Gene and Genon Concept: Coding versus Regulation -- A Conceptual and Information- Theoretic Analysis of Genetic Storage and Expression in the Light of Modern Molecular Biology Klaus Scherrer Juergen Jost SFI WORKING PAPER: 2007-08-018 SFI Working Papers contain accounts of scientific work of the author(s) and do not necessarily represent the views of the Santa Fe Institute. We accept papers intended for publication in peer-reviewed journals or proceedings volumes, but not papers that have already appeared in print. Except for papers by our external faculty, papers must be based on work done at SFI, inspired by an invited visit to or collaboration at SFI, or funded by an SFI grant. ©NOTICE: This working paper is included by permission of the contributing author(s) as a means to ensure timely distribution of the scholarly and technical work on a non-commercial basis. Copyright and all rights therein are maintained by the author(s). It is understood that all persons copying this information will adhere to the terms and constraints invoked by each author's copyright. These works may be reposted only with the explicit permission of the copyright holder. SANTA FE INSTITUTE Genon_TIB 60707 GENE AND GENON CONCEPT : CODING VERSUS REGULATION A CONCEPTUAL AND INFORMATION - THEORETIC ANALYSIS OF GENETIC STORAGE AND EXPRESSION IN THE LIGHT OF MODERN MOLECULAR BIOLOGY Essay Klaus Scherrer1 (Paris) and Jürgen Jost2 (Leipzig) 1. Institut Jacques Monod, CNRS and Univ. Paris 7, Paris, France 2. Max Planck Institute for Mathematics in the Sciences, MPI MIS, Leipzig, Germany Correspondence to : Klaus Scherrer, Institut Jacques Monod, CNRS and Univ. Paris 7, 2, place Jussieu, F-75251 Paris-Cedex 5, France. Tel./ Fax : +33 1 4707 5231, E-mail [email protected] Correspondence to : Jürgen Jost, Max Planck Institute for Mathematics in the Sciences, Inselstrasse 22, D-04103 Leipzig, Germany. Tel.: +49-341-9959-550, Fax: +49-341-9959-555, E-mail: [email protected] Submitted to "Theory in Biosciences" Table of Contents Abstract……………………………………………………………………................................................. 3 (1) Introduction……………………………………………………………................................................. 4 (2) Coding versus Control: the Genon Concept……………………..................................................... 6 (3) Gene Expression and Regulation…………………………………................................................... 7 (3.1) Protein genes……………………………………………………................................................. 7 (3.1.1) The protein-gene is the equivalent of the triplet-based coding sequence in the mRNA………………………………….......................................................................................... 7 (3.1.2) Structural protein genes (sP-genes)…………………….................................................. 8 (3.1.3) Regulatory protein genes (cP-genes)…………………... ................................................ 8 (3.2) RNA genes………………………………………………………................................................. 9 (3.2.1) Structural RNA genes……………………………………. ................................................. 9 (3.2.2) Regulatory RNA genes………………………………………………………………............ 9 (4) Genomic information not directly related to gene expression….................................................. 10 (4.1) The 3D DNA organisation according to the Unified Matrix Hypothesis……………………………………………………………................................................. 12 (4.2) Meiotic recombination, synaptonemal complex and chromosome mechanics…………………………………………….. ..................................................................... 13 (5) Development of the Genon concept………………………………. ............................................... 14 (5.1) The genon acting in cis is carried by sequence motifs in the mRNA…………………………………………………………………................................................. 14 (5.2) Proto- and Pre-genon as well as the final genon placed in cis relate to the Cascade of Regulation………………………………... ...................................................................................... 14 5.2.1 Organisation of the DNA in the 3D-space (Step 1 in Fig.10)…………………………………………………................................................. 16 (5.2.2) Activation of Chromatin Domains for eventual transcription (Step 2 in Fig.10)…………………………………….................................................................................... 18 1 Genon_TIB 60707 (5.2.3) The primary transcripts (step 3 in Fig.10)……...………................................................ 19 (5.2.4) Processing and differential splicing of pre-mRNPs. (step 4 in Fig.10)…………………………………………………………....................................................... 20 (5.2.5) Formation of the final pre-mRNP including exons of a single coding sequence. (step 5 in Fig.10)……………………...................................................................................................... 