Abstract
A human B-cell lymphoblastoid cell line heterozygous at the thymidine kinase (TK)locus (i.e., carrying one functional and one nonfunctional thymidine kinase allele) was used to study the molecular nature of mutations leading to loss of TKactivity. A total of 113 mutant clones, both spontaneous and induced, were examined by restriction enzyme mapping and by the use of a restriction fragment length polymorphism (RFLP) at the TKlocus. A majority (71%) of all mutant clones examined had lost the entire functional TKallele, becoming either homozygous or hemizygous for the nonfunctional allele. The remaining mutants had either no detectable changes (26%) or had obvious structural alterations (less than 5%) in the active TKgene. These results emphasize the importance of allele loss, presumably by mitotic chromosomal mechanisms, in mutagenesis at autosomal loci, and suggest that in vitro models for recessive somatic mutation which are based at hemizygous loci may ignore a large category of genetically significant events.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Literature cited
Thacker, J. (1985).Mutat. Res. 150:431–442.
Cavenee, W.K., Dryja, T.P., Phillips, R.A., Benedict, W.F., Godbout, R., Gallie, B., Murphree, A.L., Strong, L.C., and White, R.L. (1983).Nature 305:779–784.
Koufos, A., Hansen, M.F., Lampkin, B.C., Workman, M.L., Copeland, N.G., Jenkins, N.A., and Cavenee, W.K. (1984).Nature 309:170–172.
Orkin, S.H., Goldman, D.S., and Sallan, S.E. (1984).Nature 309:172–174.
Reeve, A.E., Housiaux, P.J., Gardner, R.J.M., Chewings, W.E., Grindley, R.M., and Millow, L.J. (1984).Nature 309:174–176.
Fearon, E.R., Vogelstein, B., and Feinberg, A.P. (1984).Nature 309:176–178.
Dryja, T.P., Rapaport, J.M., Epstein, J., Goorin, A.M., Weichselbaum, B.-T., Koufos, A. and Cavenee, W.K. (1986).Am. J. Hum. Genet. 38:59–66.
Hansen, M.F., Koufos, A., Gallie, B.L., Phillips, R.A., Fodstad, O., Brogger, A., Gedde-Dahl, T., and Cavenee, W.K. (1985).Proc. Natl. Acad. Sci. U.S.A. 82(18):6216–6220.
Mukai, S., and Dryja, T.P. (1986).Cancer Genet. Cytogenet. (in press).
Skopek, T.R., Liber, H.L., Penman, B.W., and Thilly, W.G. (1978).Biochem. Biophys. Res. Commun. 84:411–416.
Liber, H.L., and Thilly, W.G. (1982).Mutat. Res. 94:467–485.
Human Gene Mapping 7. (1984).Cytogenet. Cell Genet. 37:3–393.
Elliot, K., and Fitzsimons, D.W. (eds.). (1977).Purine and Pyrimidine Metabolism, CIBA Foundation Symposium No. 48.
Clive, D., Johnson, K.O., Spector, J.F.S., Batson, A.G., and Moore-Brown, M.M. (1979).Mutat. Res. 59:61–73.
Levy, J.A., Virolainen, M., and Defendi, V. (1968).Cancer 22:517–524.
Yandell, D.W., and Little, J.B. (1986).Cancer Genet. Cytogenet. 20:231–239.
Koch, A.L. (1982).Mutat. Res. 95:129–143.
Southern, E.M. (1975).J. Mol. Biol. 98:503–517.
Bradshaw, H.D., Jr., and Deininger, P.L. (1984).Mol. Cell. Biol. 4:2316–2320.
Moore, M.M., Clive, D., Hozier, J.C., Howard, B.E., Batson, G.A., Turner, N.T., and Sawyer, J. (1985).Mutat. Res. 151:161–174.
Moore, M.M., Clive, D., Howard, B.E., Batson, G.A., and Turner, N.T. (1985).Mutat. Res. 151:147–159.
Turner, D.R., Morley, A.A., Haliandros, M., Kutlaca, R., and Sanderson, B.J. (1985).Nature 315:343–345.
Albertini, R.A., O'Neill, J.P., Nicklas, J.A., Heintz, N.H., and Kelleher, P.C. (1985).Nature 316:369–371.
Fuscoe, J.C., Fenwick, R.G., Ledbetter, D.H., and Caskey, C.T. (1983).Mol. Cell. Biol. 3:1086–1096.
Fenwick, R.G., Fuscoe, J.C., and Caskey, C.T. (1984).Somat. Cell Mol. Genet. 10:71–84.
Simon, A.E., Taylor, M.W., Bradley, W.E.C., and Thompson, L.H. (1982).Mol. Cell. Biol. 2:1126–1133.
Simon, A.E., Taylor, M.W., and Bradley, W.E.C. (1983).Mol. Cell. Biol. 3:1703–1710.
Simon, A.E., and Taylor, M.W. (1983).Proc. Natl. Acad. Sci. U.S.A. 80:810–814.
Bradley, W.E.C, and Letovanec, D. (1982).Somat. Cell Genet. 8:51–66.
Adair, G.M., Stallings, R.L., Nairn, R.S., and Siciliano, M.J. (1983).Proc. Natl. Acad. Sci. U.S.A. 80:5961–5964.
Turker, M.S., Smith, A.C., and Martin, G.M. (1984).Somat. Cell Mol. Genet. 10:55–69.
Eves, E.M., and Farber, R.A. (1983).Somat. Cell Genet. 9:771–778.
Meuth, M., and Arrand, J.E. (1982).Mol. Cell. Biol. 2:1459–1462.
Nalbantoglu, J., Goncalves, O., and Meuth, M. (1983).J. Mol. Biol. 167:575–594.
Goncalves, O., Drobetsky, E., and Meuth, M. (1984).Mol. Cell. Biol. 4:1792–1799.
Koufos, A., Hansen, M.F., Copeland, N.G., Jenkins, N.A., Lampkin, B.C., and Cavenee, W.K. (1985).Nature 316:330–334.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yandell, D.W., Dryja, T.P. & Little, J.B. Somatic mutations at a heterozygous autosomal locus in human cells occur more frequently by allele loss than by intragenic structural alterations. Somat Cell Mol Genet 12, 255–263 (1986). https://doi.org/10.1007/BF01570784
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01570784