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Genetics, Vol 146, 1429-1439, Copyright © 1997
INVESTIGATIONS |
Single and Coincident Intragenic Mutations Attributable to Gene Conversion in a Human Cell Line
C. R. Giver and A. J. Grosovsky
Environmental Toxicology Graduate Program, University of California, Riverside, California 92521
Two polymorphic sites are located within the heterozygous TK1 locus in the human lymphoblastoid cell line TK6: an inactivating frameshift in exon 4 of the nonfunctional allele and a phenotypically silent frameshift in exon 7 of the functional allele. Through the use of these intragenic polymorphisms and microsatellite markers that flank TK1, we demonstrate that partial gene conversion accounts for 3/75 (0.04) spontaneous and 9/163 (0.06) X-ray-induced TK1(-) mutants, thus comprising a significant component of forward mutations at this locus. In all cases, the conversion tract is <1 cM, rendering double exchange a remote alternate explanation for these results. Sequence analysis of full length TK1 cDNA provides rigorous exclusion of deletion events as a mechanism for generation of these allelotypes. Detailed examination of allelotypes in TK1(-) mutants identified two mechanisms for the generation of coincident sequence alterations that sometimes accompanied gene conversions. Mutations within the conversion tract were attributed to either error-prone gap filling synthesis during recombinational repair or mismatch repair within a heteroduplex region following branch migration. These findings suggest that a proportion of point mutations may not be targeted to sites of DNA base damage, but rather may arise as secondary consequences from the repair of DNA strand breaks.
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  P. J. E. Quintana, E. A. H. Neuwirth, and A. J. Grosovsky Interchromosomal Gene Conversion at an Endogenous Human Cell Locus Genetics, June 1, 2001; 158(2): 757 - 767. [Abstract] [Full Text] [PDF]
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