Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Evolution of chromosome organization driven by selection for reduced gene expression noise


The distribution of genes on eukaryotic chromosomes is nonrandom, but the reasons behind this are not well understood. The commonly observed clustering of essential genes is a case in point. Here we model and test a new hypothesis. Essential proteins are unusual in that random fluctuations in abundance (noise) can be highly deleterious. We hypothesize that persistently open chromatin domains are sinks for essential genes, as they enable reduced noise by avoidance of transcriptional bursting associated with chromatin remodeling. Simulation of the model captures clustering and correctly predicts that (i) essential gene clusters are associated with low nucleosome occupancy (ii) noise-sensitive nonessential genes cluster with essential genes (iii) nonessential genes of similar knockout fitness are physically linked (iv) genes in domains rich in essential genes have low noise (v) essential genes are rare subtelomerically and (vi) essential gene clusters are preferentially conserved. We conclude that different noise characteristics of different genomic domains favors nonrandom gene positioning. This has implications for gene therapy and understanding transgenic phenotypes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Essential gene clusters are in open chromatin regions.
Figure 2: The evolution of essential gene clusters along a chromosome.
Figure 3: Dependence of essential gene clustering on the noise sensitivities of nonessential genes.
Figure 4: Influence of density of essential genes flanking a given gene on the noise level of the focal gene.


  1. Hurst, L.D., Pal, C. & Lercher, M.J. The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5, 299–310 (2004).

    Article  CAS  Google Scholar 

  2. Fischer, G., Rocha, E.P.C., Brunet, F., Vergassola, M. & Dujon, B. Highly variable rates of genome rearrangements between hemiascomycetous yeast lineages. PLoS Genet. [online] 2, e32 (2006) (10.1371/journal.pgen.0020032).

    Article  CAS  Google Scholar 

  3. Gerdes, S.Y. et al. Experimental determination and system level analysis of essential genes in Escherichia coli MG1655. J. Bacteriol. 185, 5673–5684 (2003).

    Article  CAS  Google Scholar 

  4. Kamath, R.S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003).

    Article  CAS  Google Scholar 

  5. Pal, C. & Hurst, L.D. Evidence for co-evolution of gene order and recombination rate. Nat. Genet. 33, 392–395 (2003).

    Article  CAS  Google Scholar 

  6. Hentges, K.E., Pollock, D.D., Liu, B. & Justice, M.J. Regional variation in the density of essential genes in mice. PLoS Genet. [online] 3, e72 (2007) (10.1371/journal.pgen.0030072).

    Article  CAS  Google Scholar 

  7. Cook, D.L., Gerber, A.N. & Tapscott, S.J. Modeling stochastic gene expression: implications for haploinsufficiency. Proc. Natl. Acad. Sci. USA 95, 15641–15646 (1998).

    Article  CAS  Google Scholar 

  8. Newman, J.R. et al. Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846 (2006).

    Article  CAS  Google Scholar 

  9. Fraser, H.B., Hirsh, A.E., Giaever, G., Kumm, J. & Eisen, M.B. Noise minimization in eukaryotic gene expression. PLoS Biol. [online] 2, e137 (2004) (10.1371/journal.pbio.0020137).

    Article  Google Scholar 

  10. Deutschbauer, A.M. et al. Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast. Genetics 169, 1915–1925 (2005).

    Article  CAS  Google Scholar 

  11. Becskei, A., Kaufmann, B.B. & van Oudenaarden, A. Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nat. Genet. 37, 937–944 (2005).

    Article  CAS  Google Scholar 

  12. Raj, A., Peskin, C.S., Tranchina, D., Vargas, D.Y. & Tyagi, S. Stochastic mRNA synthesis in mammalian cells. PLoS Biol. [online] 4, e309 (2006) (10.1371/journal.pbio.0040309).

    Article  CAS  Google Scholar 

  13. Raser, J.M. & O'Shea, E.K. Noise in gene expression: origins, consequences, and control. Science 309, 2010–2013 (2005).

    Article  CAS  Google Scholar 

  14. Lee, C.K., Shibata, Y., Rao, B., Strahl, B.D. & Lieb, J.D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    Article  CAS  Google Scholar 

  15. Seoighe, C. et al. Prevalence of small inversions in yeast gene order evolution. Proc. Natl. Acad. Sci. USA 97, 14433–14437 (2000).

    Article  CAS  Google Scholar 

  16. Maillet, L. et al. Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Genes Dev. 10, 1796–1811 (1996).

    Article  CAS  Google Scholar 

  17. Knop, M. Evolution of the hemiascomyclete yeasts: on life styles and the importance of inbreeding. Bioessays 28, 696–708 (2006).

    Article  CAS  Google Scholar 

  18. Batada, N.N., Urrutia, A.O. & Hurst, L.D. Chromatin remodeling is a major source of co-expression of linked genes in yeast. Trends Genet. (in the press).

  19. Nei, M. Modification of linkage intensity by natural selection. Genetics 57, 625–641 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Spellman, P.T. & Rubin, G.M. Evidence for large domains of similarly expressed genes in the Drosophila genome. J. Biol. 1, 5 (2002) (doi:10.1186/1475-4924-1-5).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gilbert, N., Boyle, S., Fiegler, H., Woodfine, K., Carter, N.P. & Bickmore, W.A. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118, 555–566 (2004).

    Article  CAS  Google Scholar 

  22. Amsterdam, A. et al. Identification of 315 genes essential for early zebrafish development. Proc. Natl. Acad. Sci. USA 101, 12792–12797 (2004).

    Article  CAS  Google Scholar 

  23. Krylov, D.M., Wolf, Y.I., Rogozin, I.B. & Koonin, E.V. Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution. Genome Res. 13, 2229–2235 (2003).

    Article  CAS  Google Scholar 

  24. Gustafson, A.M., Snitkin, E.S., Parker, S.C.J., DeLisi, C. & Kasif, S. Towards the identification of essential genes using targeted genome sequencing and comparative analysis. BMC Genomics 7, 265 (2006) (doi:10.1186/1471-2164-7-265).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).

    Article  CAS  Google Scholar 

Download references


N.B. is funded by a fellowship from the Canadian Institutes for Health Research.

Author information

Authors and Affiliations


Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–3, Supplementary Methods, Supplementary Discussion (PDF 591 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Batada, N., Hurst, L. Evolution of chromosome organization driven by selection for reduced gene expression noise. Nat Genet 39, 945–949 (2007).

Download citation

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing