Abstract
The spectrum of single-base-pair substitutions logged in The Human Gene Mutation Database (HGMD), comprising 7,271 different lesions in the coding regions of 547 different human genes, was analyzed for nearest-neighbor effects on relative mutation rates. Owing to its retrospective nature, HGMD allows mutation rates to be estimated only in relative terms. Therefore, a novel methodology was devised in order to obtain these estimates in iterative fashion, correcting, at the same time, for the confounding effects of differential codon usage and for the fact that different types of amino acid replacement come to clinical attention with different probabilities. Over and above the hypermutability of CpG dinucleotides, reflected in transition rates five times the base mutation rate, only a subtle and locally confined influence of the surrounding DNA sequence on relative single-base-pair substitution rates was observed, which extended no farther than 2 bp from the substitution site. A disparity between the two DNA strands was evidenced by the fact that, when substitution rates were estimated conditional on the 5' and 3' flanking nucleotides, a significant rate difference emerged for 10 of 96 possible pairs of complementary substitutional events. Mutational bias, favoring substitutions toward flanking bases, a phenomenon reminiscent of misalignment mutagenesis, was apparent and exhibited both directionality and reading-frame sensitivity. No specific preponderance of repeat-sequence motifs was observed in the vicinity of nucleotide substitutions, but a moderate correlation between the relative mutability and thermodynamic stability of DNA triplets emerged, suggesting either inefficient DNA replication in regions of high stability or the transient stabilization of misaligned intermediates.
Full Text
The Full Text of this article is available as a PDF (549.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bambara R. A., Murante R. S., Henricksen L. A. Enzymes and reactions at the eukaryotic DNA replication fork. J Biol Chem. 1997 Feb 21;272(8):4647–4650. doi: 10.1074/jbc.272.8.4647. [DOI] [PubMed] [Google Scholar]
- Beletskii A., Bhagwat A. S. Transcription-induced mutations: increase in C to T mutations in the nontranscribed strand during transcription in Escherichia coli. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13919–13924. doi: 10.1073/pnas.93.24.13919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bhatia P. K., Wang Z., Friedberg E. C. DNA repair and transcription. Curr Opin Genet Dev. 1996 Apr;6(2):146–150. doi: 10.1016/s0959-437x(96)80043-8. [DOI] [PubMed] [Google Scholar]
- Bird A. P. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. doi: 10.1038/321209a0. [DOI] [PubMed] [Google Scholar]
- Bolden A. H., Nalin C. M., Ward C. A., Poonian M. S., McComas W. W., Weissbach A. DNA methylation: sequences flanking C-G pairs modulate the specificity of the human DNA methylase. Nucleic Acids Res. 1985 May 24;13(10):3479–3494. doi: 10.1093/nar/13.10.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Breslauer K. J., Frank R., Blöcker H., Marky L. A. Predicting DNA duplex stability from the base sequence. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3746–3750. doi: 10.1073/pnas.83.11.3746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen Y. Z., Zhuang W., Prohofsky E. W. Energy flow considerations and thermal fluctuational opening of DNA base pairs at a replicating fork: unwinding consistent with observed replication rates. J Biomol Struct Dyn. 1992 Oct;10(2):415–427. doi: 10.1080/07391102.1992.10508656. [DOI] [PubMed] [Google Scholar]
- Clark S. J., Harrison J., Frommer M. CpNpG methylation in mammalian cells. Nat Genet. 1995 May;10(1):20–27. doi: 10.1038/ng0595-20. [DOI] [PubMed] [Google Scholar]
