DOCSLIB.ORG

Theory for Protein Mutability and Biogenesis (Lattice Model/Exhaustive Simulation/Random Sequences/Protein Origins/Protein Folding) KIT FUN LAU and KEN A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Theory for Protein Mutability and Biogenesis (Lattice Model/Exhaustive Simulation/Random Sequences/Protein Origins/Protein Folding) KIT FUN LAU and KEN A Proc. Nati. Acad. Sci. USA Vol. 87, pp. 638-642, January 1990 Biophysics Theory for protein mutability and biogenesis (lattice model/exhaustive simulation/random sequences/protein origins/protein folding) KIT FUN LAU AND KEN A. DILL Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143 Communicated by Frederic M. Richards, October 17, 1989 (received for review June 14, 1989) ABSTRACT Using an elementary physical model for pro- SEQUENCE CONFORMATIONAL tein folding, of self-avoiding short copolymer chains on two- SPACE SPACE ....I... dimensional square lattices, we address two questions regard- .7 HH...HHHH ing the evolution and origins of globular proteins. (i) How will COMPACT 2-< protein native structures and stabilities be affected by single- HP...HHIH probability that a HP...HHPH and double-site mutations? (ii) What is the HP...HPHH randomly chosen sequence of amino acids will be compact and HP...HPHP globular under folding conditions? For a large number of HP...HPPH C-i different sequences, we search the conformational space ex- PH...HHHH haustively to find unequivocally the "native" conformation(s), PH...HHHP ofglobal minimum free energy, for each sequence. We find that PH...HHPH Ir replacing nonpolar residues in the core by polar residues is Pp...PPPP generally destabilizing, that surface sites are less sensitive than FIG. 1. Mapping of sequence space to native structure(s). Se- core sites, that some mutations increase the degeneracy of quence space is the set of all possible sequences; conformational native states, and that overall it is most probable that a space is the set of all possible conformations. Two arrows to a native mutation will be neutral, having no effect on the native state from different sequences represents "convergence;" two ar- structure. These results support a "Continuity Principle," that rows to different native structures from a given sequence represents small changes in sequence seldom have large effects on struc- "degeneracy." H, nonpolar (hydrophobic) residue; P, other type of ture or stability of the native state. The simulations also show residue (see text). that (i) the number of "convergent" sequences (different sequences coding for the same native structure) is extremely (2D) square lattice. Thus, each amino acid is represented as large and (ii) most sequences become quite dense under folding simply occupying one lattice site, connected to its chain conditions. This implies that the probability of formation of a neighbor(s), and unable to occupy a site filled by any other globular protein from a random sequence of amino acids by residue. For each monomer, we define "connected" neigh- prebiotic or mutational methods is significantly greater than bors as units j and j + 1 adjacent along the chain, and zero. "topological" neighbors as units (i, j) adjacent in space but not adjacent in position along the sequence, i 4 j - 1, j + 1. The central question of protein evolution is how mutational Every HH contact between topological neighbors is assigned change in the amino acid sequence leads to change in the a contact energy equal to e (<0) and every other interaction structure and stability, and thereby to change in protein among all other possible types of neighbor pairs (H, P, or function. A fundamental question of protein origins is how solvent, S) has energy equal to 0. For sufficiently short chains different sequences, and how many of them, could fold up to every accessible conformation is then surveyed by computer, stable globular conformations with active sites. To address and its energy (number of HH contacts) is evaluated to find these questions of protein biogenesis and change at the the native structure(s), those with the maximum number of molecular level requires a "protein folding" algorithm, a HH contacts. For n < 11, native states are found in this predictor of the native structure of a protein from its amino manner for every possible sequence. For longer chains, we acid sequence. It further requires an algorithm sufficiently randomly choose 200 different sequences, and native states fast so as to be capable of exploring a suitably large fraction are found by exhaustive exploration ofall maximally compact of "sequence space," the set of all possible sequences of conformations (1). amino acids (Fig. 1). No such algorithm yet exists at atomic This model has the following basic features in common resolution. Our purpose here is to address these questions with real proteins (1). For small HH attraction, the predom- through use of a recently developed lower-resolution lattice inant populations of chain conformations are unfolded. For statistical mechanics model of protein folding (1). molecules composed