What is “biological information”

Information Storage and Processing in Biological Systems:

A seminar course for the Natural Sciences

Sept 16

Sept 18

Sept 23

Sept 25

Sept 30

Oct 2

Nov 6

Introduction / DNA, Gene regulation

Translation and Proteins

Enzymes and Signal transduction

Biochemical Networks

Simple Genetic Networks

Adventures in Multicellularity

Evolution, Evolvability and Robustness

Reading List for Part 1

Chapters 1-3 “The Thread of Life” S. Aldridge Cambridge University Press.

1996.

“Genes & Signals” by Mark Ptashne and Alexander Gann. (2002) CSHL

Press.

--------------------------------------------------------------------------------------------

From molecular to modular cell biology.

(1999) L. H. Hartwell, J. J.

Hopfield, S. Leibler and A. W. Murray. Nature 402 (SUPP): C47-C52.

It’s a noisy business! Genetic regulation at the nanomolar scale.

H. Harley and A Arkin. Trends In Genetics February 1999, volume 15, No. 2

The challenges of in silico biology.

(2000) B. Palsson. Nature

Biotechnology 18: 1147-1150.

What is “biological information” and how is it “Stored” and Processed”?

M.C. Escher Spirals

Genetic

What is “biological information”?

(DNA and RNA)

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)

Non-Genetic Inheritance (template dependent replication) paragenetic

Global patterning of organelles and cilia in Paramecium relies on paragenetic information and is template dependent.

Another example is Mad Cow Disease

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)

Non-Genetic Inheritance (template dependent replication)

Physiological-Cellular Level

( Structural/Metabolism/Signal Transduction)

Simplified Connectivity of Map of Metabolism

Each node represents a chemical in the cell ( E. coli )

Each connection represents an enzymatic step or steps

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)




Physiological- Organism Level

( Structural/Metabolism/Signal Transduction,

Development, Immune System)

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)







Populations (Population dynamics, Evolution)

Genetic

Epigenetic


(DNA and RNA)

(DNA modification)







Populations (Population dynamics, Evolution)

Ecosystem (Interacting Populations, environment

 populations )

The“Central Dogma”

The central dogma relates to the flow of ‘genetic’ information in biological systems.

DNA



RNA



Protein

DNA transcription mRNA translation

Protein

Overview of Biological Systems

Organization of the Tree of Life

Three evolutionary branches of life:

Eubacteria, Archaebacteria, Eukaryotes

The macroscopic world represents a small portion of the tree.

The Eubacteria (bacteria), Archaebacteria (archae), and Eukaryotes represent three fundamental branches of life and represent two fundamental differences in organization of the cell.

Major Similarities:

Genetic code

Basic machinery for interpreting the code

Major Differences:

Organization of genes

Organization of the cell sub-cellular organelles in Eukaryotes * cytoskeletal structure in Eukaryotes **

No true multicellular organization in bacteria and archae (there are many single celled eukaryotes). ( debatable )

* compartmentalization of function

** morphologically distinct cell structure

Bacteria

Morphologically “simple” - shape defined by cell surface structure.

Transcription (reading the genetic message) and Translation (converting the genetic message into protein) are coupled- they take place within the same compartment (cytoplasm).

Compartmentalization of Function in eukaryotic cells

Transcription (reading the genetic message) and Translation (converting the genetic message into protein) occur in different compartments in the eukaryotic cell.

Example of single celled eukaryotic organisms

Morphological diversity (cytoskeleton as well as cell surface structures)

There are many distinct morphological cell types within a multicellular organism.

Morphological diversity arises from cytoskeletal networks architectural proteins

Some ‘Model’ Experimental Eukaryotic Organisms

Saccharomyces cerevisiae

Caenorhabditis elegans

(round worm)

Drosophila melanogaster

(fruit fly) mouse

Zebrafish

Arabidopsis thaliana

Antirrhinum majus

(snapdragons )

Bacteriophage (Phage) and Viruses

1) genetic material / nucleic acid

2) protective coat protein

The information for their own replication and the means to “target” the correct cell/host but no interpretive machinery

Genotype

The genetic constitution of an organism.

Phenotype

The appearance or other characteristic of an organism resulting from the interaction of its genetic constitution with the environment.

Constraints in Biological Systems

Chemical/Physical constraints

• stability of biological material

• reaction rates and diffusion rates

- properties of biochemical reactions (enzymes) differ from chemical reactions

• time dependency of many steps - time scales over many orders of magnitude for different steps

-receptor ligand binding msec

-biochemical response sec

-genetic response minutes- hours-days

• statistical properties of ‘small-scale” chemistry, i.e. where concentration of reacting molecules is low.

Evolutionary constraints

• a biological system is constrained by it’s own evolutionary history (and also

‘biological’ history)

“Alarm clock” from the movie Brazil

Evolution of new functions is rarely de novo invention but is typically due to the modification of pre-existing functions/structures.

