[email protected] 1 a quote… there is no spirit-driven life force, no throbbing, heaving,...
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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
2
History, Theory, and Historical Contingency in
Biology
(or [email protected])
http://genome.ornl.gov/~v8v
Ira and the Worm: Similar Information in Genes and Gene ProductsDespite Deep
Similarity and Unity, Deep PopulationVariation
within Species
Complexityof Form & Function
Diversity of Forms and Function
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.
Now
Past
Now
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.
A Computational/Conceptual Biology Timeline
Mendel“Quantitative”
Geneticsstatistics in populations
The Modern Synthesis:The Neo-Darwinian Synthesis between
genetics and evolution.
Populations under
selection.
Darwin (& Malthus)
Population growth; intrinsic rate of
increase, r: Carrying
capacity, K
Molecular Evolution:
Molecular Biology, Protein
Structure, Biophysics;Sequence Analysis
Applied bioinformatics history: A beginning with Aristotle.
Observe Diversity What is out there?
Applied bioinformatics history: A beginning with Aristotle.
Observe Diversity What is out there?
Compare and Classify Diversity Organized what is out there by
similarity….
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.
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. )
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.
Sir Richard Owen
HOMOLOGY
“The same organ in all its varieties of form”
Serial HomologyDerived forms within the same organism
Special HomologyDerived forms between different species
Versus
Analogy Forms similar due to same function
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.
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.
CLADOGRAM ( partial) of VERTEBRATES: DESCENT WITH MODIFICATION: Macroevolution happens
Germ PlasmContinuity of the Germ Plasm; Soma vs. Germ Cells; Differentiated somatic cells share same genome information (but use it differently).
Cell Biology, and Genomics
Weismann
Modern Understanding: Source of Genotypic informationDNA 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.
Adaptive landscape
Statistical Genetics
Mathematical biology
Rediscovery of Mendelism
“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
THE MODERN SYNTHESIS
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.
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).
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
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
Evolution of Biological Sequences;Methods to compare sequences and find patterns. Gene Duplication & Divergence
MolecularEvolution
Margaret Dayhoff
Physiology and Cell-Cell Communication
Cell Type
B
Cell Type
A
A cell type produces an informational molecule (e.g.
hormone)
Another cell type is capable of sensing this informational molecule. It has a receptor
“lock” for the “key” produced by the other cell.
Networked Molecular Regulators (e.g. hormones, morphogens) communicate across cells; intracellular regulation; signal transduction
Cell Regulatory Networks
Bernard
Cells as receiving/integrator of different environmental signals.
Receptors ( a type of protein) sit in the
membrane and allow only some external information to be
received and transduced.
Cell Membranes restrict access to environmental
information; Promote “modularity” (information hiding)
Internal Methods External Methods
Developmental biology and Evolution
Long standing interest and problem, but not really part of the first Modern Synthesis…yet.
Emergence of heterogeneous phenotypes from apparent homogeneity; complexity from homogenity
Developmental
Biology
Driesch
KARL ERNST von BAER: (Not Haeckel!)
“The general features of a large group of animals appear earlier in development than do the specializedfeatures of a smaller group…The early embryo is never like a lower animal, but only like its early embryo.”
“Community of embryonicstructure reveals communityof descent.”
CHARLES DARWINStudied Barnacle classification and development
ON THE ORIGIN OF SPECIES
1859
“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.”
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
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..
What is the important information encoded in the genome?
“Gene”
hnRNA
mRNA
protein: 1D, 2D, 3D
Gene ProductSequence
A B DC
OR
‘Regulatory Sites and proteins that promote or prevent making RNA and
proteins
Control & Regulatory sites for Gene Expression
Transcription--Boolean operation--Sums Regulatory Signals--Combinatorial Complexity
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…
Unique bindingsites withineach module
Binding sites thatdefine a specificmodule
6 Modules
BP
ABCDEF
Regulatory region Coding region
1st EXON
The Sea Urchin Endo 16 gene
Redrawn from Yuh et al., Science 279, 1998
Circa 50 binding site motifs
Cell Differentiation—Stem CellsPluripotent
Restricted Fate
From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding of Phenotypic Variation and Evolutionary Adaptability
Different cell types have different GRNS and use only a fraction of the same genome information.
ON Genes
InducibleGenes
ActivelyinhibitedGenes
Off Genes ON Genes
InducibleGenes
ActivelyinhibitedGenesOff Genes
Cell Type 1
Cell Type 2
Cell Differentiation—Sensing Environments via Receptors
From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding of Phenotypic Variation and Evolutionary Adaptability
Cell Type 1What 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.
Different Cell Types: Different GRNs
A Cartoon…
A, B, C, D, EA cell will have a set of GRNs that
allow it to respond to signals (in this case, GRNs 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
Cascades of Different GRNs
A Cartoon…
A, B, C, D, E
B, C, D, E, FA, C, D, E, G
D, E, F, X, Y
How does biology build up phenotypic complexity, diversity, and variability over EVOLUTIONARY time?
A Bioinformatics Timeline
Metazoacirca 700 million years or so of multicellular animal life…
Similar gene products lay down the radically different body plans!
Similar gene products lay down the radically different body plans!
Key Genome Data & Idea
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
mRNA
Protein
Pure Bioinformatics
Believe that non-Protein Coding, regulatory sequences are most changed.
Networked Molecular Regulators communicate across cells; intracellular regulation; signal transduction (in both physiology & development)
Cell Regulatory Networks
e.g. C. Bernard
‘Small changes in the distribution in time and space of the same structures are sufficient to affect deeply form, functions, and behavior”
Gene RegulatoryNetworks
e.g. F Jacob
Some hope that one can model and study the emergence of Phenotypic complexity and heterogeneity from apparent homogeneity
Models For Morphogenesis
Complexity, Networks
e.g. Alan Turing, Erdos, Kaufman, Barabasi, Von Neuman, Wolfram
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
Implication: Must Study Networks
Genomic information
Bioinformation History: Three areas of evolutionary change…
Environmental (external) information…cell-cell
communication networks.
Internal Gene Regulatory networks
(selective use of genomic information in cells)
54
ENDJay Snoddy
Oak Ridge National Laboratory
& The University of Tennessee
[email protected] [email protected]
http://genome.ornl.gov/~v8v
A View: Biological Theory is ImportantInformation & 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.