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A Quote… There is no spirit-driven life force, no throbbing, heaving, pullulating, protoplasmic, mystic jelly. Life is just bytes and bytes and bytes of digital information.” --Richard Dawkins [email protected] 1 History, Theory, and Historical Contingency in Biology Jay Snoddy [email protected] (or [email protected]) http://genome.ornl.gov/~v8v 2 Ira and the Worm: Similar Information in Genes and Gene Products Complexity Despite of Form & Deep Function Similarity and Unity, Deep Diversity of Population Forms and Variation Function within Species [email protected] 3 Every biological fact has a “here and now” aspect of how it “works” and a historical aspect of how it got to work that way. Past [email protected] Now Now 4 History… History of Biological Thought… A history of “Applied bioinformatics” “Through the Louvre on Roller Skates” view of some conceptual views of biology, with an occasional homage to computation in biology. History of Biological Information… Pure Bioinformatics Nothing in Biology makes any sense, except when viewed in the light of evolution. [email protected] 5 A Computational/Conceptual Biology Timeline Mendel “Quantitative” Genetics statistics in populations [email protected] Darwin (& Malthus) Population growth; intrinsic rate of increase, r: Carrying capacity, K The Modern Synthesis: The NeoDarwinian Synthesis between genetics and evolution. Populations under selection. Molecular Evolution: Molecular Biology, Protein Structure, Biophysics; Sequence Analysis 6 Applied bioinformatics history: A beginning with Aristotle. Observe Diversity What is out there? [email protected] 7 Applied bioinformatics history: A beginning with Aristotle. Observe Diversity What is out there? Compare and Classify Diversity Organized what is out there by similarity…. [email protected] 8 Applied bioinformatics history: A beginning with Aristotle. Observe Diversity Compare and Classify Diversity Explain Origin of Complexity, Diversity, Similarity How is biological form and function created in new individual? Recognized two possibilities Preformed structures. (“Russian Dolls”) Information on the “possible” from parents somehow transformed into the “actual” observed phenotype: Aristotle favored the latter as most likely…most like the current idea that the possible of genotypic information somehow gets transformed each generation into a phenotypic actual. [email protected] 9 Applied Bioinformatics: Getting Data to Classify by “Voyages of Discovery” Voyages of Discovery build upon the maps created by past Voyages of Discovery… Examples Species Diversity Voyages of Humboldt, Darwin, Alfred Russel Wallace, Bates, etc. Other voyages have ventured below level of organisms (Anatomy, Development, Physiology, Cell Biology, Biochemistry, etc. ) [email protected] 10 [email protected] 11 Malthus: Rate of Increase Elephant –19,000,000 in 750 years Staphulococcus aureus—enough to cover the earth 7 feet deep in 48 hours Progeny is far in excess of what is actually capable of living in an environment. r – Intrinsic Rate of Increase. K – Carrying capacity. [email protected] 12 HOMOLOGY “The same organ in all its varieties of form” Serial Homology Derived forms within the same organism Special Homology Derived forms between different species Versus Sir Richard Owen [email protected] Analogy Forms similar due to same function 13 [email protected] 14 Be careful here….importance of “historical contingency” Owen was—for a time, at least a proponent of what could be called “Rational Morphogenesis” The similarity of shape indicated, in their view, constraints and drivers that were the cause of similarity. (simplistically put, leg bones are more like crystals that grow from common rules, and they are NOT similar due to common origin.) While there are some biophysical constraints and drivers—esp. at more molecular level—it should be clear that a lot of similarity is due to a common origin and the historically-contingent events along the lines of descent. [email protected] 15 MECHANISM of DARWINIAN NATURAL SELECTION Variation exists in the population Competition for survival, dying before leaving offspring often Survival of those most fit for the environment (or genetic drift) Offspring are from the survivors Offspring tend to have the genes that made their parents fit for the environment. [email protected] 16 Darwin Finches: Geospiza fortis Microevolution happens [email protected] 17 CLADOGRAM ( partial) of VERTEBRATES: DESCENT WITH MODIFICATION: Macroevolution happens [email protected] 18 Germ Plasm Cell Biology, and Genomics Continuity of the Germ Plasm; Soma vs. Germ Cells; Differentiated somatic cells share same genome information (but use it differently). Weismann [email protected] 19 Modern Understanding: Source of Genotypic information DNA in chromosomes DNA coiled in chromosomes DNA passed in special cells (germ cells) from a generation to next. DNA helps direct a developmental program to create a new individual (soma) during embryogenesis from the fused germ cells. [email protected] 20 Rediscovery of Mendelism Adaptive landscape Statistical Genetics Mathematical biology [email protected] 21 THE MODERN SYNTHESIS “Evolution is a change in the genetic composition of populations. The study of the mechanisms of evolution falls within the province of population genetics.” --Theodosius Dobzhansky. 