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Kolmogorov: Complexity of an object is the shortest length of a computer program that creates the object
The Human Genome, and Human ComplexityYoni Toker
ViewpointGENE NUMBER:
What If There Are Only 30,000 Human Genes?Jean-Michel Claverie
Humans: ~ 30,000 genes
Worm (Caenorhabditis elegans) :~20,000 genes
Are we not much more complicated than worms?
Science 16 February 2001:Vol. 291. no. 5507, pp. 1255 - 1257
Mapping of the Human genome
1953Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA.
Mid 1980’sHuman Genome Project Suggested
Objections to the Human Genome Project
•Too hard:Human genome is 3e+9 base pairs long. A lab (in the 1980’s) could sequence 500 base pairs a day.
3e+9/500/365~~16,000
Base pairs
BP’s a day
Days a year
years
Objections to the Human Genome Project
•Too hard:Human genome is 3e+9 base pairs long. A lab (in the 1980’s) could sequence 500 base pairs a day.
•Too expensive!
•Not the way to do biology:
Biology is hypothesis driven experiments, not a fishing expedition
Mapping of the Human genome1953Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA.
Mid 1980’sHuman Genome Project Suggested
1990Human Genome project announced: Goal: sequence the entire human genome in 15 years, with a budget of $3 billion
Comparison:LHC budget ~5 billionAircraft carrier ~10 billion
Mapping of the Human genome1953Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA.
Mid 1980’sHuman Genome Project Suggested
1990Human Genome project announced: Goal: sequence the entire human genome in 15 years, with a budget of $3 billion
1998Only 5% of genome sequenced
I (Celera) will decode the entire human genome in just 3 years with
a budget of only $300 Million Dollars
Sequencing small pieces of DNA
A C G TA
C T
primer A C
G
TAA
C
F. Sanger et al., Nature 265, 687 (1977).
E. C. Strauss, J. A. Kobori, G. Siu, L. E. Hood, Anal.Biochem. 154, 353 (1986).
Sequencing small pieces of DNAA C G TAprimer A C
A C G TAprimer A C
A C G TAprimer A C
A C G TAprimer A C
A C G TAprimer A C
A C G TAprimer A C
T G
T G C
T G C AT T
T G C
T G C T
T
T G
T G C
T G C AT T
T G C
T G C T
T
Sequencing small pieces of DNA
Sequencing Large DNAsThe whole shotgun method
Fierce competition .. Comes to a drawJune 26, 2000 President Clinton, with J. Craig Venter, left, and Francis Collins, announces completion of "the first survey of the entire human genome."
Technology is getting better: Solexa sequencing
Technology is getting better!
1960 1970 1980 1990 200010
0
102
104
106
108
1010
Year of Publication
size
of l
arg
est
pro
ject
(b
p)
SequencingSyntheis
1e+5
A
DMT
A
DMT
C
A
A
C
A
A
G
T
T
G
T
T
Oligonucleotide Synthesis
• 1) De-Blocking dichloroacetic acid (DCA) or trichloroacetic acid in dichloromethane (DCM)
DMT= dimethoxytrity
A A
C
A
A
C
A
A
Oligonucleotide Synthesis
• 1) De-BlockingC
DMT
C
DMT
C
DMT
C
DMT
•2) Base Condensation
A A
C
A
A
C
A
A
Oligonucleotide Synthesis
• 1) De-Blocking
C
DMT
•2) Base Condensation
•3) Capping
•4) Oxidation
A A
C
A
A
C
A
A
Oligonucleotide Synthesis
• 1) De-Blocking
C
DMT
•2) Base Condensation
•3) Capping
•4) Oxidation
A
DMTA
DMT
DNA Synthesis
Genetic Code
4 base pairs 20 amino acids
Example:
CCG Proline
Every 3 base pairs code for an amino acid
From DNA to Proteins
Some of the things we learned
•Human genome contains 3e+9 base pairs
•Less then 2% of the genome is genes
•Gene average length 3,000 base pairs
•Number of genes ~30,000
•98% genes identical between all people:
only 1-2% of genes responsible for color of eyes, genetic diseases…
SpeciesSize of genomeNumber of genesHuman
2900 e+6 base pairs30,000
Fruit fly (Drosophila melanogaster)120 e+6 base pairs13,601
Baker's yeast (Saccharomyces
cerevisiae)12 e+6 base pairs 6 ,275
Worm (Caenorhabditis elegans)97 e+6 base pairs19,000
E. coli4.1 e+6 base pairs 4,800
Arabidopsis (Arabidopsis thaliana)125 e+6 base pairs25,000
Genome Size
ViewpointGENE NUMBER:
What If There Are Only 30,000 Human Genes?Jean-Michel Claverie
Humans: ~ 30,000 genes
Worm (Caenorhabditis elegans) :~20,000 genes
Are we not much more complicated than worms?
Science 16 February 2001:Vol. 291. no. 5507, pp. 1255 - 1257
ViewpointGENE NUMBER:
What If There Are Only 30,000 Human Genes?Jean-Michel Claverie
•Are we really more complicated then flies and worms?
• 30,000 is much more complicated then 20,000
• Gene number isn’t everything
210,000
30,000 is much more complicated then 20,000
230,000
220,000
103000~~
Gene Number isn’t everything
mRNA
30,000 genes, but more than 85,000 mRNA species
Alternative splicingmRNA editing
Vertebrate Immune System
Gene sites
Anti body
Complexity comes from more sophisticated regulation mechanisims!
More sophisticated methods of gene expression and regulation
…
mRNA editing Proteins change their function:•Number of sugars attached•Folding/Unfolding•….
mRNA
Genetic Networks
Calverie:Every gene connected on average to 4-5 other genes
We are not much more complicated then an airplane!
But: Genetic networks follow a power law distribution
Genetic Networks
Number of connections
Average is not very meaningful!
Summary
Human Genome Project •Decoding the “part list” of humans
•Extraordinary technological advances
Complexity: Genome is just the beginning
Aim High!Dream On!
Aim High Dream On!
•Sequence more and more organisms
•Creation of Synthetic life
•Find the genes for genetic diseases
•Reconstruct the tree of life
•Learn more of nature’s tricks
• DNA nanotechnology
• Producing clean energy, depositing C02…