Modularity

• Is the cell/organism designed in a modular fashion?

• Can we approximate cell behavior into modules?

• Can interactions of cells, individuals, organisms be treated in a similar way?

Coarse graining

• At what level of detail do we need to study/model a system to extract information about the underlying mechanisms?

• What level of detail is required to define the “state” of the cell, the individual, the population and ecosystem…?

• Can we define the “state” of the cell or only “states” of modules?

Stochastic variations and Individuality

• What is the source of stochastic variation (independent of genetic variation)?

• In genetically identical populations, does this play a role in adaptation?

• What role do stochastic processes play in development?

Robustness

• Despite stochastic variations, many cellular processes are extremely robust

(genetic networks, biochemical networks, cell divisions, development,…)

• How does the cell overcome the limitations imposed by stochastic variations?

• Where does robustness arise? Is it a network property?

Redundancy

- Many biological processes are duplicated so that the same function is present in multiple elements. Mutations (changes in genotype) may have no apparent phenotype or one that is less severe than expected.

- Many biological systems are degenerate , they can occur by alternative pathways.

Complexity

“the whole is greater than the sum of its parts.”

Genotype



Phenotype

Can we understand the mechanisms and processes that shape the expression of genetic variation in phenotypes?

The Natural History of Dictyostelium discoideum

Adventures in Multicellularity

The social amoeba (a.k.a. slime molds)







DNA Basics

Four bases

A - adenine

T - thymine

C - cytosine

G - guanine anti- parallel double stranded structure with specific bonding between the two strands:

A



T base pairing

C



G base pairing

A T

C G

G C

A T

T A

G C

G C

G C

T A

DNA Structure

• DNA is composed of two strands

• Each strand is composed of a sugar phosphate backbone with one of four bases attached to each sugar

•The arrangement of bases along a strand is aperiodic

• The two strands are arranged anti-parallel

• There is base specific pairing between the strands such that A pairs with T and C with G, consequently knowing the sequence of one strand gives us the sequence of the opposite strand.

Chemical Structure of DNA The Double Helix

DNA Replication

• Template copying

• Semi-conservative

A T

C G

G C

A T

T A

G C

G C

G C

T A

A T

G

C

T

C

C

A

C

A

G

A

A

C

G

G

T

G

T A

A T

C G

G C

A T

T A

G C

G C

G C

T A

A T

C G

G C

A T

T A

G C

G C

G C

T A

The Genetic Code – Triplet Code

- directional (always read 5’  3’)

- each triplet of bases codes one amino acid (Codon)

- degenerate (many AA have more than one codon)

For a given sequence there are three possible reading frames

DNA contains information about the start and end of the gene as well as when to make or if to make transcribe the information.

DNA as an information molecule

• DNA sequence itself

• DNA sequence as a code of protein

(sequence/properties of the protein)

• DNA sequence as controlling elements and recognition sites for cellular machinery

• DNA secondary structure and chemical modifications (e.g. methylation)

• genetic networks from multiple controlling elements and recognition sites with multiple genes and feedback and or feedforward systems

5001 CATAAACCGG GGTTAATTTA AATACTGGAA CCGCTTACCA ATAAGACTAA

GTATTTGGCC CCAATTAAAT TTATGACCTT GGCGAATGGT TATTCTGATT

-2 end of luxS ***I

 ? gene start

+1 MetGlnPhe LeuGlnPhe PhePheArgGln ArgGlnLeu PheIleAla

5051 AT ATG CAATT CCTGCAGTTT TTCTTTCGGC AGCGCCAGCT CTTTATTGCT

TATACGTTAA GGACGTCAAA AAGAAAGCCG TCGCGGTCGA GAAATAACGA

-2 leHisLeuGlu GlnLeuLys GluLysProLeu AlaLeuGlu LysAsnSer

+1 hrProAspArg ArgArgLeu HisProGlyMet IleAspCys GluAlaIle

5501 CCCCGGACCG CCGGCGCTTG CATCCGGGTA TGATCGACTG CGAAGCTATC

GGGGCCTGGC GGCCGCGAAC GTAGGCCCAT ACTAGCTGAC GCTTCGATAG

-2 lyArgValAla ProAlaGln MetArgThrHis AspValAla PheSerAsp

+1 *** end of ? gene

5551 TAATAATGGC ATTTAGTCAC CTCCGATAAT TTTTTAAAAA TAAACTGAAC

ATTATTACC G TA AATCAGTG GAGGCTATTA AAAAATTTTT ATTTGACTTG

-2 LeuLeuProMet  luxS start

Two ways of thinking about “information” in DNA

1) DNA has sequence information which is TRANSCRIBED into RNA (i.e. it is a template) and TRANSLATED from RNA into protein (Genetic Code).