21 (5.2.6) Final processing of pre-mRNPs. (step 6 in Fig.10)………………………………………………………………. .............................................. 21 (5.2.7) Import of mRNA into the cytoplasm (step 7 in Fig.10)………………………………………………………………. .............................................. 22 (5.2.8) Formation of cytoplasmic inactive (ribosome-)"free" mRNP (step 8 in Fig.10)…………………………………………............................. ............................................... 22 (5.2.9) Activation of mRNA and polyribosome formation (step 9 in Fig.10)………………………………………………………….….................................................. 22 (5.2.10) Translation of the coding sequence in mRNA. (step 10 in Fig.10)………………………………………………………….….................................................. 24 (5.2.11) Formation of the nascent primary polypeptide and higher order protein structure, gene function and protein homeostasis (step11 in Fig.10)…………………………………...................................... ................................................. 24 (5.3) The transgenon, the trans-acting program carried by the factors acting onto a given (proto/pre-)genon placed in cis……….......................................................................................... 24 (5.3.1) Nucleic acid-binding proteins as carriers of the transgenon…………………………………………………………................................................ 25 (5.3.2) RNA interference and the transgenon…………………………………………………………................................................ 26 (6) Mathematical Analysis of Genetic Information and Gene Expression……………………………………………………………….. ............................................... 26 (6.1) General considerations……………………………………….................................................. 26 (6.2) The questions………………………………………………...…………… ................................ 28 (6.3) Information theory and molecular biology…………………………………………………………………................................................ 30 (6.3.1) The concept of information…………………………...... ................................................ 30 (6.3.2) Ensemble and sequence entropy………………………………………………………….. .................................................................................................................................................. 30 (6.3.3) Applications of information theory to molecular biology……………………………………………………............................................................. .32 (6.4) Product information………………………………………………………………………………..33 (6.4.1) Information in cis……………………………………….. ................................................. 33 (6.4.2) Information provided by the genon in an ensemble of functional products derived from a coding region in the DNA………………………………….…………………………….. ............ 36 (6.4.3) Sequence information of the genon………………………………..……………………………. ................................................. 38 (6.5) Process information provided by the genon………………………………………………….. 38 (6.5.1) The genon in cis………………………………………......................................................39 (6.5.2) The contribution of the transgenon…………………………….…………………………...40 (6.6) Conclusion………………………………………………………………………………………….40 References………………………………………………………………………………………………41 (7) Concluding Remarks…………………………………………………………………………………... 42 (8) Glossary and Abbreviations……………………………………...................................................... 42 Acknowledgements………………………...................................................................................... 44 (9) References………………………………………………………..…................................................. 44 Figure legends……………………………………………………..……................................................. 54 2 Genon_TIB 60707 Abstract We analyse here the definition of the gene in order to distinguish, on the basis of modern insight in molecular biology, what the gene is coding for, namely a specific polypeptide, and how its expression is realized and controlled. Before the coding role of the DNA was discovered, a gene was identified with a specific phenotypic trait, from Mendel through Morgan up to Benzer. Subsequently, however, molecular biologists ventured to define a gene at the level of the DNA sequence in terms of coding. As is becoming ever more evident, the relations between information stored at DNA level and functional products are very intricate, and the regulatory aspects are as important and essential as the information coding for products. This approach led, thus, to a conceptual hybrid that confused coding, regulation and functional aspects. In this essay, we develop a definition of the gene that once again starts from the functional aspect. A cellular function can be represented by a polypeptide or an RNA. In the case of the polypeptide, its biochemical identity