Order‐preserving principles underlying genotype–phenotype maps ensure high additive proportions of genetic variance

In quantitative genetics, the degree of resemblance between parents and offspring is described in terms of the additive variance (VA) relative to genetic (VG) and phenotypic (VP) variance. For populations with extreme allele frequencies, high VA/VG can be explained without considering properties of the genotype–phenotype (GP) map. We show that randomly generated GP maps in populations with intermediate allele frequencies generate far lower VA/VG values than empirically observed. The main reason is that order‐breaking behaviour is ubiquitous in random GP maps. Rearrangement of genotypic values to introduce order‐preservation for one or more loci causes a dramatic increase in VA/VG. This suggests the existence of order‐preserving design principles in the regulatory machinery underlying GP maps. We illustrate this feature by showing how the ubiquitously observed monotonicity of dose–response relationships gives much higher VA/VG values than a unimodal dose–response relationship in simple gene network models.

[1]  C. Cockerham,et al.  An Extension of the Concept of Partitioning Hereditary Variance for Analysis of Covariances among Relatives When Epistasis Is Present. , 1954, Genetics.

[2]  P. Keightley Models of quantitative variation of flux in metabolic pathways. , 1989, Genetics.

[3]  T. Mestl,et al.  A mathematical framework for describing and analysing gene regulatory networks. , 1995, Journal of theoretical biology.

[4]  H. Kacser,et al.  The molecular basis of dominance. , 1981, Genetics.

[5]  Hidde de Jong,et al.  The Carbon Assimilation Network in Escherichia coli Is Densely Connected and Largely Sign-Determined by Directions of Metabolic Fluxes , 2010, PLoS Comput. Biol..

[6]  Developmental Phenotypic Landscapes , 2008, Evolutionary Biology.

[7]  U. Alon,et al.  Plasticity of the cis-Regulatory Input Function of a Gene , 2006, PLoS biology.

[8]  Richard A. Watson,et al.  PERSPECTIVE:SIGN EPISTASIS AND GENETIC CONSTRAINT ON EVOLUTIONARY TRAJECTORIES , 2005 .

[9]  E. Davidson The Regulatory Genome: Gene Regulatory Networks In Development And Evolution , 2006 .

[10]  Adi Livnat,et al.  A mixability theory for the role of sex in evolution , 2008, Proceedings of the National Academy of Sciences.

[11]  Thomas Mestl,et al.  A methodological basis for description and analysis of systems with complex switch-like interactions , 1998, Journal of mathematical biology.

[12]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1961 .

[13]  M Ptashne,et al.  Autoregulation and function of a repressor in bacteriophage lambda. , 1976, Science.

[14]  Subodh B. Rawool,et al.  Biological significance of autoregulation through steady state analysis of genetic networks. , 2006, Bio Systems.

[15]  U. Alon,et al.  Detailed map of a cis-regulatory input function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Stig W Omholt,et al.  Statistical Epistasis Is a Generic Feature of Gene Regulatory Networks , 2007, Genetics.

[17]  A. Jacquard,et al.  Heritability: one word, three concepts. , 1983, Biometrics.

[18]  G. Wagner,et al.  Evolution of Dominance in Metabolic Pathways , 2004, Genetics.

[19]  Howard L. Jones,et al.  Exact Lower Moments of Order Statistics in Small Samples from a Normal Distribution , 1948 .

[20]  E. Plahte,et al.  Gene regulatory networks generating the phenomena of additivity, dominance and epistasis. , 2000, Genetics.

[21]  A. Bennett The Origin of Species by means of Natural Selection; or the Preservation of Favoured Races in the Struggle for Life , 1872, Nature.

[22]  J. Cheverud,et al.  Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the intercross of SM/J and LG/J inbred mouse strains , 2006, Mammalian Genome.

[23]  Adi Livnat,et al.  Sex, mixability, and modularity , 2010, Proceedings of the National Academy of Sciences.

[24]  Detlef Weigel,et al.  QTL Mapping in New Arabidopsis thaliana Advanced Intercross-Recombinant Inbred Lines , 2009, PloS one.

[25]  José M. Álvarez-Castro,et al.  Estimation of Genetic Effects and Genotype-Phenotype Maps , 2008, Evolutionary bioinformatics online.

[26]  M. Pakaluk Aristotle , 2008, The Classical Review.

[27]  P. Phillips The language of gene interaction. , 1998, Genetics.

[28]  Debbie S. Yuster,et al.  A complete classification of epistatic two-locus models , 2006, BMC Genetics.

[29]  Uri Alon,et al.  The incoherent feed-forward loop can generate non-monotonic input functions for genes , 2008, Molecular systems biology.

[30]  Kent Vander Velden,et al.  The selective values of alleles in a molecular network model are context dependent. , 2004, Genetics.

[31]  W. G. Hill,et al.  Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits , 2008, PLoS genetics.

[32]  K. L. Wang,et al.  Positive and Negative Autoregulation ofREB1 Transcription in Saccharomyces cerevisiae , 1998, Molecular and Cellular Biology.

[33]  R. Veitia,et al.  A sigmoidal transcriptional response: cooperativity, synergy and dosage effects , 2003, Biological reviews of the Cambridge Philosophical Society.

[34]  J. Staub,et al.  Generation means analysis of plant architectural traits and fruit yield in melon , 2006 .

[35]  H. Blau,et al.  Graded transcriptional response to different concentrations of a single transactivator. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Hernan G. Garcia,et al.  Transcriptional Regulation by the Numbers 2: Applications , 2004, q-bio/0412011.

[37]  Sebastiaan A.L.M. Kooijman,et al.  Dynamic Energy and Mass Budgets in Biological Systems , 2000 .

[38]  N. Syed,et al.  Genetics of quantitative traits in Arabidopsis thaliana , 2003, Heredity.

[39]  Sorin Istrail,et al.  Logic Functions of the Genomic Cis-regulatory Code , 2005, UC.

[40]  F. Cole Aristotle Generation of Animals , 1944, Nature.

[41]  Z. Zeng,et al.  Modeling Quantitative Trait Loci and Interpretation of Models , 2005, Genetics.

[42]  Sanjoy Das,et al.  Flowering time control: gene network modelling and the link to quantitative genetics , 2005 .

[43]  S. Fan,et al.  Quantitative inheritance of leaf morphological traits in upland cotton , 2008, The Journal of Agricultural Science.

[44]  O. Carlborg,et al.  A Unified Model for Functional and Statistical Epistasis and Its Application in Quantitative Trait Loci Analysis , 2007, Genetics.

[45]  Claudio Altafini,et al.  Monotonicity, frustration, and ordered response: an analysis of the energy landscape of perturbed large-scale biological networks , 2010, BMC Systems Biology.

[46]  R. Weiss,et al.  Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Swain,et al.  Gene Regulation at the Single-Cell Level , 2005, Science.

[48]  C. Peterson,et al.  Transcriptional Regulation in Eukaryotes: Concepts, Strategies and Techniques , 2000 .

[49]  Terence Hwa,et al.  Transcriptional regulation by the numbers: models. , 2005, Current opinion in genetics & development.

[50]  Nicolas E. Buchler,et al.  On schemes of combinatorial transcription logic , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  E. Davidson,et al.  Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control. , 2001, Development.