- Clay O., Schaffner W., Matsuo K. Periodicity of eight nucleotides in purine distribution around human genomic CpG dinucleotides. Somat Cell Mol Genet. 1995 Mar;21(2):91–98. doi: 10.1007/BF02255784. [DOI] [PubMed] [Google Scholar]
- Cooper D. N., Krawczak M. The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet. 1990 Jun;85(1):55–74. doi: 10.1007/BF00276326. [DOI] [PubMed] [Google Scholar]
- Cooper D. N., Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. doi: 10.1007/BF00278187. [DOI] [PubMed] [Google Scholar]
- Drapkin R., Sancar A., Reinberg D. Where transcription meets repair. Cell. 1994 Apr 8;77(1):9–12. doi: 10.1016/0092-8674(94)90228-3. [DOI] [PubMed] [Google Scholar]
- Ehrlich M., Norris K. F., Wang R. Y., Kuo K. C., Gehrke C. W. DNA cytosine methylation and heat-induced deamination. Biosci Rep. 1986 Apr;6(4):387–393. doi: 10.1007/BF01116426. [DOI] [PubMed] [Google Scholar]
- Golding G. B., Glickman B. W. Evidence for local DNA influences on patterns of substitutions in the human alpha-interferon gene family. Can J Genet Cytol. 1986 Aug;28(4):483–496. doi: 10.1139/g86-072. [DOI] [PubMed] [Google Scholar]
- Grantham R. Amino acid difference formula to help explain protein evolution. Science. 1974 Sep 6;185(4154):862–864. doi: 10.1126/science.185.4154.862. [DOI] [PubMed] [Google Scholar]
- Hanawalt P. C. Transcription-coupled repair and human disease. Science. 1994 Dec 23;266(5193):1957–1958. doi: 10.1126/science.7801121. [DOI] [PubMed] [Google Scholar]
- Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
- Hornstra I. K., Yang T. P. High-resolution methylation analysis of the human hypoxanthine phosphoribosyltransferase gene 5' region on the active and inactive X chromosomes: correlation with binding sites for transcription factors. Mol Cell Biol. 1994 Feb;14(2):1419–1430. doi: 10.1128/mcb.14.2.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jamieson R. V., Tam P. P., Gardiner-Garden M. X-chromosome activity: impact of imprinting and chromatin structure. Int J Dev Biol. 1996 Dec;40(6):1065–1080. [PubMed] [Google Scholar]
- Kainz M., Roberts J. Structure of transcription elongation complexes in vivo. Science. 1992 Feb 14;255(5046):838–841. doi: 10.1126/science.1536008. [DOI] [PubMed] [Google Scholar]
- Kay P. H., Harmon D., Fletcher S., Ziman M., Jacobsen P. F., Papadimitriou J. M. Variation in the methylation profile and structure of Pax3 and Pax7 among different mouse strains and during expression. Gene. 1997 Jan 3;184(1):45–53. doi: 10.1016/s0378-1119(96)00572-0. [DOI] [PubMed] [Google Scholar]
- Krawczak M., Cooper D. N. Single base-pair substitutions in pathology and evolution: two sides to the same coin. Hum Mutat. 1996;8(1):23–31. doi: 10.1002/(SICI)1098-1004(1996)8:1<23::AID-HUMU3>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- Krawczak M., Smith-Sorensen B., Schmidtke J., Kakkar V. V., Cooper D. N., Hovig E. Somatic spectrum of cancer-associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutation and by selection. Hum Mutat. 1995;5(1):48–57. doi: 10.1002/humu.1380050107. [DOI] [PubMed] [Google Scholar]
- Krawczak M., Wacey A., Cooper D. N. Molecular reconstruction and homology modelling of the catalytic domain of the common ancestor of the haemostatic vitamin-K-dependent serine proteinases. Hum Genet. 1996 Sep;98(3):351–370. doi: 10.1007/s004390050222. [DOI] [PubMed] [Google Scholar]
- Kunkel T. A. The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations. J Biol Chem. 1985 May 10;260(9):5787–5796. [PubMed] [Google Scholar]
- Leader D. P., Peter B., Ehmer B. Analysis of CpG dinucleotide frequency in relationship to translational reading frame suggests a class of genes in which mutation of this dinucleotide is asymmetric with respect to DNA strand. FEBS Lett. 1995 Dec 4;376(3):125–129. doi: 10.1016/0014-5793(95)01268-3. [DOI] [PubMed] [Google Scholar]
