Introducció a la Bioinformàtica Roderic Guigó i Serra Bioinformàtica, UPF Curs

Van Leeuwenhoek In 1676 his credibility was questioned when he sent the Royal Society a copy of his first observations of microscopic single celled organisms. Heretofore, the existence of single celled organisms was entirely unknown … The Royal Society arranged to send an English vicar, as well as a team of respected jurists and doctors to Delft, Holland to determine whether it was in fact Van Leeuwenhoek's ability to observe and reason clearly (wikipedia)

ACTCAGCCCCAGCGGAGGTGAAGGACGTCCTTCCCCAGGAGCCGGTGAGAAGCGCAGTCGGGGGCACGGGGATG AGCTCAGGGGCCTCTAGAAAGATGTAGCTGGGACCTCGGGAAGCCCTGGCCTCCAGGTAGTCTCAGGAGAGCTAC TCAGGGTCGGGCTTGGGGAGAGGAGGAGCGGGGGTGAGGCCAGCAGCAGGGGACTGGACCTGGGAAGGGCTGG GCAGCAGAGACGACCCGACCCGCTAGAAGGTGGGGTGGGGAGAGCATGTGGACTAGGAGCTAAGCCACAGCAGG ACCCCCACGAGTTGTCACTGTCATTTATCGAGCACCTACTGGGTGTCCCCAGTGTCCTCAGATCTCCATAACTGGGA AGCCAGGGGCAGCGACACGGTAGCTAGCCGTCGATTGGAGAACTTTAAAATGAGGACTGAATTAGCTCATAAATGG AAAACGGCGCTTAAATGTGAGGTTAGAGCTTAGAATGTGAAGGGAGAATGAGGAATGCGAGACTGGGACTGAGATG GAACCGGCGGTGGGGAGGGGGAGGGGGTGTGGAATTTGAACCCCGGGAGAGAAAGATGGAATTTTGGCTATGGA GGCCGACCTGGGGATGGGGAAATAAGAGAAGACCAGGAGGGAGTTAAATAGGGAATGGGTTGGGGGCGGCTTGGT AACTGTTTGTGCTGGGATTAGGCTGTTGCAGATAATGGAGCAAGGCTTGGAAGGCTAACCTGGGGTGGGGCCGGGT TGGGGTCGGGCTGGGGGCGGGAGGAGTCCTCACTGGCGGTTGATTGACAGTTTCTCCTTCCCCAGACTGGCCAATC ACAGGCAGGAAGATGAAGGTTCTGTGGGCTGCGTTGCTGGTCACATTCCTGGCAGGTATGGGGCGGGGCTTGCTCG GTTTTCCCCGCTTCTCCCCCTCTCATCCTCACCTCAACCTCCTGGCCCCATTCAAGCACACCCTGGGCCCCCTCTTC TTCTGCTGGTCTGTCCCCTGAGGGGAAAGCCCAGGTCTGAGGCTTCTATGCTGCTTTCTGGCTCAGAACAGCGATTT GACGCTCTGTGAGCCTCGGTTCCTCCCCCGCTTTTTTTTTTTCAGCCAGAGTCTCACTCTGTCGCCCAGGCTGGAGT GCAGTGGCGCAATCTCAGCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCTATTCTCCCGCCTCAGCCTCCCGAGT AGCTGGGACTACAGGCGCCCGCCACCATGCCCGGCTAATTTTTTGTACTTTGAGTAGGGAAGGGGTTTCACTGTATT ATCCAGGATGGTCTCTATCTCCTGACCTCGTGATCTGCCCGCCTGGCCTCCCAAAGTGCTGGAATTACAGGCGTGAG CCTCCGCGCCCGGCCTCCCCATCCTTAATATAGGAGTTAGAAGTTTTTGTTTGTTTGTTTTGTTTTGTTTTTGTTTTGTT