introducci ó a la bioinformàtica roderic guigó i serra roderic.guigo@crgt

Introducció a la BioinformàticaRoderic Guigó i [email protected]

Bioinformàtica, UPF Curs 2012-2013

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)

ACTCAGCCCCAGCGGAGGTGAAGGACGTCCTTCCCCAGGAGCCGGTGAGAAGCGCAGTCGGGGGCACGGGGATGAGCTCAGGGGCCTCTAGAAAGATGTAGCTGGGACCTCGGGAAGCCCTGGCCTCCAGGTAGTCTCAGGAGAGCTACTCAGGGTCGGGCTTGGGGAGAGGAGGAGCGGGGGTGAGGCCAGCAGCAGGGGACTGGACCTGGGAAGGGCTGGGCAGCAGAGACGACCCGACCCGCTAGAAGGTGGGGTGGGGAGAGCATGTGGACTAGGAGCTAAGCCACAGCAGGACCCCCACGAGTTGTCACTGTCATTTATCGAGCACCTACTGGGTGTCCCCAGTGTCCTCAGATCTCCATAACTGGGAAGCCAGGGGCAGCGACACGGTAGCTAGCCGTCGATTGGAGAACTTTAAAATGAGGACTGAATTAGCTCATAAATGGAAAACGGCGCTTAAATGTGAGGTTAGAGCTTAGAATGTGAAGGGAGAATGAGGAATGCGAGACTGGGACTGAGATGGAACCGGCGGTGGGGAGGGGGAGGGGGTGTGGAATTTGAACCCCGGGAGAGAAAGATGGAATTTTGGCTATGGAGGCCGACCTGGGGATGGGGAAATAAGAGAAGACCAGGAGGGAGTTAAATAGGGAATGGGTTGGGGGCGGCTTGGTAACTGTTTGTGCTGGGATTAGGCTGTTGCAGATAATGGAGCAAGGCTTGGAAGGCTAACCTGGGGTGGGGCCGGGTTGGGGTCGGGCTGGGGGCGGGAGGAGTCCTCACTGGCGGTTGATTGACAGTTTCTCCTTCCCCAGACTGGCCAATCACAGGCAGGAAGATGAAGGTTCTGTGGGCTGCGTTGCTGGTCACATTCCTGGCAGGTATGGGGCGGGGCTTGCTCGGTTTTCCCCGCTTCTCCCCCTCTCATCCTCACCTCAACCTCCTGGCCCCATTCAAGCACACCCTGGGCCCCCTCTTCTTCTGCTGGTCTGTCCCCTGAGGGGAAAGCCCAGGTCTGAGGCTTCTATGCTGCTTTCTGGCTCAGAACAGCGATTTGACGCTCTGTGAGCCTCGGTTCCTCCCCCGCTTTTTTTTTTTCAGCCAGAGTCTCACTCTGTCGCCCAGGCTGGAGTGCAGTGGCGCAATCTCAGCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCTATTCTCCCGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCCGCCACCATGCCCGGCTAATTTTTTGTACTTTGAGTAGGGAAGGGGTTTCACTGTATTATCCAGGATGGTCTCTATCTCCTGACCTCGTGATCTGCCCGCCTGGCCTCCCAAAGTGCTGGAATTACAGGCGTGAGCCTCCGCGCCCGGCCTCCCCATCCTTAATATAGGAGTTAGAAGTTTTTGTTTGTTTGTTTTGTTTTGTTTTTGTTTTGTTTTGAGATGAAGTCCCTCTGTCGCCCAGGCTGGAGTGCAGTGGCTCCCAGGCTGGAGTTCAGTGGCTGGATCTCGGCTCACTGCAAGCTCCGCCTCCCAGGTTCACGCCATTCTCCTGCCTCAGCCTCCGGAGTAGCTGGGACTACAGGAACATGCCACCACACCCGACTAACTTTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTGGAACTCCTGACCTCAGGTGATCTGCCTGCTTCAACCTCCCAAAGTGCTGGGATTACAGACGTGGGCCACCGCGCCCGGCTGGGAGTTAAGAGGTTTCTAATGCATTGCATTAGAATACCAGACACGGGACAGCTGTGATCTTTATTCTCCATCACCCCACACAGCCCTGCCTGGGGCACACAAGGACACTCAATACACGCTTTTCGGGCGCGGTGGCTCAAGCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGTGGTACATGAGGTCAGGAGATCGAGACCATCCTGGCTAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAAACTAGCCCGGGCGTGGTGGCGGGCGCCTGTAGTCCCAGCTACTCGGAGGCTGAGGCAGGAGAATGGCGTGAACCTGGGAGGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGGGTGACACAGCGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATACACGCTTTTCCGCTAGGCACGGTGGCTCACCCCTGTAATCCCAGCATTTTGGGAGGCCAAGGTGGGAGGATCACTTGAGCCCAGGAGTTCAACACCAGACTCAGCAACATAGTGAGACTCTCTCTACTAAAAATACAAAAATTAGCCAGGCCTGGTGCCACACACCTGTGGTCCCAGCTACTCAGAAGGCTAAGGCAGGAGGATCGCTTAAGCCCAGAAGGTCAAGGTTGCAGTGAACCACGTTCAGGCCACTGCAGTCCAGCCTGGGTGACAGAGCAAGACCCTGTCTGTAAATAAATAACGCTTTTCAAGTGATTAAACAGACTCCCCCCTCACCCTGCCCACCATGGCTCCAAAGCAGCATTTGTGGAGCACCTTCTGTGTGCCCCTAGGTACTAGCTGCCTGGACGGGGTCAGAAGGAACCTGAACCACCTTCAACTTGTTCCACACAGGATGCCAGGCCAAGGTGGAGCAACCGGTGGAGCCAGAGACAGAACCCGACGTTCGCCAGCAGGCTGAGTGGCAGAGCGGCCAGCCCTGGGAGCTGGCACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTGCAGACACTGTCTGAGCAGGTGCAGGAGGAGCTGCTCAGCCCCCAGGTCACCCAGGAACTGACGTGAGTGTCCCCATCCCGGCCCTTGACCCTCCTGGTGGGCGGCTATACCTCCCCAGGTCCAGGTTTCATTCTGCCCCTGCCACTAAGTCTTGGGGGCCTGGGTCTCTGCTGGTTCTAGCTTCCTCTTCCCATTTCTGACTCCTGGCTTTAGCTCTCTGGAATTCTCTCTCTCAGTTCTGTTTCTCCCTCTTCCCTTCTGACTCAGCCTGTCACACTCGTCCTGGCGCTGTCTCTGTCCTTCACTAGCTCTTTTATATAGAGACAGAGAGATGGGGTCTCACTGTGTTGCCCAGGCTGGTCTTGAACTTCTGGGCTCAAGCGATCCTCCCACCTCGCCTCCCAAAGTGCTGGGAATAGAGACATGAGCCACCTTGCTCGGCCTCCTAGCTCTTTCTTCGTCTCTGCCTCTGCTCTCTGCGTCTGTCTTTGTCTCCTCTCTGCCTCTGTCCCGTTCCTTCTCTCTTGGTTCACTGCCCTTCTGTCTCTCCCTGTTCTCCTTAGGAGACTCTCCTCTCTTCCTTCTCGAGTCTCTCTGGCTGATCCCCATCTCACCCACACCTATCC

