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Characterizing the physical genome

Nature Genetics volume 32, pages 515–521 (2002)Cite this article

Abstract

The genome of an organism is a dynamic physical entity, comprising genomic DNA bound to many different proteins and organized into chromosomes. A thorough characterization of the physical genome is relevant to our understanding of processes such as the regulation of gene expression, DNA replication and repair, recombination, chromosome segregation, epigenetic inheritance and genomic instability. Methods based on microarrays are beginning to provide a detailed picture of this physical genome, and they complement the genome-wide studies of mRNA expression profiling that have previously been so successful.

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Figure 1: Strategy for mapping genome-wide DNA–protein interactions using intergenic microarrays.

Bob Crimi

Figure 2: Differential methylation hybridization.

Bob Crimi

Figure 3: Comparative genomic hybridization to microarrays (array CGH).

Bob Crimi

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References

  1. Reid, J.L., Iyer, V.R., Brown, P.O. & Struhl, K. Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esa1 histone acetylase. Mol. Cell 6, 1297–1307 (2000).

    Article  CAS  Google Scholar 

  2. Iyer, V.R. et al. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409, 533–538 (2001).

    Article  CAS  Google Scholar 

  3. Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).

    Article  CAS  Google Scholar 

  4. Simon, I. et al. Serial regulation of transcriptional regulators in the yeast cell cycle. Cell 106, 697–708 (2001).

    Article  CAS  Google Scholar 

  5. Lieb, J.D., Liu, X., Botstein, D. & Brown, P.O. Promoter-specific binding of Rap1 revealed by genome-wide maps of protein–DNA association. Nature Genet. 28, 327–334 (2001).

    Article  CAS  Google Scholar 

  6. Wyrick, J.J. et al. Genome-wide distribution of ORC and MCM proteins in S. cerevisiae: high-resolution mapping of replication origins. Science 294, 2357–2360 (2001).

    Article  CAS  Google Scholar 

  7. Kurdistani, S.K., Robyr, D., Tavazoie, S. & Grunstein, M. Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nature Genet. 31, 248–254 (2002).

    Article  CAS  Google Scholar 

  8. Robyr, D. et al. Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109, 437–446 (2002).

    Article  CAS  Google Scholar 

  9. Damelin, M. et al. The genome-wide localization of Rsc9, a component of the RSC chromatin-remodeling complex, changes in response to stress. Mol. Cell 9, 563–573 (2002).

    Article  CAS  Google Scholar 

  10. Ng, H.H., Robert, F., Young, R.A. & Struhl, K. Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complex. Genes Dev. 16, 806–819 (2002).

    Article  CAS  Google Scholar 

  11. Spellman, P.T. et al. Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297 (1998).

    Article  CAS  Google Scholar 

  12. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

    Article  CAS  Google Scholar 

  13. Sun, Z.W. & Allis, C.D. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108 (2002).

    Article  CAS  Google Scholar 

  14. van Steensel, B., Delrow, J. & Henikoff, S. Chromatin profiling using targeted DNA adenine methyltransferase. Nature Genet. 27, 304–308 (2001).

    Article  CAS  Google Scholar 

  15. Meselson, M. & Stahl, F. The replication of DNA in Escherichia coli. Proc. Natl Acad. Sci. USA 44, 671–682 (1958).

    Article  CAS  Google Scholar 

  16. Raghuraman, M.K. et al. Replication dynamics of the yeast genome. Science 294, 115–121 (2001).

    Article  CAS  Google Scholar 

  17. Khodursky, A.B. et al. Analysis of topoisomerase function in bacterial replication fork movement: use of DNA microarrays. Proc. Natl Acad. Sci. USA 97, 9419–9424 (2000).

    Article  CAS  Google Scholar 

  18. Gerton, J.L. et al. Inaugural article: global mapping of meiotic recombination hotspots and coldspots in the yeast Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 97, 11383–11390 (2000).

    Article  CAS  Google Scholar 

  19. Ng, H.H. & Bird, A. DNA methylation and chromatin modification. Curr. Opin. Genet. Dev. 9, 158–163 (1999).

    Article  CAS  Google Scholar 

  20. Jones, P.A. & Laird, P.W. Cancer epigenetics comes of age. Nature Genet. 21, 163–167 (1999).

    Article  CAS  Google Scholar 

  21. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31–39 (2001).