TTGAGATGAAGTCCCTCTGTCGCCCAGGCTGGAGTGCAGTGGCTCCCAGGCTGGAGTTCAGTGGCTGGATCTCGGC TCACTGCAAGCTCCGCCTCCCAGGTTCACGCCATTCTCCTGCCTCAGCCTCCGGAGTAGCTGGGACTACAGGAACA TGCCACCACACCCGACTAACTTTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTGGAA CTCCTGACCTCAGGTGATCTGCCTGCTTCAACCTCCCAAAGTGCTGGGATTACAGACGTGGGCCACCGCGCCCGGC TGGGAGTTAAGAGGTTTCTAATGCATTGCATTAGAATACCAGACACGGGACAGCTGTGATCTTTATTCTCCATCACCC CACACAGCCCTGCCTGGGGCACACAAGGACACTCAATACACGCTTTTCGGGCGCGGTGGCTCAAGCTGTAATCCCA GCACTTTGGGAGGCTGAGGCGGGTGGTACATGAGGTCAGGAGATCGAGACCATCCTGGCTAACATGGTGAAACCC CGTCTCTACTAAAAATACAAAAAACTAGCCCGGGCGTGGTGGCGGGCGCCTGTAGTCCCAGCTACTCGGAGGCTGA GGCAGGAGAATGGCGTGAACCTGGGAGGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGG GTGACACAGCGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATACACGCTTTTCCGCTAGGCA CGGTGGCTCACCCCTGTAATCCCAGCATTTTGGGAGGCCAAGGTGGGAGGATCACTTGAGCCCAGGAGTTCAACAC CAGACTCAGCAACATAGTGAGACTCTCTCTACTAAAAATACAAAAATTAGCCAGGCCTGGTGCCACACACCTGTGGT CCCAGCTACTCAGAAGGCTAAGGCAGGAGGATCGCTTAAGCCCAGAAGGTCAAGGTTGCAGTGAACCACGTTCAG GCCACTGCAGTCCAGCCTGGGTGACAGAGCAAGACCCTGTCTGTAAATAAATAACGCTTTTCAAGTGATTAAACAGA CTCCCCCCTCACCCTGCCCACCATGGCTCCAAAGCAGCATTTGTGGAGCACCTTCTGTGTGCCCCTAGGTACTAGCT GCCTGGACGGGGTCAGAAGGAACCTGAACCACCTTCAACTTGTTCCACACAGGATGCCAGGCCAAGGTGGAGCAA CCGGTGGAGCCAGAGACAGAACCCGACGTTCGCCAGCAGGCTGAGTGGCAGAGCGGCCAGCCCTGGGAGCTGG CACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTGCAGACACTGTCTGAGCAGGTGCAGGAGGAGCTGCTCAGCC CCCAGGTCACCCAGGAACTGACGTGAGTGTCCCCATCCCGGCCCTTGACCCTCCTGGTGGGCGGCTATACCTCCCC AGGTCCAGGTTTCATTCTGCCCCTGCCACTAAGTCTTGGGGGCCTGGGTCTCTGCTGGTTCTAGCTTCCTCTTCCCAT TTCTGACTCCTGGCTTTAGCTCTCTGGAATTCTCTCTCTCAGTTCTGTTTCTCCCTCTTCCCTTCTGACTCAGCCTGTC ACACTCGTCCTGGCGCTGTCTCTGTCCTTCACTAGCTCTTTTATATAGAGACAGAGAGATGGGGTCTCACTGTGTTGC CCAGGCTGGTCTTGAACTTCTGGGCTCAAGCGATCCTCCCACCTCGCCTCCCAAAGTGCTGGGAATAGAGACATGA GCCACCTTGCTCGGCCTCCTAGCTCTTTCTTCGTCTCTGCCTCTGCTCTCTGCGTCTGTCTTTGTCTCCTCTCTGCCTC TGTCCCGTTCCTTCTCTCTTGGTTCACTGCCCTTCTGTCTCTCCCTGTTCTCCTTAGGAGACTCTCCTCTCTTCCTTCT CGAGTCTCTCTGGCTGATCCCCATCTCACCCACACCTATCC