of certain sequences (which we refer to as "folding" sequences), increasing the HH attraction leads The Lattice Model of Protein Sequence/Structure to a transition to a native state characterized by a very small number of conformations (most often, only one). The native The model has been described in detail elsewhere (1); we just conformations have the properties that they (i) are maximally summarize the principal aspects here. Each protein is a linear compact, (ii) are composed of a core of predominantly H chain of a specific sequence of n amino acids. Each amino residues, and (iii) have considerable amounts of 2D equiva- acid can be either oftwo types: H (nonpolar) or P (other). The lents of secondary structures: helices and sheets, principally fraction of the n residues which are of type H is (D; hence the antiparallel (2, 3). Moreover, their distributions of secondary fraction of type P is 1 - 41. A chain conformation is structures are approximately the same as those observed in represented as a self-avoiding walk on a two-dimensional three-dimensional (3D) protein structures (H. S. Chan and K.A.D., unpublished results). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: 2D and 3D, two- and three-dimensional or dimen- in accordance with 18 U.S.C. §1734 solely to indicate this fact. sions. 638 Downloaded by guest on October 2, 2021 Biophysics: Lau and Dill Proc. Natl. Acad. Sci. USA 87 (1990) 639 There are two principal virtues of this approach. (i) The with too few H residues do not have compact native struc- model is physical; it is based on the dominant driving forces tures, and sequences with too many H residues have many for folding: the solvent aversion ofnonpolar residues in water different compact structures of equal lowest energy and thus and the conformational freedom and excluded volume of the are not singly degenerate. chain. It has no adjustable parameters or additional ad hoc assumptions. (ii) It is sufficiently simple that for any given Plasticity of Native Structures to Sequence Mutations sequence, the entire conformational space can be searched exhaustively to determine unequivocally the "native" struc- First, we ask: if a sequence is changed at one or two residue ture(s), those which are at the global minimum offree energy. positions, then how much will the native structure and energy Moreover, the native structures can be found for a large change? The question is whether proteins are either (i) highly number of different sequences, permitting a broad explora- "plastic," whereby single-site mutations would seldom lead tion (exhaustive, in some cases) of the full sequence space. to a change ofthe native structure, or (ii) so precisely crafted This model is intended to address questions of general that a single mutation would usually significantly alter the principle rather than of atomic detail. For questions of this native structure. We test this here by choosing a sequence type, justification is given elsewhere (1) that the shortness of with known native structure, and making each possible the chains and 2D nature of the model should not be signif- single-site change, from H to P, or P to H, whichever is icantly limiting. We consider here only the nature of the appropriate, then determining the "mutant" native structure compact folded conformations of chains; we do not address and energy. For this purpose, from about 1000 random the thermodynamics offolding, which will be more sensitive sequences, 251 were chosen as good folders with singly to simplifications of this type. The native conformations are degenerate native states. We characterize structural change simply those of lowest energy, found by taking the limit e by a quantity Ad (defined by equation 13 of ref. 1), which -00 (1), which we refer to as "folding conditions." The simply counts the number ofbond rotation changes, weighted distinction that e is actually a free energy rather than an by the relative magnitude of each change. energy is irrelevant for present purposes. The distribution of structural change resulting from 3263 To decide whether a sequence is a "folder" or not, we use different single-site mutations on chains of length n = 13 is the compactness (1-3) p = t/tmax, where t is the total number shown in Fig. 2B. It is clear from Fig. 2 that proteins are of topological neighbors in a given conformation and tmax is predicted to be nearly maximally insensitive to single-site the maximum possible number of topological neighbors change. In this case, nearly 90% of all possible single-site which could be achieved by any conformation of a given changes cause no change in the native structure. It is inter- chain length. Below we consider different criteria for glob- esting that when a mutation does change the structure, it does ularity, ranging from the most strict (t = tmax) to less strict (t so cooperatively: the small peak at Ad = 3-8 implies that the 2 tmaX - 2); a conformation is considered folded if it satisfies typical single-site-modified mutant native structure has sev- this criterion under folding conditions.