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

MALWTRLRPLLALLALWPPPPARAFVNQHLCGSHLVEALYLVCGERGFFYTPKARREVEGPQVGALELAGGPGAGGLEGPPQKRGIVEQCCASVCSLYQLENYCN

Amino acid sequence of the bovine insuline

http://www.ict-science-to-society.org/

Early 60s: the genetic code

GAGTTTTATCGCTTCCATGACGCAGAAGTTAACACTTTCGGATATTTCTGATGAGTCGAAAAATTATCTTGATAAAGCAGGAATTACTACTGCTTGTTTACGAATTAAATCGAAGTGGACTGCTGGCGGAAAATGAGAAAATTCGACCTATCCTTGCGCAGCTCGAGAAGCTCTTACTTTGCGACCTTTCGCCATCAACTAACGATTCTGTCAAAAACTGACGCGTTGGATGAGGAGAAGTGGCTTAATATGCTTGGCACGTTCGTCAAGGACTGGTTTAGATATGAGTCACATTTTGTTCATGGTAGAGATTCTCTTGT

MALWTRLRPLLALLALWPPPPARAFVNQHLCGSHLVEALYLVCGERGFFYTPKARREVEGPQVGALELAGGPGAGGLEGPPQKRGIVEQCCASVCSLYQLENYCN

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 +1+3-1+3-2+2=6 -1+0+1+3-2+2=3

The total number of possible alignments between two sequences of length 100 is approximately 10200.