La matèria cromosòmica és “un cristall aperiòdic”, constituït per la successió d'un nombre petit d'elements isomèrics*, la seqüència concreta dels quals és la responsable de la seva funcionalitat. (*) “ the number of atoms in such a structure need not to be very large to produce an almost unlimited number of possible arrangements. For illustration, think of the Morse code…” La matèria cromosòmica és “un cristall aperiòdic”, constituït per la successió d'un nombre petit d'elements isomèrics*, la seqüència concreta dels quals és la responsable de la seva funcionalitat. (*) “ the number of atoms in such a structure need not to be very large to produce an almost unlimited number of possible arrangements. For illustration, think of the Morse code…” 1943: Schroëdinger, “What is life?”

ENIAC Late 40s: first digital computers

MALWTRLRPLLALLALWPPPPARAFVNQHLCGS HLVEALYLVCGERGFFYTPKARREVEGPQVGAL ELAGGPGAGGLEGPPQKRGIVEQCCASVCSLYQ LENYCN Amino acid sequence of the bovine insuline

Early 60s: the genetic code

GAGTTTTATCGCTTCCATGACGCAGAAGTTAACACTTTCGGATATTTCTGATGAGT CGAAAAATTATCTTGATAAAGCAGGAATTACTACTGCTTGTTTACGAATTAAATCG AAGTGGACTGCTGGCGGAAAATGAGAAAATTCGACCTATCCTTGCGCAGCTCGA GAAGCTCTTACTTTGCGACCTTTCGCCATCAACTAACGATTCTGTCAAAAACTGA CGCGTTGGATGAGGAGAAGTGGCTTAATATGCTTGGCACGTTCGTCAAGGACTG GTTTAGATATGAGTCACATTTTGTTCATGGTAGAGATTCTCTTGT MALWTRLRPLLALLALWPPPPARAFVNQHLCGSHLVEALYLVCGERGFFY TPKARREVEGPQVGALELAGGPGAGGLEGPPQKRGIVEQCCASVCSLYQ LENYCN

1957: invention of the programming language FORTRAN

Computers become smaller and therefore faster and cheaper During the 60s computers are introduced into bancs, financial institutions, universities and research centers 60s: Transistors and integrated circuits

Sequence alignment and comparison

substitution matrices

Sequence alignment The substitution matrices provided a model under which the concept of optimal alignment could be formalized, and computed. The optimal alignment between two sequences is the alignment that maximizes the sum of the amino acid substitution values at each aligned position. A R N D C Q A R N D C Q S K - E A E - S K E A E = =3

The total number of possible alignments between two sequences of length 100 is approximately With DP the number of operations required to obtain the optimal alignment is aproximately 3x100 2 Query: 25 IPREVIERLARSQIHSIRDLQRLLEIDSVGSEDSLDTSLRAHGVHATKHVPEKRPLPIRR 84 IP E+ + L+ I S DLQRLL+ DS G ED + L H+ + R Sbjct: 10 IPEELYKMLSGHSIRSFDDLQRLLQGDS-GKEDGAELDLNMTRSHSGGELESLA----RG 64 Query: 85 KRSI------EEAVPAVCKTRTVIYEIPRSQVDPTSANFLIWPPCVEVKRCTGCCNTSSV 138 KRS+ E A+ A CKTRT ++EI R +D T+ANFL+WPPCVEV+RC+GCCN +V Sbjct: 65 KRSLGSLSVAEPAMIAECKTRTEVFEISRRLIDRTNANFLVWPPCVEVQRCSGCCNNRNV 124 Query: 139 KCQPSRVHHRSVKVAKVEYVRKKPKLKEVQVRLEEHLECAC 179 +C+P++V R V+V K+E VRKKP K+ V LE+HL C C Sbjct: 125 QCRPTQVQLRPVQVRKIEIVRKKPIFKKATVTLEDHLACKC 165 DYNAMIC PROGRAMMING, Nedleman and Wunsch, 1970 Smith and Waterman, ’s: Optimal sequence alignment

mid70’s: DNA sequencing, Sanger. Maxam and Gilbert By the end of the sixties, hundreds of proteins had been sequenced, but the sequencing on nucleic acids remained elusive Sanger (Cambridge) Maxam and Gilbert (Harvard)