Load more

Recommended publications
  • Recombination and the Evolution of Mutational Robustness
    ARTICLE IN PRESS Journal of Theoretical Biology 241 (2006) 707–715 www.elsevier.com/locate/yjtbi Recombination and the evolution of mutational robustness Andy Gardnera,b,c,Ã, Alex T. Kalinkaa aInstitute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK bDepartment of Mathematics & Statistics, Queen’s University, Kingston, Ont., Canada K7L 3N6 cDepartment of Biology, Queen’s University, Kingston, Ont., Canada K7L 3N6 Received 25 July 2005; received in revised form 8 December 2005; accepted 5 January 2006 Available online 20 February 2006 Abstract Mutational robustness is the degree to which a phenotype, such as fitness, is resistant to mutational perturbations. Since most of these perturbations will tend to reduce fitness, robustness provides an immediate benefit for the mutated individual. However, robust systems decay due to the accumulation of deleterious mutations that would otherwise have been cleared by selection. This decay has received very little theoretical attention. At equilibrium, a population or asexual lineage is expected to have a mutation load that is invariant with respect to the selection coefficient of deleterious alleles, so the benefit of robustness (at the level of the population or asexual lineage) is temporary. However, previous work has shown that robustness can be favoured when robustness loci segregate independently of the mutating loci they act upon. We examine a simple two-locus model that allows for intermediate rates of recombination and inbreeding to show that increasing the effective recombination rate allows for the evolution of greater mutational robustness. r 2006 Elsevier Ltd. All rights reserved. Keywords: Canalization; Epistasis; Linkage disequilibrium; Multilocus methodology; Mutation–selection balance 1.
    [Show full text]
  • Antigen-Receptor Degeneracy and Immunological Paradigms Irun R
    Molecular Immunology 40 (2004) 993–996 Antigen-receptor degeneracy and immunological paradigms Irun R. Cohen a,∗, Uri Hershberg b, Sorin Solomon c a The Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel b Interdisciplinary Center for Neuronal Computation, The Hebrew University of Jerusalem, Jerusalem, Israel c The Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem, Israel Abstract This paper discusses some consequences of the discovery that antigen receptors are degenerate: Immune specificity, in contrast to the tenets of the clonal selection paradigm, must be generated by the immune response down-stream of initial antigen recognition; and specificity is a property of a collective of cells and not of single clones. © 2003 Elsevier Ltd. All rights reserved. Keywords: T cells; T-cell receptor; Inflammation; Specificity; Degeneracy; Clonal selection; Cognitive paradigm 1. Degeneracy problems characterized by extreme poly-clonality; in fact, most nat- ural T-cell responses are oligo-clonal (Douek et al., 2003). Degeneracy, in the present discourse, refers to the capac- So, there must be a mechanism or mechanisms that operate ity of any single antigen receptor to bind and respond to to restrict poly-clonality in wild-type adaptive immune sys- (recognize) many different ligands. The Oxford English Dic- tems. The inherent potential for extreme poly-clonality, in tionary (Second Edition, 1989) defines the primary meaning practice, may be tempered by clonal competition. Compe- of degeneracy as: tition among clones for access, energy or space will most likely reward the fast and the avid. Since the best clones Having lost the qualities proper to the race or kind; having should win, clonal competition does not threaten the logic declined from a higher to a lower type; hence, declined of the clonal selection theory (CST) of adaptive immunity.
    [Show full text]
  • Multiple Receptor Tyrosine Kinases Are Expressed in Adult Rat Retinal Ganglion Cells As Revealed by Single-Cell Degenerate Primer Polymerase Chain Reaction
    Upsala Journal of Medical Sciences. 2010; 115: 65–80 ORIGINAL ARTICLE Multiple receptor tyrosine kinases are expressed in adult rat retinal ganglion cells as revealed by single-cell degenerate primer polymerase chain reaction NICLAS LINDQVIST1, ULRIKA LÖNNGREN1, MARTA AGUDO2,3, ULLA NÄPÄNKANGAS1, MANUEL VIDAL-SANZ2 & FINN HALLBÖÖK1 1Department of Neuroscience, Unit for Developmental Neuroscience, Biomedical Center, Uppsala University, 75123 Uppsala, Sweden, 2Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain, and 3Fundación para la Formación e Investigación Sanitaria de la Región de Murcia, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain Abstract Background. To achieve a better understanding of the repertoire of receptor tyrosine kinases (RTKs) in adult retinal ganglion cells (RGCs) we performed polymerase chain reaction (PCR), using degenerate primers directed towards conserved sequences in the tyrosine kinase domain, on cDNA from isolated single RGCs univocally identified by retrograde tracing from the superior colliculi. Results. All the PCR-amplified fragments of the expected sizes were sequenced, and 25% of them contained a tyrosine kinase domain. These were: Axl, Csf-1R, Eph A4, Pdgfrb, Ptk7, Ret, Ros, Sky, TrkB, TrkC, Vegfr-2, and Vegfr-3. Non-RTK sequences were Jak1 and 2. Retinal expression of Axl, Csf-1R, Pdgfrb, Ret, Sky, TrkB, TrkC, Vegfr-2, and Vegfr-3, as well as Jak1 and 2, was confirmed by PCR on total retina cDNA. Immunodetection of Csf-1R, Pdgfra/b, Ret, Sky, TrkB, and Vegfr-2 on retrogradely traced retinas demonstrated that they were expressed by RGCs. Co-localization of Vegfr-2 and Csf-1R, of Vegfr-2 and TrkB, and of Csf-1R and Ret in retrogradely labelled RGCs was shown.
