Small-scale copy number variation and large-scale changes in gene expression

The expression dynamics of interacting genes depends, in part, on the structure of regulatory networks. Genetic regulatory networks include an overrepresentation of subgraphs commonly known as network motifs. In this article, we demonstrate that gene copy number is an omnipresent parameter that can dramatically modify the dynamical function of network motifs. We consider positive feedback, bistable feedback, and toggle switch motifs and show that variation in gene copy number, on the order of a single or few copies, can lead to multiple orders of magnitude change in gene expression and, in some cases, switches in deterministic control. Further, small changes in gene copy number for a 3-gene motif with successive inhibition (the “repressilator”) can lead to a qualitative switch in system behavior among oscillatory and equilibrium dynamics. In all cases, the qualitative change in expression is due to the nonlinear nature of transcriptional feedback in which duplicated motifs interact via common pools of transcription factors. We are able to implicitly determine the critical values of copy number which lead to qualitative shifts in system behavior. In some cases, we are able to solve for the sufficient condition for the existence of a bifurcation in terms of kinetic rates of transcription, translation, binding, and degradation. We discuss the relevance of our findings to ongoing efforts to link copy number variation with cell fate determination by viruses, dynamics of synthetic gene circuits, and constraints on evolutionary adaptation.

[1]  M. Ehrenberg,et al.  Noise in a minimal regulatory network: plasmid copy number control , 2001, Quarterly Reviews of Biophysics.

[2]  G. K. Ackers,et al.  Quantitative model for gene regulation by lambda phage repressor. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Yuanfang Guan,et al.  Functional Analysis of Gene Duplications in Saccharomyces cerevisiae , 2007, Genetics.

[4]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[5]  B. Birren,et al.  Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae , 2004, Nature.

[6]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[7]  R. Reeves,et al.  Understanding the Basis for Down Syndrome Phenotypes , 2006, PLoS genetics.

[8]  A. Ninfa,et al.  Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli , 2003, Cell.

[9]  D. Endy Foundations for engineering biology , 2005, Nature.

[10]  A. van Oudenaarden,et al.  Noise Propagation in Gene Networks , 2005, Science.

[11]  Joshua M. Korn,et al.  Mapping and sequencing of structural variation from eight human genomes , 2008, Nature.

[12]  Fernando A. Villanea,et al.  Diet and the evolution of human amylase gene copy number variation , 2007, Nature Genetics.

[13]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[14]  Philippe Kourilsky,et al.  Lysogenization by bacteriophage lambda , 1973, Molecular and General Genetics MGG.

[15]  Sean B. Carroll,et al.  Gene duplication and the adaptive evolution of a classic genetic switch , 2007, Nature.

[16]  A. Wagner Robustness against mutations in genetic networks of yeast , 2000, Nature Genetics.

[17]  Dr. Susumu Ohno Evolution by Gene Duplication , 1970, Springer Berlin Heidelberg.

[18]  M. Bennett,et al.  Transient dynamics of genetic regulatory networks. , 2007, Biophysical journal.

[19]  Steven H. Strogatz,et al.  Nonlinear Dynamics and Chaos , 2024 .

[20]  F R Adler,et al.  How to make a biological switch. , 2000, Journal of theoretical biology.

[21]  E. Davidson,et al.  Gene Regulatory Networks and the Evolution of Animal Body Plans , 2006, Science.

[22]  A. Griffiths Introduction to Genetic Analysis , 1976 .

[23]  T. Schmidt,et al.  rRNA Operon Copy Number Reflects Ecological Strategies of Bacteria , 2000, Applied and Environmental Microbiology.

[24]  Farren J. Isaacs,et al.  Computational studies of gene regulatory networks: in numero molecular biology , 2001, Nature Reviews Genetics.

[25]  Nicole C Riddle,et al.  Dosage balance in gene regulation: biological implications. , 2005, Trends in genetics : TIG.

[26]  Eberhard O Voit,et al.  Collective decision making in bacterial viruses. , 2008, Biophysical journal.

[27]  Nicholas T. Ingolia,et al.  Positive-Feedback Loops as a Flexible Biological Module , 2007, Current Biology.

[28]  J. Timmer,et al.  Design principles of a bacterial signalling network , 2005, Nature.

[29]  Margaret Ann Shea,et al.  Quantitative model for gene regulation by ? phage repressor , 1997 .

[30]  Nir Friedman,et al.  Quantitative kinetic analysis of the bacteriophage λ genetic network , 2005 .

[31]  J. Leemans,et al.  Engineering herbicide resistance in plants , 1988 .

[32]  S. Antonarakis,et al.  Gene duplication: a drive for phenotypic diversity and cause of human disease. , 2007, Annual review of genomics and human genetics.

[33]  Ash A. Alizadeh,et al.  Genome-wide analysis of DNA copy-number changes using cDNA microarrays , 1999, Nature Genetics.

[34]  X. Gu,et al.  Expression divergence between duplicate genes. , 2005, Trends in genetics : TIG.

[35]  Kalin H. Vetsigian,et al.  Exposing the fitness contribution of duplicated genes , 2008, Nature Genetics.

[36]  Philip M. Kim,et al.  The current excitement about copy-number variation: how it relates to gene duplications and protein families. , 2008, Current opinion in structural biology.

[37]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Dmitri A. Petrov,et al.  Pervasive and Persistent Redundancy among Duplicated Genes in Yeast , 2008, PLoS genetics.

[39]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Zhaolei Zhang,et al.  The extensive and condition-dependent nature of epistasis among whole-genome duplicates in yeast. , 2008, Genome research.

[41]  M. Ptashne,et al.  Genes and Signals , 2001 .

[42]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[43]  E. Eichler,et al.  Mutational and selective effects on copy-number variants in the human genome , 2007, Nature Genetics.

[44]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[45]  Manolis Kellis,et al.  The evolutionary dynamics of the Saccharomyces cerevisiae protein interaction network after duplication , 2008, Proceedings of the National Academy of Sciences.

[46]  M. Lynch,et al.  The evolutionary fate and consequences of duplicate genes. , 2000, Science.

[47]  Nicholas J. Guido,et al.  A bottom-up approach to gene regulation , 2006, Nature.

[48]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[49]  T. Schmidt,et al.  Life History Implications of rRNA Gene Copy Number in Escherichia coli , 2004, Applied and Environmental Microbiology.

[50]  X. Estivill,et al.  Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability , 2007, Nature Reviews Genetics.

[51]  M. Kessel,et al.  Bacteriophage infection is targeted to cellular poles , 2008, Molecular microbiology.

[52]  Uri Alon,et al.  An Introduction to Systems Biology , 2006 .

[53]  L. Mirny,et al.  Kinetics of protein-DNA interaction: facilitated target location in sequence-dependent potential. , 2004, Biophysical journal.

[54]  POPULATION GENETICS MODELS OF TRANSPOSABLE ELEMENTS , 1997 .

[55]  Andreas Wagner,et al.  Robustness Can Evolve Gradually in Complex Regulatory Gene Networks with Varying Topology , 2007, PLoS Comput. Biol..