DNA

RNA

PROTEIN

5’---CTCAGCGTTACCAT---3’

3’---GAGTCGCAATGGTA---5’

Transcription

5’---CUCAGCGUUACCAU---3’

Translation

N---Leu-Ser-Val-Thr---C

• In RNA T’s are replaced by U’s

• Some gene products are RNA, i.e. they are not translated (e.g. tRNA, rRNA)

Two ways of thinking about “information” in DNA

2) DNA has sequence information at a structural level. This form of information directs the ‘interpretative machinery’ in the cell (protein complexes), in most instances binding sites for proteins. This type of

‘information’ is important for example in determining where (along a sequence of DNA) and when a gene may be turned on, initiation of DNA replication, packaging of DNA etc… i.e - Regulation

The Basic Transcription Components (Bacterial) s factor a

2 bb ’holoenzyme

RNA Polymerase start

-35 -10

Transcription

Machinery

DNA

Promoter binding site for RNA polymerase , defines where the process will begin.

Promoter Binding

-35 -10

Open Complex Formation

Promoter Clearance

Messenger RNA (mRNA)

Regulation of Gene Expression: The Basics

Transcriptional Regulators are proteins that act to modulate gene expression.

Proteins that negatively regulate expression (i.e decrease transcription) are called Repressors and those that act positively (i.e. increase transcription of a gene) are called Activators .

These proteins act by binding at specific DNA sites are modulate RNA polymerase function. These binding sites are called operators .

start operator

-35 -10 promoter

Repressor

X start

-35 -10

Repression can be viewed as a competition for binding between the polymerase and the repressor (an oversimplification).

Activator start operator

-35 -10 promoter

An Activator promotes RNA polymerase biding activity through direct protein-protein interactions (an oversimplification).

• Any DNA binding protein, with an appropriately placed binding site can act as a repressor. Activation requires specific protein-protein interaction between the activator and RNA polymerase.

• Typically bacterial promoters are regulated by a few proteins at most and the control regions tend to be quite small.

• Eukaryotic gene regulatory regions can be very large and involve many transcriptional regulators.

• Activation and repression depend on positioning of operator sites.

• Multiple inputs can be integrated at the level of gene expression.

Consensus Binding Sites

The interaction of a DNA-Binding Protein (such as RNA Polymerase or transcriptional regulators) is dependent on the ‘ affinity ’ of the protein for the binding site. This affinity will vary under different physiological conditions, as the concentration of the protein changes and also will depend on the binding site itself.

The optimal binding site is usually close to the consensus sequence for that site obtain by aligning all the know binding sites. On can thus have a range of

‘activity’ at different promoters/operators by having differences in DNA binding sites.

E. coli Promoters

-35 box -10 box

Consensus TTGACA- N

17

- TATAAT

Examples: TTGA T A- N

16

- TATAAT

TT CCA A- N

17

- TATA C T

TGT ACA- N

19

C ATAAT

TTGA TC - N

17

- TA CT AT

TTGACA- N

17

- TA GCT T

“Activity” of Transcriptional

Regulators in Response to ‘Signals’

Case 1. Affinity of the protein for DNA may be modified by binding a ‘ligand’

( Allosteric mechanism ).

Case 2. Affinity of the protein may be affected by covalent modification such as phosphorylation .

R

DNA x

R-DNA

DNA

Rx-DNA Rx

DNA

Both of these mechanisms ( ligand binding and posttranslational modification ) are common themes in the regulation of proteins, not just in transcription control.

Regulation of Gene Expression

DNA

RNA polymerase binding

Open Complex Formation

Transcription mRNA mRNA stability

Translation

Protein

Polypeptide folding

Protein stability

Both positive and negative regulation can occur at any step in this process.

General Principles of Regulation of Gene Expression

- Regulation occurs through recruitment or preventing recruitment of transcription machinery.

-Repressors typically prevent recruitment of polymerase

-Activators increase recruitment of polymerase

- Multiple inputs from different transcription factors (TFs) can be integrated or compete.

-Protein-DNA interactions (TF, RNAP) can have different affinities, ie can act differently at different promoters at the same level of activity.

Eukaryotic Gene Expression

- the same principles but added complexity



“simple’ RNA polymerase replaced by a large transcription complex (As many as 50 proteins)



O3 CAP O1 e.g. E. coli lac , ~250 bp, 2 inputs

O2

Drosophila eve stripe 2 enhancer, >1000bp, multiple TFs

Relatively compact regulatory regions in bacteria are spread over larger regions, more transcription factors

- more inputs /signal integrations.



The added regulatory components increases the potential complexity of gene regulation in eukaryotic cells.

Organism complexity a number of genes

Organism complexity a regulatory elements

Organism

Mycoplasma genetalium

Escherichia coli

Pseudomonas aeruginosa

Saccharomyces cerevisiae

Caenorhabditis elegans

Drosophila melanogaster

Homo sapiens (man)

# of genes

750

5000

6000

6000

19,000

15,000

40,000

What is “biological information”

Genotype

Phenotype

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Phenotype

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