    [Show full text]
  • Degeneracy in Hippocampal Physiology and Plasticity
    bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted July 30, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Degeneracy in hippocampal physiology and plasticity * Rahul Kumar Rathour and Rishikesh Narayanan Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India. * Corresponding Author Rishikesh Narayanan, Ph.D. Molecular Biophysics Unit Indian Institute of Science Bangalore 560 012, India. e-mail: [email protected] Phone: +91-80-22933372 Fax: +91-80-23600535 Abbreviated title: Degeneracy in the hippocampus Keywords: hippocampus; degeneracy; learning; memory; encoding; homeostasis; plasticity; physiology; causality; reductionism; holism; structure-function relationships; variability; compensation; intrinsic excitability 1 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted July 30, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis, that demonstrate the expression of degeneracy in hippocampal physiology and plasticity.
    [Show full text]
  • An Interdisciplinary Perspective on Artificial Immune Systems
    Evol. Intel. (2008) 1:5–26 DOI 10.1007/s12065-007-0004-2 REVIEW ARTICLE An interdisciplinary perspective on artificial immune systems J. Timmis Æ P. Andrews Æ N. Owens Æ E. Clark Received: 7 September 2007 / Accepted: 11 October 2007 / Published online: 10 January 2008 Ó Springer-Verlag 2008 Abstract This review paper attempts to position the area 1 Introduction of Artificial Immune Systems (AIS) in a broader context of interdisciplinary research. We review AIS based on an Artificial Immune Systems (AIS) is a diverse area of established conceptual framework that encapsulates math- research that attempts to bridge the divide between ematical and computational modelling of immunology, immunology and engineering and are developed through abstraction and then development of engineered systems. the application of techniques such as mathematical and We argue that AIS are much more than engineered systems computational modelling of immunology, abstraction from inspired by the immune system and that there is a great those models into algorithm (and system) design and deal for both immunology and engineering to learn from implementation in the context of engineering. Over recent each other through working in an interdisciplinary manner. years there have been a number of review papers written on AIS with the first being [25] followed by a series of others Keywords Artificial immune systems Á that either review AIS in general, for example, [29, 30, 43, Immunological modelling Á Mathematical modelling Á 68, 103], or more specific aspects of AIS such as data Computational modelling Á mining [107], network security [71], applications of AIS Applications of artificial immune systems Á [58], theoretical aspects [103] and modelling in AIS [39].
    [Show full text]
  • Degeneracy and Genetic Assimilation in RNA Evolution Reza Rezazadegan1* and Christian Reidys1,2
    Rezazadegan and Reidys BMC Bioinformatics (2018) 19:543 https://doi.org/10.1186/s12859-018-2497-3 RESEARCH ARTICLE Open Access Degeneracy and genetic assimilation in RNA evolution Reza Rezazadegan1* and Christian Reidys1,2 Abstract Background: The neutral theory of Motoo Kimura stipulates that evolution is mostly driven by neutral mutations. However adaptive pressure eventually leads to changes in phenotype that involve non-neutral mutations. The relation between neutrality and adaptation has been studied in the context of RNA before and here we further study transitional mutations in the context of degenerate (plastic) RNA sequences and genetic assimilation. We propose quasineutral mutations, i.e. mutations which preserve an element of the phenotype set, as minimal mutations and study their properties. We also propose a general probabilistic interpretation of genetic assimilation and specialize it to the Boltzmann ensemble of RNA sequences. Results: We show that degenerate sequences i.e. sequences with more than one structure at the MFE level have the highest evolvability among all sequences and are central to evolutionary innovation. Degenerate sequences also tend to cluster together in the sequence space. The selective pressure in an evolutionary simulation causes the population to move towards regions with more degenerate sequences, i.e. regions at the intersection of different neutral networks, and this causes the number of such sequences to increase well beyond the average percentage of degenerate sequences in the sequence space. We also observe that evolution by quasineutral mutations tends to conserve the number of base pairs in structures and thereby maintains structural integrity even in the presence of pressure to the contrary.
