmental Toxicology Graduate Program, University of California, Riverside 92521, USA.
Mutagenesis. 1995 Jan;10(1):53-8. doi: 10.1093/mutage/10.1.53.
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.
为了研究杂合性缺失（LOH）事件对突变率的影响，我们研究了两种密切相关的人类淋巴母细胞系，AHH-1（h2E1.v2）和MCL-5，它们在tk基因座（染色体17q23 - 25）处为杂合子。尽管它们在hprt基因座处具有相似的突变率，但AHH-1中tk的突变率和突变频率要高四到五倍。对来自AHH-1和MCL-5的58个自发TK-突变体的分析表明，AHH-1中LOH事件的发生频率（23/24）高于MCL-5（16/34）。一组五个微卫星多态性位点用于绘制沿染色体17q的LOH范围。在AHH-1细胞中，23个LOH事件中有15个涵盖了至少35%的染色体17q性平均遗传长度（98 cM）。此外，下一个最广泛的LOH类别占23个TK-突变体中的5个，涵盖至少17 cM。相比之下，在MCL-5中观察到的LOH事件范围非常有限；只有一个LOH片段从tk延伸到4 cM。因此，AHH-1中tk较高的突变率可以完全归因于在存活的正常生长的TK-突变体中染色体规模的LOH的恢复。此外，这些数据表明，LOH的区域可能性可能是该染色体片段内基因座突变率的重要决定因素。