    Article  CAS  Google Scholar 

  22. Karpf, A.R. et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA 96, 14007–14012 (1999).

    Article  CAS  Google Scholar 

  23. Liang, G., Gonzales, F.A., Jones, P.A., Orntoft, T.F. & Thykjaer, T. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2′-deoxycytidine. Cancer Res. 62, 961–966 (2002).

    CAS  Google Scholar 

  24. Suzuki, H. et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nature Genet. 31, 141–149 (2002).

    Article  CAS  Google Scholar 

  25. Huang, T.H., Perry, M.R. & Laux, D.E. Methylation profiling of CpG islands in human breast cancer cells. Hum. Mol. Genet. 8, 459–470 (1999).

    Article  CAS  Google Scholar 

  26. Tompa, R. et al. Genome-wide profiling of DNA methylation reveals transposon targets of CHROMOMETHYLASE3. Curr. Biol. 12, 65–68 (2002).

    Article  CAS  Google Scholar 

  27. Yan, P.S. et al. Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res. 61, 8375–8380 (2001).

    CAS  Google Scholar 

  28. Yan, P.S. et al. CpG island arrays: an application toward deciphering epigenetic signatures of breast cancer. Clin. Cancer Res. 6, 1432–1438 (2000).

    CAS  Google Scholar 

  29. Wei, S.H. et al. Methylation microarray analysis of late-stage ovarian carcinomas distinguishes progression-free survival in patients and identifies candidate epigenetic markers. Clin. Cancer Res. 8, 2246–2252 (2002).

    CAS  Google Scholar 

  30. Shi, H. et al. Expressed CpG island sequence tag microarray for dual screening of DNA hypermethylation and gene silencing in cancer cells. Cancer Res. 62, 3214–3220 (2002).

    CAS  Google Scholar 

  31. Gitan, R.S., Shi, H., Chen, C.M., Yan, P.S. & Huang, T.H. Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res. 12, 158–164 (2002).

    Article  CAS  Google Scholar 

  32. Adorjan, P. et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res. 30, e21 (2002).

    Article  Google Scholar 

  33. Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818–821 (1992).

    Article  CAS  Google Scholar 

  34. Solinas-Toldo, S. et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosom. Cancer 20, 399–407 (1997).

    Article  CAS  Google Scholar 

  35. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genet. 20, 207–211 (1998).

    Article  CAS  Google Scholar 

  36. Pollack, J.R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 23, 41–46 (1999).

    Article  CAS  Google Scholar 

  37. Snijders, A.M. et al. Assembly of microarrays for genome-wide measurement of DNA copy number. Nature Genet. 29, 263–264 (2001).

    Article  CAS  Google Scholar 

  38. Cai, W.W. et al. Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays. Nature Biotechnol. 20, 393–396 (2002).

    Article  CAS  Google Scholar 

  39. Hodgson, G. et al. Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. Nature Genet. 29, 459–464 (2001).

    Article  CAS  Google Scholar 

  40. Massion, P.P. et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res. 62, 3636–3640 (2002).

    CAS  Google Scholar 

  41. Heiskanen, M.A. et al. Detection of gene amplification by genomic hybridization to cDNA microarrays. Cancer Res. 60, 799–802 (2000).

    CAS  Google Scholar 

  42. Geschwind, D.H. et al. Klinefelter's syndrome as a model of anomalous cerebral laterality: testing gene dosage in the X chromosome pseudoautosomal region using a DNA microarray. Dev. Genet. 23, 215–229 (1998).

    Article  CAS  Google Scholar 

  43. Lucito, R. et al. Detecting gene copy number fluctuations in tumor cells by microarray analysis of genomic representations. Genome Res. 10, 1726–1736 (2000).

    Article  CAS  Google Scholar 

  44. Kato-Maeda, M. et al. Comparing genomes within the species Mycobacterium tuberculosis. Genome Res. 11, 547–554 (2001).

    Article  CAS  Google Scholar 

  45. Steinmetz, L.M. et al. Dissecting the architecture of a quantitative trait locus in yeast. Nature 416, 326–330 (2002).

    Article  CAS  Google Scholar 

  46. Lindblad-Toh, K. et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nature Biotechnol. 18, 1001–1005 (2000).

    Article  CAS  Google Scholar 

  47. Mei, R. et al. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 10, 1126–1137 (2000).

    Article  CAS  Google Scholar 

  48. Schubert, E.L. et al. Single nucleotide polymorphism array analysis of flow-sorted epithelial cells from frozen versus fixed tissues for whole genome analysis of allelic loss in breast cancer. Am. J. Pathol. 160, 73–79 (2002).