    [Show full text]
  • Tyrosine Kinases
    KEVANM SHOKAT MINIREVIEW Tyrosine kinases: modular signaling enzymes with tunable specificities Cytoplasmic tyrosine kinases are composed of modular domains; one (SHl) has catalytic activity, the other two (SH2 and SH3) do not. Kinase specificity is largely determined by the binding preferences of the SH2 domain. Attaching the SHl domain to a new SH2 domain, via protein-protein association or mutation, can thus dramatically change kinase function. Chemistry & Biology August 1995, 2:509-514 Protein kinases are one of the largest protein families identified, This is a result of the overlapping substrate identified to date; over 45 new members are identified specificities of many tyrosine kinases, which makes it each year. It is estimated that up to 4 % of vertebrate pro- difficult to dissect the individual signaling pathways by teins are protein kinases [l].The protein kinases are cate- scanning for unique target motifs [2]. gorized by their specificity for serineithreonine, tyrosine, or histidine residues. Protein tyrosine kinases account for The apparent promiscuity of individual tyrosine kinases roughly half of all kinases. They occur as membrane- is a result of their unique structural organization. bound receptors or cytoplasmic proteins and are involved Enzyme specificity is typically programmed by one in a wide variety of cellular functions, including cytokine binding site, which recognizes the substrate and also con- responses, antigen-dependent immune responses, cellular tains exquisitely oriented active-site functional groups transformation by RNA viruses, oncogenesis, regulation that help to lower the energy of the transition state for of the cell cycle, and modification of cell morphology the conversion of specific substrates to products.Tyrosine (Fig.
    [Show full text]
  • A Numerical Representation and Classification of Codons To
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.02.971036; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A Numerical Representation and Classication of Codons to Investigate Codon Alternation Patterns during Genetic Mutations on Disease Pathogenesis Antara Senguptaa, Pabitra Pal Choudhuryd, Subhadip Chakrabortyb,e, Swarup Royc,∗∗, Jayanta Kumar Dasd,∗, Ditipriya Mallicke, Siddhartha S Janae aDepartment of Master of Computer Applications, MCKV Institute of Engineering, Liluah, India bDepartment of Botany, Nabadwip Vidyasagar College, Nabadwip, India cDepartment of Computer Applications,Sikkim University, Gangtok, Sikkim, India dApplied Statistical Unit, Indian Statistical Institute, Kolkata, India eSchool of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India 1. Introduction Genes are the functional units of heredity [4]. It is mainly responsible for the structural and functional changes and for the variation in organisms which could be good or bad. DNA (Deoxyribose Nucleic Acid) sequences build the genes of organisms which in turn encode for particular protein us- ing codon. Any uctuation in this sequence (codons), for example, mishaps during DNA transcription, might lead to a change in the genetic code which alter the protein synthesis. This change is called mutation. Mutation diers from Single Nucleotide Polymorphism(SNP) in many ways [23]. For instance, occurrence of mutation in a population should be less than 1% whereas SNP occurs with greater than 1%. Mutation always occurs in diseased group whereas SNP is occurs in both diseased and control population. Mutation is responsible for some disease phenotype but SNP may or may not be as- sociated with disease phenotype.
    [Show full text]
  • The Immune System in Pieces: Computational Lessons from Degeneracy in the Immune System (Special Session: Foundations of Artificial Immune Systems) M
    Proceedings of the 2007 IEEE Symposium on Foundations of Computational Intelligence (FOCI 2007) The Immune System in Pieces: Computational Lessons from Degeneracy in the Immune System (Special session: Foundations of Artificial Immune Systems) M. Mendao∗, J. Timmis∗†, P. S. Andrews∗ and M. Davies‡ ∗Department of Computer Science, University of York, Heslington, York, UK Email: [email protected] †Department of Electronics, University of York, Heslington, York, UK ‡Jenner Institute, University of Oxford. UK Abstract— The concept of degeneracy in biology, including the of the immune response. The next stage is to develop a high- immune system, is well accepted and has been demonstrated to level algorithm that is derived from the model. Independently, be present at many different levels. We explore this concept from recent work by Bersini [7] has highlighted the benefits of a computational point of view and demonstrate how we can use computational models of degeneracy to aid the development of adopting object orientated methodologies in the use of mod- more biologically plausible Artificial Immune Systems (AIS). The elling biological systems. In our work, we have made use of outcome of these models has lead us to perform an analysis of the the Unified Modelling language (UML), not only to represent receptor dynamics in the model and we discuss the computational our agent model, but also to aid the development of a high- implications of a “degenerate” repertoire. Through the use of level algorithm that we have derived from the model. It should the Unified Modelling language (UML) we have abstracted a high level immune inspire algorithm that will be used as part of be noted that the model we have developed and the high-level a larger project to develop an immune inspired bioinformatics algorithm that we have derived is only the first step towards the system.