1951 [email protected] 22 Hardy-Weinberg equilibrium: Assumes organisms are diploid sexually reproducing randomly mating And have no drift (i.e. an "infinite" population) no selection no mutation no migration (gene flow) Two allele case for a gene: allele A allele has frequency, p, The allele a has a frequency, q p + q =1 AA homozygote is p2, the Aa heterozygote 2pq, the aa homozygote is q2. [email protected] 23 Now add “fitness” functions and adaptive landscapes…to these population genetics equations…. Adaptive Landscape : An adaptive landscape is a surface in multidimensional space (analogous to a mountain range) that represents the mean fitness of a population (not the fitness of a genotype). An individual is represented as a point on the surface (mountain) and a population is represented as a cloud of points. “Adaptive landscape is probably the most common metaphor in evolutionary genetic[s]” Futuyma (1998) Evolutionary Biology pg. 403 Evolution may be envisioned as the movement of a population of points (individuals) on the w surface (adaptive landscape). The points move up-slope until it arrives at the peak (mountain top). [email protected] 24 Evolution is a change in the gene pool of a population over time. Evolution is the cornerstone of modern biology. It unites all the fields of biology under one theoretical umbrella. It is not a difficult concept, but very few people -- the majority of biologists included -have a satisfactory grasp of it. One common mistake is believing that species can be arranged on an evolutionary ladder from bacteria through "lower" animals, to "higher" animals and, finally, up to man. Mistakes permeate popular science expositions of evolutionary biology. Mistakes even filter into biology journals and texts. For example, Lodish, et. al., in their cell biology text, proclaim, "It was Charles Darwin's great insight that organisms are all related in a great chain of being..." In fact, the idea of a great chain of being, which traces to Linnaeus, was overturned by Darwin's idea of common descent. Misunderstandings about evolution are damaging to the study of evolution and biology as a whole. People who have a general interest in science are likely to dismiss evolution as a soft science after absorbing the pop science nonsense that abounds. The impression of it being a soft science is reinforced when biologists in unrelated fields speculate publicly about evolution. http://www.talkorigins.org/faqs/faq-intro-to-biology.html [email protected] 25 Molecular evolution When looked at molecular sequences in 1960 and 70s … Recognized that these changes are result of Mutation Selection Primarily purifying selection or near-neutral mutations Not primarily result of directional selection!!! Genetic Drift [email protected] Molecular Evolution Evolution of Biological Sequences; Methods to compare sequences and find patterns. Gene Duplication & Divergence Margaret Dayhoff 26 Physiology and Cell-Cell Communication Networked Molecular Cell Regulatory Regulators Networks (e.g. hormones, morphogens) communicate across cells; intracellular regulation; signal transduction Bernard Cell Type B A cell type produces an informational molecule (e.g. hormone) [email protected] Cell Type A Another cell type is capable of sensing this informational molecule. It has a receptor “lock” for the “key” produced by the other cell. 27 Cells as receiving/integrator of different environmental signals. Cell Membranes restrict access to environmental information; Promote “modularity” (information hiding) Internal Methods External Methods [email protected] Receptors ( a type of protein) sit in the membrane and allow only some external information to be received and transduced. 28 Developmental biology and Evolution Developmental Biology Emergence of heterogeneous phenotypes from apparent homogeneity; complexity from homogenity Driesch Long standing interest and problem, but not really part of the first Modern Synthesis…yet. [email protected] 29 KARL ERNST von BAER: (Not Haeckel!) “The general features of a large group of animals appear earlier in development than do the specialized features of a smaller group…The early embryo is never like a lower animal, but only like its early embryo.” [email protected] 30 CHARLES DARWIN Studied Barnacle classification and development ON THE ORIGIN OF SPECIES 1859 “Community of embryonic structure reveals community of descent.” “Embryology rises greatly in interest, when we look at the embryo as a picture, more or less obscured, of the progenitor, either in its class or larval state, of all the members of the same great class.” [email protected] 31 COMPLEXITY How do Genomes build up phenotypic Complexity during development? Phenotypic complexity is created during development of an embryo; Development a) [Gene Regulation]/t &b) [Cell communication]/t [email protected] 32 How Do we explain this emergence of complexity? Over developmental time… Largely