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Genome wide spontaneous mutation in human cells determined by the spectrum of mutations in hprt cDNA genes. 1993

E G Lichtenauer-Kaligis, and J Thijssen, and H den Dulk, and P van de Putte, and J G Tasseron-de Jong, and M Giphart-Gassler
Department of Molecular Genetics, Gorlaeus Laboratoria, University of Leiden, The Netherlands.

We have studied spontaneous mutagenesis in five hprt cDNA genes integrated at five different genomic positions in a human lymphoblastoid cell line (TK6). The spectra of 40 mutants from each position were combined to obtain a mutation spectrum of the overall genome. This collection of mutants was used to assess the contribution of several mutagenic processes to spontaneous mutagenesis. Deletions and single base pair changes account for the majority of the mutants and arise in approximately equal amounts (43 and 41%, respectively). The majority of the deletions and insertions are < 5 bp and are likely to be caused by template-directed misalignment (slippage) during replication. To account for frameshifts at non-iterated sites we propose a slightly different template-directed replication error model. A considerable amount of the observed base pair changes can also be explained by this last model, but several other processes leading to base pair changes such as depurination, deamination or spontaneously arising DNA damage are likely to contribute as well. We have compared this spectrum with mutation spectra in the endogenous hprt genes using published mutation data. It is shown that in the endogenous genes the contribution of base pair substitutions is much larger (71%) than in the hprt cDNA integrates and that deletions are less frequently observed (20%). The mutation rates of the integrated hprt cDNA genes show a mean increase of 30-fold as compared with the endogenous hprt gene. This results in a 60-fold increase of the absolute rate of deletion in the hprt cDNA genes and in a 15-fold increase of the base pair substitution rate. Replication errors such as slippage or the mechanism proposed in this study probably account to a large extent for this increase.

UI MeSH Term Description Entries
D007041 Hypoxanthine Phosphoribosyltransferase An enzyme that catalyzes the conversion of 5-phosphoribosyl-1-pyrophosphate and hypoxanthine, guanine, or MERCAPTOPURINE to the corresponding 5'-mononucleotides and pyrophosphate. The enzyme is important in purine biosynthesis as well as central nervous system functions. Complete lack of enzyme activity is associated with the LESCH-NYHAN SYNDROME, while partial deficiency results in overproduction of uric acid. EC 2.4.2.8. Guanine Phosphoribosyltransferase,HPRT,Hypoxanthine-Guanine Phosphoribosyltransferase,IMP Pyrophosphorylase,HGPRT,HPRTase,Hypoxanthine Guanine Phosphoribosyltransferase,Phosphoribosyltransferase, Guanine,Phosphoribosyltransferase, Hypoxanthine,Phosphoribosyltransferase, Hypoxanthine-Guanine,Pyrophosphorylase, IMP
D008957 Models, Genetic Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment. Genetic Models,Genetic Model,Model, Genetic
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009838 Oligodeoxyribonucleotides A group of deoxyribonucleotides (up to 12) in which the phosphate residues of each deoxyribonucleotide act as bridges in forming diester linkages between the deoxyribose moieties. Oligodeoxynucleotide,Oligodeoxyribonucleotide,Oligodeoxynucleotides
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004261 DNA Replication The process by which a DNA molecule is duplicated. Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000228 Adenine Phosphoribosyltransferase An enzyme catalyzing the formation of AMP from adenine and phosphoribosylpyrophosphate. It can act as a salvage enzyme for recycling of adenine into nucleic acids. EC 2.4.2.7. AMP Pyrophosphorylase,Transphosphoribosidase,APRTase,Phosphoribosyltransferase, Adenine,Pyrophosphorylase, AMP

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