    [Show full text]
  • Network, Degeneracy and Bow Tie. Integrating Paradigms And
    Tieri et al. Theoretical Biology and Medical Modelling 2010, 7:32 http://www.tbiomed.com/content/7/1/32 RESEARCH Open Access Network, degeneracy and bow tie. Integrating paradigms and architectures to grasp the complexity of the immune system Paolo Tieri1,2*, Andrea Grignolio1, Alexey Zaikin3, Michele Mishto1,4, Daniel Remondini1, Gastone C Castellani1, Claudio Franceschi1,2 * Correspondence: [email protected] Abstract 1Interdept. Center “Luigi Galvani” for Bioinformatics, Biophysics and Recently, the network paradigm, an application of graph theory to biology, has pro- Biocomplexity (CIG), University of ven to be a powerful approach to gaining insights into biological complexity, and Bologna, Via F. Selmi 3, 40126 Bologna, Italy has catalyzed the advancement of systems biology. In this perspective and focusing on the immune system, we propose here a more comprehensive view to go beyond the concept of network. We start from the concept of degeneracy, one of the most prominent characteristic of biological complexity, defined as the ability of structurally different elements to perform the same function, and we show that degeneracy is highly intertwined with another recently-proposed organizational principle, i.e. ‘bow tie architecture’. The simultaneous consideration of concepts such as degeneracy, bow tie architecture and network results in a powerful new interpretative tool that takes into account the constructive role of noise (stochastic fluctuations) and is able to grasp the major characteristics of biological complexity, i.e. the capacity to turn an apparently chaotic and highly dynamic set of signals into functional information. Background - the complexity of the immune system The vertebrate immune system (IS) is the result of a long evolutionary history and has a fundamental role in host defence against bacteria, viruses and parasites.
    [Show full text]
  • Histone Methylation Regulation in Neurodegenerative Disorders
    International Journal of Molecular Sciences Review Histone Methylation Regulation in Neurodegenerative Disorders Balapal S. Basavarajappa 1,2,3,4,* and Shivakumar Subbanna 1 1 Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; [email protected] 2 New York State Psychiatric Institute, New York, NY 10032, USA 3 Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA 4 New York University Langone Medical Center, Department of Psychiatry, New York, NY 10016, USA * Correspondence: [email protected]; Tel.: +1-845-398-3234; Fax: +1-845-398-5451 Abstract: Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttransla- tional modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation- mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disor- ders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific Citation: Basavarajappa, B.S.; Subbanna, S.
    [Show full text]
  • Human Epigenetic Aging Is Logarithmic with Time Across the Entire Lifespan
    bioRxiv preprint doi: https://doi.org/10.1101/401992; this version posted August 29, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Human Epigenetic Aging is Logarithmic with Time across the Entire LifeSpan Sagi Snir1 and Matteo Pellegrini2z 1Dept. of Evolutionary Biology, University of Haifa, Israel; 2Dept. of Molecular, Cell and Developmental Biology; University of California, Los Angeles, CA 90095, USA; Abstract It is well established that organisms undergo epigenetic changes both during develop- ment and aging. Developmental changes have been extensively studied to characterize the differentiation of stem cells into diverse lineages. Epigenetic changes during aging have been characterized by multiple epigenetic clocks, that allow the prediction of chronolog- ical age based on methylation status. Despite their accuracy and utility, epigenetic age biomarkers leave many questions about epigenetic aging unanswered. Specifically, they do not permit the unbiased characterization of non-linear epigenetic aging trends across entire life spans, a critical question underlying this field of research. Here we a provide an integrated framework to address this question. Our model, inspired from evolutionary models, is able to account for acceleration/deceleration in epigenetic changes by fitting an individuals model age, the epigenetic age, which is related to chronological age in a non-linear fashion. We have devised a two stage procedure leveraging these model ages to infer aging trends over the entire lifespan of a population. Application of this procedure to real data measured across broad age ranges, from before birth to old age, and from two tissue types, suggests a universal logarithmic trend characterizes epigenetic aging across entire lifespans.
    [Show full text]