Anys 70: Internet. Advanced Research Projects Agency

gagttttatcgcttccatgacgcagaagttaacactttcggatatttctgatgagtcgaaaaattatcttgataaagcaggaattactactgcttgtttacgaattaaat cgaagtggactgctggcggaaaatgagaaaattcgacctatccttgcgcagctcgagaagctcttactttgcgacctttcgccatcaactaacgattctgtcaaaaactg acgcgttggatgaggagaagtggcttaatatgcttggcacgttcgtcaaggactggtttagatatgagtcacattttgttcatggtagagattctcttgttgacatttta aaagagcgtggattactatctgagtccgatgctgttcaaccactaataggtaagaaatcatgagtcaagttactgaacaatccgtacgtttccagaccgctttggcctct attaagctcattcaggcttctgccgttttggatttaaccgaagatgatttcgattttctgacgagtaacaaagtttggattgctactgaccgctctcgtgctcgtcgctg cgttgaggcttgcgtttatggtacgctggactttgtgggataccctcgctttcctgctcctgttgagtttattgctgccgtcattgcttattatgttcatcccgtcaaca ttcaaacggcctgtctcatcatggaaggcgctgaatttacggaaaacattattaatggcgtcgagcgtccggttaaagccgctgaattgttcgcgtttaccttgcgtgta cgcgcaggaaacactgacgttcttactgacgcagaagaaaacgtgcgtcaaaaattacgtgcggaaggagtgatgtaatgtctaaaggtaaaaaacgttctggcgctcgc cctggtcgtccgcagccgttgcgaggtactaaaggcaagcgtaaaggcgctcgtctttggtatgtaggtggtcaacaattttaattgcaggggcttcggccccttacttg aggataaattatgtctaatattcaaactggcgccgagcgtatgccgcatgacctttcccatcttggcttccttgctggtcagattggtcgtcttattaccatttcaacta ctccggttatcgctggcgactccttcgagatggacgccgttggcgctctccgtctttctccattgcgtcgtggccttgctattgactctactgtagacatttttactttt tatgtccctcatcgtcacgtttatggtgaacagtggattaagttcatgaaggatggtgttaatgccactcctctcccgactgttaacactactggttatattgaccatgc cgcttttcttggcacgattaaccctgataccaataaaatccctaagcatttgtttcagggttatttgaatatctataacaactattttaaagcgccgtggatgcctgacc gtaccgaggctaaccctaatgagcttaatcaagatgatgctcgttatggtttccgttgctgccatctcaaaaacatttggactgctccgcttcctcctgagactgagctt tctcgccaaatgacgacttctaccacatctattgacattatgggtctgcaagctgcttatgctaatttgcatactgaccaagaacgtgattacttcatgcagcgttacca tgatgttatttcttcatttggaggtaaaacctcttatgacgctgacaaccgtcctttacttgtcatgcgctctaatctctgggcatctggctatgatgttgatggaactg accaaacgtcgttaggccagttttctggtcgtgttcaacagacctataaacattctgtgccgcgtttctttgttcctgagcatggcactatgtttactcttgcgcttgtt cgttttccgcctactgcgactaaagagattcagtaccttaacgctaaaggtgctttgacttataccgatattgctggcgaccctgttttgtatggcaacttgccgccgcg tgaaatttctatgaaggatgttttccgttctggtgattcgtctaagaagtttaagattgctgagggtcagtggtatcgttatgcgccttcgtatgtttctcctgcttatc accttcttgaaggcttcccattcattcaggaaccgccttctggtgatttgcaagaacgcgtacttattcgccaccatgattatgaccagtgtttccagtccgttcagttg ttgcagtggaatagtcaggttaaatttaatgtgaccgtttatcgcaatctgccgaccactcgcgattcaatcatgacttcgtgataaaagattgagtgtgaggttataac gccgaagcggtaaaaattttaatttttgccgctgaggggttgaccaagcgaagcgcggtaggttttctgcttaggagtttaatcatgtttcagacttttatttctcgcca taattcaaactttttttctgataagctggttctcacttctgttactccagcttcttcggcacctgttttacagacacctaaagctacatcgtcaacgttatattttgata gtttgacggttaatgctggtaatggtggttttcttcattgcattcagatggatacatctgtcaacgccgctaatcaggttgtttctgttggtgctgatattgcttttgat gccgaccctaaattttttgcctgtttggttcgctttgagtcttcttcggttccgactaccctcccgactgcctatgatgtttatcctttgaatggtcgccatgatggtgg ttattataccgtcaaggactgtgtgactattgacgtccttccccgtacgccgggcaataacgtttatgttggtttcatggtttggtctaactttaccgctactaaatgcc gcggattggtttcgctgaatcaggttattaaagagattatttgtctccagccacttaagtgaggtgatttatgtttggtgctattgctggcggtattgcttctgctcttg ctggtggcgccatgtctaaattgtttggaggcggtcaaaaagccgcctccggtggcattcaaggtgatgtgcttgctaccgataacaatactgtaggcatgggtgatgct ggtattaaatctgccattcaaggctctaatgttcctaaccctgatgaggccgcccctagttttgtttctggtgctatggctaaagctggtaaaggacttcttgaaggtac gttgcaggctggcacttctgccgtttctgataagttgcttgatttggttggacttggtggcaagtctgccgctgataaaggaaaggatactcgtgattatcttgctgctg catttcctgagcttaatgcttgggagcgtgctggtgctgatgcttcctctgctggtatggttgacgccggatttgagaatcaaaaagagcttactaaaatgcaactggac aatcagaaagagattgccgagatgcaaaatgagactcaaaaagagattgctggcattcagtcggcgacttcacgccagaatacgaaagaccaggtatatgcacaaaatga gatgcttgcttatcaacagaaggagtctactgctcgcgttgcgtctattatggaaaacaccaatcttcccaagcaacagcaggtttccgagattatgcgccaaatgctta ctcaagctcaaacggctggtcagtattttaccaatgaccaaatcaaagaaatgactcgcaaggttagtgctgaggttgacttagttcatcagcaaacgcagaatcagcgg tatggctcttctcatattggcgctactgcaaaggatatttctaatgtcgtcactgatgctgcttctggtgtggttgatatttttcatggtattgataaagctgttgccga tacttggaacaatttctggaaagacggtaaagctgatggtattggctctaatttgtctaggaaataaccgtcaggattgacaccctcccaattgtatgttttcatgcctc caaatcttggaggcttttttatggttcgttcttattacccttctgaatgtcacgctgattattttgactttgag 1977:  X174 virus genome

