Kolmogorov: Complexity of an object is the shortest length of a computer program that creates the object The Human Genome, and Human Complexity Yoni Toker

Viewpoint GENE 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 no. 5507, pp

Mapping of the Human genome 1953 Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA. Mid 1980’s Human 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 genome 1953 Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA. Mid 1980’s Human Genome Project Suggested 1990 Human Genome project announced: Goal: sequence the entire human genome in 15 years, with a budget of $3 billion Comparison: LHC budget ~5 billion Aircraft carrier ~10 billion

Mapping of the Human genome 1953 Rosalind Franklin, James Watson and Francis Crick discover the double helical structure of DNA. Mid 1980’s Human Genome Project Suggested 1990 Human Genome project announced: Goal: sequence the entire human genome in 15 years, with a budget of $3 billion 1998 Only 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 ACGTA C T primerAC G T A A 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 DNA ACGTAprimerACACGTA ACACGTA ACACGTA ACACGTA ACACGTA AC T G TG C TGCAT T TG C TGC T T

T G TG C TGCAT T TG C TGC T T Sequencing small pieces of DNA

Sequencing Large DNAs The whole shotgun method

Fierce competition..Comes to a draw June 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! 1e+5

A DMT A 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

AA C A A C A A Oligonucleotide Synthesis 1) De-Blocking C DMT C C C 2) Base Condensation

AA C A A C A A Oligonucleotide Synthesis 1) De-Blocking C DMT 2) Base Condensation 3) Capping 4) Oxidation

AA C A A C A A Oligonucleotide Synthesis 1) De-Blocking C DMT 2) Base Condensation 3) Capping 4) Oxidation A DMT A

DNA Synthesis

Genetic Code 4 base pairs 20 amino acids Example: CCGProline 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 genes Human 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 pairs6, 275 Worm (Caenorhabditis elegans)97 e+6 base pairs19,000 E. coli 4.1 e+6 base pairs4,800 Arabidopsis (Arabidopsis thaliana)125 e+6 base pairs25,000 Genome Size

Viewpoint GENE 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 no. 5507, pp

Viewpoint GENE 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

2 10,000 30,000 is much more complicated then 20, , , ~ ~

Gene Number isn’t everything mRNA 30,000 genes, but more than 85,000 mRNA species Alternative splicing mRNA 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 C0 2 …