Journal of Theoretical Biology 244 (2007) 621–630 Evolutionary coupling between the deleteriousness of gene mutations and the amount of non-coding sequences Carole Knibbe a,b , Olivier Mazet c , Fabien Chaudier d , Jean-Michel Fayard b , Guillaume Beslon a,Ã a Computer Science Department, INSA Lyon, Bat. Blaise Pascal, 69621 Villeurbanne Cedex, France b Laboratoire de Biologie Fonctionnelle, Insectes et Interactions, UMR INRA/INSA 203, INSA Lyon, Bat. Louis Pasteur, 69621 Villeurbanne Cedex, France c Camille Jordan Institute of Mathematics, INSA Lyon, Bat. Leonard de Vinci, 69621 Villeurbanne Cedex, France d Biosciences Department, INSA Lyon, Bat. Louis Pasteur, 69621 Villeurbanne Cedex, France Received 31 March 2006; received in revised form 20 July 2006; accepted 6 September 2006 Available online 12 September 2006 Abstract The phenotypic effects of random mutations depend on both the architecture of the genome and the gene–trait relationships. Both levels thus play a key role in the mutational variability of the phenotype, and hence in the long-term evolutionary success of the lineage. Here, by simulating the evolution of organisms with flexible genomes, we show that the need for an appropriate phenotypic variability induces a relationship between the deleteriousness of gene mutations and the quantity of non-coding sequences maintained in the genome. The more deleterious the gene mutations, the shorter the intergenic sequences. Indeed, in a shorter genome, fewer genes are affected by rearrangements (duplications, deletions, inversions, translocations) at each replication, which compensates for the higher impact of each gene mutation. This spontaneous adjustment of genome structure allows the organisms to retain the same average fitness loss per replication, despite the higher impact of single gene mutations. These results show how evolution can generate unexpected couplings between distinct organization levels. r 2006 Elsevier Ltd. All rights reserved. Keywords: Genome evolution; Non-coding DNA; Mutation effect; Variability; Robustness 1. Introduction Mutations act on the hereditary material, while selection acts on the morphological and physiological traits of the organism. This is why the relationship between the genotype and the phenotype lies at the heart of evolu- tionary biology. Although the one-gene-one-character view of early Mendelism was already questioned in Morgan’s The theory of the gene (Morgan, 1926), this simplification was widely used in classical genetics until the 1960s (Morange, 2000). It had to be abandoned when molecular biology redefined genes as sequences of nucleotides encoding proteins. However, the relationship between proteins and characters still remained mysterious (Mor- ange, 2000). The complexity of this relationship was plainly revealed when progress in high-throughput measurements allowed for the discovery of large and interconnected protein networks, including metabolic, regulatory, signal- ling or protein–protein interaction networks (Barabasi and Oltvai, 2004). In this complex genotype–phenotype map, polygeny and pleiotropy (Wright, 1968) are the rule rather than the exception: most biological traits result from the interactions of many proteins, and reciprocally, most proteins are involved in several processes. The genotype–phenotype map plays a critical role in the evolutionary fate of a lineage, because it determines the sensitivity of the phenotype to the mutations in the genes. This sensitivity cannot be too high, otherwise the lineage would quickly die off. There is a long-term pressure to limit the phenotypic variation from one generation to another ARTICLE IN PRESS www.elsevier.com/locate/yjtbi 0022-5193/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jtbi.2006.09.005 Ã Corresponding author. Tel.: +33 4 72 43 84 87; fax: +33 4 72 43 83 14. E-mail addresses: carole.knibbe@insa-lyon.fr (C. Knibbe), olivier.mazet@insa-lyon.fr (O. Mazet), fabien.chaudier@insa-lyon.fr (F. Chaudier), jean-michel.fayard@insa-lyon.fr (J.-M. Fayard), guillaume.beslon@insa-lyon.fr (G. Beslon).