With DP the number of operations required to obtain the optimal alignment is aproximately 3x1002

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 +VSbjct: 65 KRSLGSLSVAEPAMIAECKTRTEVFEISRRLIDRTNANFLVWPPCVEVQRCSGCCNNRNV 124

Query: 139 KCQPSRVHHRSVKVAKVEYVRKKPKLKEVQVRLEEHLECAC 179 +C+P++V R V+V K+E VRKKP K+ V LE+HL C CSbjct: 125 QCRPTQVQLRPVQVRKIEIVRKKPIFKKATVTLEDHLACKC 165

DYNAMIC PROGRAMMING,Nedleman and Wunsch, 1970Smith and Waterman, 1981

70’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

gagttttatcgcttccatgacgcagaagttaacactttcggatatttctgatgagtcgaaaaattatcttgataaagcaggaattactactgcttgtttacgaattaaatcgaagtggactgctggcggaaaatgagaaaattcgacctatccttgcgcagctcgagaagctcttactttgcgacctttcgccatcaactaacgattctgtcaaaaactgacgcgttggatgaggagaagtggcttaatatgcttggcacgttcgtcaaggactggtttagatatgagtcacattttgttcatggtagagattctcttgttgacattttaaaagagcgtggattactatctgagtccgatgctgttcaaccactaataggtaagaaatcatgagtcaagttactgaacaatccgtacgtttccagaccgctttggcctctattaagctcattcaggcttctgccgttttggatttaaccgaagatgatttcgattttctgacgagtaacaaagtttggattgctactgaccgctctcgtgctcgtcgctgcgttgaggcttgcgtttatggtacgctggactttgtgggataccctcgctttcctgctcctgttgagtttattgctgccgtcattgcttattatgttcatcccgtcaacattcaaacggcctgtctcatcatggaaggcgctgaatttacggaaaacattattaatggcgtcgagcgtccggttaaagccgctgaattgttcgcgtttaccttgcgtgtacgcgcaggaaacactgacgttcttactgacgcagaagaaaacgtgcgtcaaaaattacgtgcggaaggagtgatgtaatgtctaaaggtaaaaaacgttctggcgctcgccctggtcgtccgcagccgttgcgaggtactaaaggcaagcgtaaaggcgctcgtctttggtatgtaggtggtcaacaattttaattgcaggggcttcggccccttacttgaggataaattatgtctaatattcaaactggcgccgagcgtatgccgcatgacctttcccatcttggcttccttgctggtcagattggtcgtcttattaccatttcaactactccggttatcgctggcgactccttcgagatggacgccgttggcgctctccgtctttctccattgcgtcgtggccttgctattgactctactgtagacatttttactttttatgtccctcatcgtcacgtttatggtgaacagtggattaagttcatgaaggatggtgttaatgccactcctctcccgactgttaacactactggttatattgaccatgccgcttttcttggcacgattaaccctgataccaataaaatccctaagcatttgtttcagggttatttgaatatctataacaactattttaaagcgccgtggatgcctgaccgtaccgaggctaaccctaatgagcttaatcaagatgatgctcgttatggtttccgttgctgccatctcaaaaacatttggactgctccgcttcctcctgagactgagctttctcgccaaatgacgacttctaccacatctattgacattatgggtctgcaagctgcttatgctaatttgcatactgaccaagaacgtgattacttcatgcagcgttaccatgatgttatttcttcatttggaggtaaaacctcttatgacgctgacaaccgtcctttacttgtcatgcgctctaatctctgggcatctggctatgatgttgatggaactgaccaaacgtcgttaggccagttttctggtcgtgttcaacagacctataaacattctgtgccgcgtttctttgttcctgagcatggcactatgtttactcttgcgcttgttcgttttccgcctactgcgactaaagagattcagtaccttaacgctaaaggtgctttgacttataccgatattgctggcgaccctgttttgtatggcaacttgccgccgcgtgaaatttctatgaaggatgttttccgttctggtgattcgtctaagaagtttaagattgctgagggtcagtggtatcgttatgcgccttcgtatgtttctcctgcttatcaccttcttgaaggcttcccattcattcaggaaccgccttctggtgatttgcaagaacgcgtacttattcgccaccatgattatgaccagtgtttccagtccgttcagttgttgcagtggaatagtcaggttaaatttaatgtgaccgtttatcgcaatctgccgaccactcgcgattcaatcatgacttcgtgataaaagattgagtgtgaggttataacgccgaagcggtaaaaattttaatttttgccgctgaggggttgaccaagcgaagcgcggtaggttttctgcttaggagtttaatcatgtttcagacttttatttctcgccataattcaaactttttttctgataagctggttctcacttctgttactccagcttcttcggcacctgttttacagacacctaaagctacatcgtcaacgttatattttgatagtttgacggttaatgctggtaatggtggttttcttcattgcattcagatggatacatctgtcaacgccgctaatcaggttgtttctgttggtgctgatattgcttttgatgccgaccctaaattttttgcctgtttggttcgctttgagtcttcttcggttccgactaccctcccgactgcctatgatgtttatcctttgaatggtcgccatgatggtggttattataccgtcaaggactgtgtgactattgacgtccttccccgtacgccgggcaataacgtttatgttggtttcatggtttggtctaactttaccgctactaaatgccgcggattggtttcgctgaatcaggttattaaagagattatttgtctccagccacttaagtgaggtgatttatgtttggtgctattgctggcggtattgcttctgctcttgctggtggcgccatgtctaaattgtttggaggcggtcaaaaagccgcctccggtggcattcaaggtgatgtgcttgctaccgataacaatactgtaggcatgggtgatgctggtattaaatctgccattcaaggctctaatgttcctaaccctgatgaggccgcccctagttttgtttctggtgctatggctaaagctggtaaaggacttcttgaaggtacgttgcaggctggcacttctgccgtttctgataagttgcttgatttggttggacttggtggcaagtctgccgctgataaaggaaaggatactcgtgattatcttgctgctgcatttcctgagcttaatgcttgggagcgtgctggtgctgatgcttcctctgctggtatggttgacgccggatttgagaatcaaaaagagcttactaaaatgcaactggacaatcagaaagagattgccgagatgcaaaatgagactcaaaaagagattgctggcattcagtcggcgacttcacgccagaatacgaaagaccaggtatatgcacaaaatgagatgcttgcttatcaacagaaggagtctactgctcgcgttgcgtctattatggaaaacaccaatcttcccaagcaacagcaggtttccgagattatgcgccaaatgcttactcaagctcaaacggctggtcagtattttaccaatgaccaaatcaaagaaatgactcgcaaggttagtgctgaggttgacttagttcatcagcaaacgcagaatcagcggtatggctcttctcatattggcgctactgcaaaggatatttctaatgtcgtcactgatgctgcttctggtgtggttgatatttttcatggtattgataaagctgttgccgatacttggaacaatttctggaaagacggtaaagctgatggtattggctctaatttgtctaggaaataaccgtcaggattgacaccctcccaattgtatgttttcatgcctccaaatcttggaggcttttttatggttcgttcttattacccttctgaatgtcacgctgattattttgactttgag