- Lin M. M., Zhu M., Scharff M. D. Sequence dependent hypermutation of the immunoglobulin heavy chain in cultured B cells. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5284–5289. doi: 10.1073/pnas.94.10.5284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamura Y., Wada K., Wada Y., Doi H., Kanaya S., Gojobori T., Ikemura T. Codon usage tabulated from the international DNA sequence databases. Nucleic Acids Res. 1996 Jan 1;24(1):214–215. doi: 10.1093/nar/24.1.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ollila J., Lappalainen I., Vihinen M. Sequence specificity in CpG mutation hotspots. FEBS Lett. 1996 Nov 4;396(2-3):119–122. doi: 10.1016/0014-5793(96)01075-7. [DOI] [PubMed] [Google Scholar]
- Petruska J., Goodman M. F. Influence of neighboring bases on DNA polymerase insertion and proofreading fidelity. J Biol Chem. 1985 Jun 25;260(12):7533–7539. [PubMed] [Google Scholar]
- Rodenhiser D. I., Andrews J. D., Mancini D. N., Jung J. H., Singh S. M. Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene. Mutat Res. 1997 Feb 3;373(2):185–195. doi: 10.1016/s0027-5107(96)00171-6. [DOI] [PubMed] [Google Scholar]
- Rodenhiser D., Chakraborty P., Andrews J., Ainsworth P., Mancini D., Lopes E., Singh S. Heterogenous point mutations in the BRCA1 breast cancer susceptibility gene occur in high frequency at the site of homonucleotide tracts, short repeats and methylatable CpG/CpNpG motifs. Oncogene. 1996 Jun 20;12(12):2623–2629. [PubMed] [Google Scholar]
- Rodin S. N., Holmquist G. P., Rodin A. S. CpG transition strand asymmetry and hitch-hiking mutations as measures of tumorigenic selection in shaping the p53 mutation spectrum. Int J Mol Med. 1998 Jan;1(1):191–199. doi: 10.3892/ijmm.1.1.191. [DOI] [PubMed] [Google Scholar]
- Rogozin I. B., Kolchanov N. A. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta. 1992 Nov 15;1171(1):11–18. doi: 10.1016/0167-4781(92)90134-l. [DOI] [PubMed] [Google Scholar]
- Shen J. C., Rideout W. M., 3rd, Jones P. A. The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res. 1994 Mar 25;22(6):972–976. doi: 10.1093/nar/22.6.972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sibghat-Ullah, Day R. S., 3rd DNA-substrate sequence specificity of human G:T mismatch repair activity. Nucleic Acids Res. 1993 Mar 11;21(5):1281–1287. doi: 10.1093/nar/21.5.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Skandalis A., Ford B. N., Glickman B. W. Strand bias in mutation involving 5-methylcytosine deamination in the human hprt gene. Mutat Res. 1994 Jan;314(1):21–26. doi: 10.1016/0921-8777(94)90057-4. [DOI] [PubMed] [Google Scholar]
- Smith S. S., Baker D. J. Stalling of human methyltransferase at single-strand conformers from the Huntington's locus. Biochem Biophys Res Commun. 1997 May 8;234(1):73–78. doi: 10.1006/bbrc.1997.6581. [DOI] [PubMed] [Google Scholar]
- Smith S. S. Biological implications of the mechanism of action of human DNA (cytosine-5)methyltransferase. Prog Nucleic Acid Res Mol Biol. 1994;49:65–111. doi: 10.1016/s0079-6603(08)60048-3. [DOI] [PubMed] [Google Scholar]
- Todorova A., Danieli G. A. Large majority of single-nucleotide mutations along the dystrophin gene can be explained by more than one mechanism of mutagenesis. Hum Mutat. 1997;9(6):537–547. doi: 10.1002/(SICI)1098-1004(1997)9:6<537::AID-HUMU7>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
- Tornaletti S., Pfeifer G. P. Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene. 1995 Apr 20;10(8):1493–1499. [PubMed] [Google Scholar]
- Woodcock D. M., Crowther P. J., Jefferson S., Diver W. P. Methylation at dinucleotides other than CpG: implications for human maintenance methylation. Gene. 1988 Dec 25;74(1):151–152. doi: 10.1016/0378-1119(88)90273-9. [DOI] [PubMed] [Google Scholar]
- Wu C. I., Maeda N. Inequality in mutation rates of the two strands of DNA. Nature. 1987 May 14;327(6118):169–170. doi: 10.1038/327169a0. [DOI] [PubMed] [Google Scholar]