    Article  CAS  Google Scholar 

  49. Dean, F.B. et al. Comprehensive human genome amplification using multiple displacement amplification. Proc. Natl Acad. Sci. USA 99, 5261–5266 (2002).

    Article  CAS  Google Scholar 

  50. Wilhelm, M. et al. Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res. 62, 957–960 (2002).

    CAS  Google Scholar 

  51. Fritz, B. et al. Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma. Cancer Res. 62, 2993–2998 (2002).

    CAS  Google Scholar 

  52. Takeo, S. et al. Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis. Cancer. Genet. Cytogenet. 130, 127–132 (2001).

    Article  CAS  Google Scholar 

  53. Hui, A.B., Lo, K.W., Yin, X.L., Poon, W.S. & Ng, H.K. Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. Lab. Invest. 81, 717–723 (2001).

    Article  CAS  Google Scholar 

  54. Hui, A.B., Lo, K.W., Teo, P.M., To, K.F. & Huang, D.P. Genome wide detection of oncogene amplifications in nasopharyngeal carcinoma by array based comparative genomic hybridization. Int. J. Oncol. 20, 467–473 (2002).

    CAS  Google Scholar 

  55. Zhao, J. et al. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosom. Cancer 34, 48–57 (2002).

    Article  CAS  Google Scholar 

  56. Kauraniemi, P., Barlund, M., Monni, O. & Kallioniemi, A. New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res. 61, 8235–8240 (2001).

    CAS  Google Scholar 

  57. Clark, J. et al. Identification of amplified and expressed genes in breast cancer by comparative hybridization onto microarrays of randomly selected cDNA clones. Genes Chromosom. Cancer 34, 104–114 (2002).

    Article  CAS  Google Scholar 

  58. Pollack, J.R. et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc. Natl Acad. Sci. USA 99, 12963–12968 (2002).

    Article  CAS  Google Scholar 

  59. Varis, A. et al. Targets of gene amplification and overexpression at 17q in gastric cancer. Cancer Res. 62, 2625–2629 (2002).

    CAS  Google Scholar 

  60. Bruder, C.E. et al. High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH. Hum. Mol. Genet. 10, 271–282 (2001).

    Article  CAS  Google Scholar 

  61. Veltman, J.A. et al. High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am. J. Hum. Genet. 70, 1269–1276 (2002).

    Article  CAS  Google Scholar 

  62. Lin, J.Y. et al. Physical mapping of genes in somatic cell radiation hybrids by comparative genomic hybridization to cDNA microarrays. Genome Biol. 3, research0026.1–research0026.7 (2002).

  63. Behr, M.A. et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284, 1520–1523 (1999).

    Article  CAS  Google Scholar 

  64. Weinmann, A.S., Yan, P.S., Oberley, M.J., Huang, T.H. & Farnham, P.J. Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev. 16, 235–244 (2002).

    Article  CAS  Google Scholar 

  65. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 16, 245–256 (2002).

    Article  CAS  Google Scholar 

  66. Berman, B.P. et al. Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl Acad. Sci. USA 99, 757–762 (2002).

    Article  CAS  Google Scholar 

  67. Markstein, M., Markstein, P., Markstein, V. & Levine, M.S. Genome-wide analysis of clustered dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc. Natl Acad. Sci. USA 99, 763–768 (2002).

    Article  CAS  Google Scholar 

  68. Levy, S., Hannenhalli, S. & Workman, C. Enrichment of regulatory signals in conserved non-coding genomic sequence. Bioinformatics 17, 871–877 (2001).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, CCSR Building, Room 3245A, 269 Campus Drive, Stanford, 94305-5176, California, USA

    Jonathan R. Pollack

  2. Institute for Cellular and Molecular Biology and Section of Molecular Genetics and Microbiology, University of Texas at Austin, 1 University Station A4800, Austin, 78712-0159, Texas, USA

    Vishwanath R. Iyer

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Pollack, J., Iyer, V. Characterizing the physical genome. Nat Genet 32 (Suppl 4), 515–521 (2002). https://doi.org/10.1038/ng1035

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