by a change in gene regulation and cell-cell communication…. The same genes in the body, but different expression of those genes in different cells and different types of cells.. [email protected] 33 Change in Gene Regulation [email protected] 34 What is the important information encoded in the genome? Control & Regulatory sites for OR Gene Expression Gene Product Sequence “Gene” A B C D ‘Regulatory Sites and proteins that promote or prevent making RNA and proteins hnRNA mRNA protein: 1D, 2D, 3D [email protected] 35 Transcription --Boolean operation --Sums Regulatory Signals --Combinatorial Complexity [email protected] 36 Think of logical gates!!! While there are subtleties (and things may not work as well in very simple systems as predicted)… …repressors and activators of gene expression can be thought of as acting as AND, NOT, OR, NAND gates… [email protected] 37 The Sea Urchin Endo 16 gene 6 Modules F E D C B A BP Unique binding sites within each module 1st EXON Binding sites that define a specific module Circa 50 binding site motifs Regulatory region Coding region Redrawn from Yuh et al., Science 279, 1998 [email protected] 38 Change in Cell-Cell Communication [email protected] 39 [email protected] 40 Cell Differentiation—Stem Cells Pluripotent Restricted Fate From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding of Phenotypic Variation and Evolutionary Adaptability [email protected] 41 Different cell types have different GRNS and use only a fraction of the same genome information. ON Genes Inducible Genes Actively inhibited Genes Off Genes Cell Type 2 ON Genes Inducible Genes Cell Type 1 [email protected] Actively inhibited Genes Off Genes 42 Cell Differentiation—Sensing Environments via Receptors Cell Type 1 What should I do? A signal produced by other cells in a region or position in body that is received by the cell helps decide on path. From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding of Phenotypic Variation and Evolutionary Adaptability [email protected] 43 Different Cell Types: Different GRNs A cell will have a set of GRNs that allow it to respond to signals (in this case, GRNs A, B, C, D, E,) A, B, C, D, E A different cell type (even in the same lineage) can have a different set of GRNs that allow it to respond to different signals D, E, F, X, Y A Cartoon… [email protected] 44 Cascades of Different GRNs A, B, C, D, E A, C, D, E, G B, C, D, E, F D, E, F, X, Y A Cartoon… [email protected] 45 How does biology build up phenotypic complexity, diversity, and variability over EVOLUTIONARY time? [email protected] 46 A Bioinformatics Timeline [email protected] 47 A Bioinformatics Timeline Metazoa circa 700 million years or so of multicellular animal life… [email protected] 48 Key Genome Data & Idea Similar gene products lay down the radically different body plans! [email protected] 49 Very Different Body Plans, yet remarkably similar protein-coding `11 [email protected] 50 Pure Bioinformatics Phenotypic Complexity in Bilateria not created with protein coding… Greater complexity of gene regulation (e.g. more binding sites and more proteins that could regulate expression of genes) Cellular compartmentalization and selective use of genome information in different cells “Gene” hnRNA Believe that non-Protein Coding, regulatory sequences are most changed. [email protected] mRNA Protein 51 Some things that may be needed to explain this apparent “sameness”… Evolution is a tinkerer, not an engineer ….and she often tinkers with networks that create emergent phenotypic complexity from genotype Gene ‘Small changes Regulatory in the Networks distribution in time and space of the same structures are sufficient to affect deeply form, functions, and behavior” e.g. F Jacob Networked Molecular Cell Regulatory Regulators Networks communicate across cells; intracellular regulation; signal transduction (in both physiology & development) e.g. C. Bernard Models For Morphogenesis Complexity, Networks Some hope that one can model and study the emergence of Phenotypic complexity and heterogeneity from apparent homogeneity e.g. Alan Turing, Erdos, Kaufman, Barabasi, Von Neuman, Wolfram Implication: Must Study Networks [email protected] 52 Bioinformation History: Three areas of evolutionary change… Genomic information Internal Gene Regulatory networks (selective use of genomic information in cells) Environmental (external) information…cell-cell communication networks. [email protected] 53 END Jay Snoddy Oak Ridge National Laboratory & The University of Tennessee [email protected] Or [email protected] http://genome.ornl.gov/~v8v 54 A View: Biological Theory is Important Information & Evolutionary Adaptation ‘It is important for biologists to know some physics…[in part because it is}..best examplar of kinds of theories that can exist and of the ways that can explain reality. But it is also important for physical scientists moving into biology to recognize that they are entering a strange territory in which two unfamiliar concepts—information and adaptation—are central.’ From Shaping Life:Genes, Embryos, and Evolution by John Maynard Smith. And historical contingency …and population. [email protected] 55