1982: the first electronic databases

FASTA, 1982: Wilbur and Lipman, 1985: Lipman and Pearson BLAST, 1990: Altschul, Gish, Miller, Myers and Lipman accelerating database searches hash methods WATSNANDCRICK ACDIKNRSTW Query Sequence Hash table K=1

Search of the Platelet Derived Growth Factor sequence 1982, Doolittle: relationship between oncogenes and growth factors

1990:The human genome project THE HUMAN GENOME PROGRAM (HGP) is producing large quantities of complex map and DNA sequence data. Informatics projects in algorithms, software, and databases are crucial in accumulating and interpreting these data in a robust and automated fashion at genome and sequencing centers Computer systems play essential roles in all aspects of genome research, from data acquisition and analysis to data management. Without powerful computers and appropriately designed data–management systems, high– volume genome research cannot proceed.

This proposal concerns the management of general information about accelerators and experiments at CERN. It discusses the problems of loss of information about complex evolving systems and derives a solution based on a distributed hypertext system (Tim Berners-Lee) 1990:WWW at CERN

Human Genome Project Milestones

2001: la culminació del projecte

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Bioinformatics, Genomics, Systems Biology in Medline

What is past, is a prologue W. Shakespeare, La Tempestad,

mid70’s: DNA sequencing, Sanger. Maxam and Gilbert By the end of the sixties, hundreds of proteins had been sequenced, but the sequencing on nucleic acids remained elusive Sanger (Cambridge) Maxam and Gilbert (Harvard)

ABI PRISM 3700 DNA Analyzer

2008: Major genome centers can sequence the same number of base pairs every 4 days 1000 Genome project launched World-wide capacity dramatically increasing Further Evolution of Large-scale Genome Sequencing 2000: Human genome working drafts Data unit of approximately 10x coverage of human –10 years and cost about $3 billion 2009: Every 4 hours ($25,000) 2010: Every 14 minutes ($5,000) Illumina HiSeq2000 machine produces 200 gigabases per 8 day run (BGI have ordered have 128) Slide from Paul Flicek. EBI Bioinformatics Advisory Council

ENIAC, 1950s 2.4 x 0.9 x 30 (m)  385 operations/second operations/second/cm 3

ENIAC, 1950s 2.4 x 0.9 x 30 (m)  385 operations/second operations/second/cm 3 MAC AIR, 2010s ~1 x 32.5 x 22.7 (cm)  133,656,056 operations/second operations/second/cm 3

CELERA GENOMICS, year ,000 m 2. 2 yr.  3GB at 10x 5x10 -6 Gb/day/m 3

CELERA GENOMICS, year ,000 m 2. 2 yr.  3GB at 10x 5x10 -6 Gb/day/m 3 HISEQ year x 94 x 76 (cm). 1 day  120 Gb 10 2 Gb/day/m 3

Moore’s Law