1977: X174 virus genome

1982: the first electronic databases

FASTA, 1982: Wilbur and Lipman, 1985: Lipman and PearsonBLAST, 1990: Altschul, Gish, Miller, Myers and Lipman

accelerating database searches hash methods

1 2 3 4 5 6 7 8 9 10 11 12 13

W A T S N A N D C R I C K

A C D I K N R S T W26

912

8 11

13

57

10 4 3 1

Query Sequence

Hash table K=1

http://www.ccl.rutgers.edu/~ouyang/5020/FASTA-BLAST.ppt

http://www.ccl.rutgers.edu/~ouyang/5020/FASTA-BLAST.ppt

Search of the Platelet Derived Growth Factor sequence

1982, Doolittle: relationship between oncogenes and growth factors

1990:The human genome projectTHE 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

bioinformatics

Medline articles with keyword Bioinformatics.

year # articlesTo 1990 0

bioinformatics



1990-1994 15

bioinformatics



1990-1994 151995-1999 823

bioinformatics



1990-1994 151995-1999 8232000-2004 7827

bioinformatics



1990-1994 151995-1999 8232000-2004 78272005-2008 18822

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, 1950s2.4 x 0.9 x 30 (m) 385 operations/second. 10-6 operations/second/cm3

ENIAC, 1950s2.4 x 0.9 x 30 (m) 385 operations/second. 10-6 operations/second/cm3

MAC AIR, 2010s~1 x 32.5 x 22.7 (cm) 133,656,056 operations/second. 105 operations/second/cm3

CELERA GENOMICS, year 20001,000 m2. 2 yr. 3GB at 10x5x10-6 Gb/day/m3

CELERA GENOMICS, year 20001,000 m2. 2 yr. 3GB at 10x5x10-6 Gb/day/m3

HISEQ 2500. year 2012119 x 94 x 76 (cm). 1 day 120 Gb102 Gb/day/m3

Moore’s Law

introducci ó a la bioinformàtica roderic guigó i serra roderic.guigo@crgt

Documents

royal society

fact van leeuwenhoeks

upf curs

team of respected jurists

bioinformticaroderic

english vicar