Abstract
Thousands of genes are expressed at such very low levels (< or =1 copy per cell) that global gene expression analysis of rarer transcripts remains problematic. Ambiguity in identification of rarer transcripts creates considerable uncertainty in fundamental questions such as the total number of genes expressed in an organism and the biological significance of rarer transcripts. Knowing the distribution of the true number of genes expressed at each level and the corresponding gene expression level probability function (GELPF) could help resolve these uncertainties. We found that all observed large-scale gene expression data sets in yeast, mouse, and human cells follow a Pareto-like distribution model skewed by many low-abundance transcripts. A novel stochastic model of the gene expression process predicts the universality of the GELPF both across different cell types within a multicellular organism and across different organisms. This model allows us to predict the frequency distribution of all gene expression levels within a single cell and to estimate the number of expressed genes in a single cell and in a population of cells. A random "basal" transcription mechanism for protein-coding genes in all or almost all eukaryotic cell types is predicted. This fundamental mechanism might enhance the expression of rarely expressed genes and, thus, provide a basic level of phenotypic diversity, adaptability, and random monoallelic expression in cell populations.
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- Biol M. C., Martin A., Louisot P., Richard M. Characterization of a mannosyl-lipid compound of microsomal fractions of rat pancreas and influence of diet. Comp Biochem Physiol B. 1982;72(2):179–185. doi: 10.1016/0305-0491(82)90033-5. [DOI] [PubMed] [Google Scholar]
- Bishop J. O., Morton J. G., Rosbash M., Richardson M. Three abundance classes in HeLa cell messenger RNA. Nature. 1974 Jul 19;250(463):199–204. doi: 10.1038/250199a0. [DOI] [PubMed] [Google Scholar]
- Caron H., van Schaik B., van der Mee M., Baas F., Riggins G., van Sluis P., Hermus M. C., van Asperen R., Boon K., Voûte P. A. The human transcriptome map: clustering of highly expressed genes in chromosomal domains. Science. 2001 Feb 16;291(5507):1289–1292. doi: 10.1126/science.1056794. [DOI] [PubMed] [Google Scholar]
- Chelly J., Concordet J. P., Kaplan J. C., Kahn A. Illegitimate transcription: transcription of any gene in any cell type. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2617–2621. doi: 10.1073/pnas.86.8.2617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen J. J., Rowley J. D., Wang S. M. Generation of longer cDNA fragments from serial analysis of gene expression tags for gene identification. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):349–353. doi: 10.1073/pnas.97.1.349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eddy S. R. Non-coding RNA genes and the modern RNA world. Nat Rev Genet. 2001 Dec;2(12):919–929. doi: 10.1038/35103511. [DOI] [PubMed] [Google Scholar]
- Fiering S., Whitelaw E., Martin D. I. To be or not to be active: the stochastic nature of enhancer action. Bioessays. 2000 Apr;22(4):381–387. doi: 10.1002/(SICI)1521-1878(200004)22:4<381::AID-BIES8>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
- Gomez S. M., Lo S. H., Rzhetsky A. Probabilistic prediction of unknown metabolic and signal-transduction networks. Genetics. 2001 Nov;159(3):1291–1298. doi: 10.1093/genetics/159.3.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holstege F. C., Jennings E. G., Wyrick J. J., Lee T. I., Hengartner C. J., Green M. R., Golub T. R., Lander E. S., Young R. A. Dissecting the regulatory circuitry of a eukaryotic genome. Cell. 1998 Nov 25;95(5):717–728. doi: 10.1016/s0092-8674(00)81641-4. [DOI] [PubMed] [Google Scholar]
