Bioinformatics: Data-driven molecular biology Mikhail Gelfand A.A.Kharkevich Institute for Information Transmission Problems, RAS Moscow II Испано-российский форум по информационным и коммуникационным технологиям Madrid, / IX / 2009

Exponential increase of data volume red – papers (PubMed) blue – sequence fragments (GenBank) green – nucleorides (GenBank) of 18 million papers in PubMed, ~675 thousand have keywords “bioinformat* OR comput*”

622 complete genomes (bacteria)

>45 thousand Google hits on “genome deciphered” Top 10 hits: bioremediation –bacterium Pseudomonas agriculture and biotech –crop and biofuel plant Sorghum –rice medicine –pathogenic bacterium Staphylococcus –SARS (atypical pneumonia) virus –Brugia worm (elephantiasis) individual genome (medicine) –James Watson science / model organism –macaque science / evolution –mammoth (mitochondrial) –platypus

Sequencing is just the beginning Bacterial genome: several million nucleotides 600 through 9,000 genes (~ 90% of a genome codes for proteins) This slide: 0,1% of the Escherichia coli genome Human genome: 3 billion nucleotides, thousand genes polymorphisms (individual differences): ~ 1 for 1000 nucleotides differences between human and chimpanzee: ~ 1 of 100

Not just genomes Other types of large-scale experiments / datasets: State of the genome (gene expression) –methylation –nucleosome positioning –histone modifications Transcriptomics, protein abundance (gene expression) Protein-protein interactions –signaling etc. –functional complexes Protein-DNA interactions (regulation) etc.

Goals Functional annotation of genes and proteins –biological function –regulation (in what conditions) Functional annotation of genomes –metabolic reconstruction and modeling –regulatory networks and development –prediction of organism properties from its genome

Applications: biotechnology Improvement of production strains (chemistry, pharma, food industry) –via modeling of metabolic pathways New enzymes (new functions, stress tolerance) –via sequencing and functional annotation Biofuels –fast-growing, stress-tolerant plants; identification of genes –microbes as producers of ethanol or fatty acids: targeted genome design

Applications: medicine and pharma Personalized medicine –identification of predisposing alleles: lifestyle –pharmacogenomics (metabolic alleles) –diagnostics Drug targets (chronic disease) –analysis of signaling pathways Anti-infectives –identification of drug targets Drug design; identification of drug candidates –modeling of protein structure and interactions of proteins with small molecules

Methods. Integration of data Systems biology: Integration of diverse datasets for one organism Comparative genomics: Simultaneous analysis of genomic data for many organisms Comparative systems biology: understanding the evolution of gene regulation and expression, signaling etc. Comparative structural biology

Bioinformatics in Russia Few high-throughput experiments –Open data –Collaborations –Theory (evolution), methods, algorithms Highlights: –Evolution (IITP RAS) and taxonomy (IPCB MSU) –Regulation (FBB MSU, GosNIIGenetika, IITP RAS, ICaG SB RAS) –Annotation (FBB MSU, IITP RAS) –Protein Structure (IPR RAS, IMB RAS, IPCB MSU, BF MSU) –Modeling Metabolism (IPCB MSU, ICaG SB RAS) Regulation (SpBSPU, ICaG SB RAS) –Drug design (IBMC RAMS)

Research and Training Center “Bioinformatics”, Institute of Information Transmission Problems (5 years: ) Molecular evolution –Alternative splicing as a driver of evolution in eukaryotes –Positive selection Comparative genomics of regulation in bacteria –Evolution of regulatory pathways –Protein-DNA interactions Annotation –Gene recognition –Functional annotation –Regulation

Comparative genomics in action: confirmed predictions Regulatory mechanisms –riboswitches (riboflavin – vitamin B1, thiamin – vitamin B2) –antisense regulation of the methionine-cysteine pathway –role of the ribosome in zinc homeostasis Regulators: NrdR, MtaR/MetR, CmbR, NiaR Enzymes: FadE, ThiN, TenA, CobZ, CobX/CbiZ, PduX, NagP, NagB-II Microcins (capistruin, Burkholderia thailandensis) Transporters –АВС-transporters with universal energizing components: Co, Ni, biotin (vitamin H), thiamin (vitamin B2), riboflavin (vitamin B1) –other: threonin, methionin, oligogalacturonides, N-acetylglucosamin, corrinoids, nyacin, riboflacin, Co Regulatory motifs: nitrogen-fixation, fatty acid biosynthesis, iron homeostasis, catabolism of chitin and pectin Regulatory sites: several dozens

Functional annotation of genomes First Russian bacterial genome, Acholeplasma laidlawii (2008): sequencing and proteomics: Institute of Physico-Chemical Medicine; annotation: IITP: ~1,5 Mb; ~1400 genes. Established function for ~80% genes; metabolic reconstruction

Publications (refereed)

Collaborations European Laboratory of Molecular Biology * Germany –Humboldt University, Berlin –Munich Technical University France –Lyon University United Kingdom –University of East Anglia Spain –Center for Genome Regulation (Barcelona) USA –MIT –Burnham Institute * –Lawrence Berkeley National Laboratory * –Stowers Institute * –Rutgers University China –China-Germany Partner Institute of Molecular Genetics (Shanghai) Industry –Biomax (Germany) –Interated Genomics (USA) Bold: on-going * Former students