- Huang S. P., Weir B. S. Estimating the total number of alleles using a sample coverage method. Genetics. 2001 Nov;159(3):1365–1373. doi: 10.1093/genetics/159.3.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hume D. A. Probability in transcriptional regulation and its implications for leukocyte differentiation and inducible gene expression. Blood. 2000 Oct 1;96(7):2323–2328. [PubMed] [Google Scholar]
- Iyer V., Struhl K. Absolute mRNA levels and transcriptional initiation rates in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5208–5212. doi: 10.1073/pnas.93.11.5208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson D. A., Pombo A., Iborra F. The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells. FASEB J. 2000 Feb;14(2):242–254. [PubMed] [Google Scholar]
- Jelinsky S. A., Estep P., Church G. M., Samson L. D. Regulatory networks revealed by transcriptional profiling of damaged Saccharomyces cerevisiae cells: Rpn4 links base excision repair with proteasomes. Mol Cell Biol. 2000 Nov;20(21):8157–8167. doi: 10.1128/mcb.20.21.8157-8167.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jelinsky S. A., Samson L. D. Global response of Saccharomyces cerevisiae to an alkylating agent. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1486–1491. doi: 10.1073/pnas.96.4.1486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jeong H., Tombor B., Albert R., Oltvai Z. N., Barabási A. L. The large-scale organization of metabolic networks. Nature. 2000 Oct 5;407(6804):651–654. doi: 10.1038/35036627. [DOI] [PubMed] [Google Scholar]
- Ko M. S. Induction mechanism of a single gene molecule: stochastic or deterministic? Bioessays. 1992 May;14(5):341–346. doi: 10.1002/bies.950140510. [DOI] [PubMed] [Google Scholar]
- Lander E. S., Linton L. M., Birren B., Nusbaum C., Zody M. C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921. doi: 10.1038/35057062. [DOI] [PubMed] [Google Scholar]
- McAdams H. H., Arkin A. It's a noisy business! Genetic regulation at the nanomolar scale. Trends Genet. 1999 Feb;15(2):65–69. doi: 10.1016/s0168-9525(98)01659-x. [DOI] [PubMed] [Google Scholar]
- Newlands S., Levitt L. K., Robinson C. S., Karpf A. B., Hodgson V. R., Wade R. P., Hardeman E. C. Transcription occurs in pulses in muscle fibers. Genes Dev. 1998 Sep 1;12(17):2748–2758. doi: 10.1101/gad.12.17.2748. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ross I. L., Browne C. M., Hume D. A. Transcription of individual genes in eukaryotic cells occurs randomly and infrequently. Immunol Cell Biol. 1994 Apr;72(2):177–185. doi: 10.1038/icb.1994.26. [DOI] [PubMed] [Google Scholar]
- Stanley H. E., Buldyrev S. V., Goldberger A. L., Havlin S., Peng C. K., Simons M. Scaling features of noncoding DNA. Physica A. 1999;273(1-2):1–18. doi: 10.1016/s0378-4371(99)00407-0. [DOI] [PubMed] [Google Scholar]
- Stollberg J., Urschitz J., Urban Z., Boyd C. D. A quantitative evaluation of SAGE. Genome Res. 2000 Aug;10(8):1241–1248. doi: 10.1101/gr.10.8.1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strausberg R. L., Buetow K. H., Emmert-Buck M. R., Klausner R. D. The cancer genome anatomy project: building an annotated gene index. Trends Genet. 2000 Mar;16(3):103–106. doi: 10.1016/s0168-9525(99)01937-x. [DOI] [PubMed] [Google Scholar]
- Sutherland H. G., Kearns M., Morgan H. D., Headley A. P., Morris C., Martin D. I., Whitelaw E. Reactivation of heritably silenced gene expression in mice. Mamm Genome. 2000 May;11(5):347–355. doi: 10.1007/s003350010066. [DOI] [PubMed] [Google Scholar]
- Velculescu V. E., Madden S. L., Zhang L., Lash A. E., Yu J., Rago C., Lal A., Wang C. J., Beaudry G. A., Ciriello K. M. Analysis of human transcriptomes. Nat Genet. 1999 Dec;23(4):387–388. doi: 10.1038/70487. [DOI] [PubMed] [Google Scholar]
- Velculescu V. E., Zhang L., Vogelstein B., Kinzler K. W. Serial analysis of gene expression. Science. 1995 Oct 20;270(5235):484–487. doi: 10.1126/science.270.5235.484. [DOI] [PubMed] [Google Scholar]
- Wiesenfeld Kurt, Jaramillo Fernan. Minireview of stochastic resonance. Chaos. 1998 Sep;8(3):539–548. doi: 10.1063/1.166335. [DOI] [PubMed] [Google Scholar]
