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Michael Schroeder
Biotechnology Center TU Dresden
DNA – the molecule of life
http://www.ornl.gov/hgmis
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Introduction Applied Bioinformatics Michael Schroeder - - PowerPoint PPT Presentation
Introduction Applied Bioinformatics Michael Schroeder - - PowerPoint PPT Presentation
Introduction Applied Bioinformatics Michael Schroeder Biotechnology Center TU Dresden DNA the molecule of life http://www.ornl.gov/hgmis 2 High-throughput Technology 1950s: 2000s: 2010s: Watson and Crick Sanger Center BGI,
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1950s: Watson and Crick
High-throughput Technology
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2000s: Sanger Center
Cambridge
2010s: BGI,
Beijing
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Drug Discovery
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10 20 30 40 50 60 70 80 60 65 70 75 80 85 90 95 Year New drugs per year 5 10 15 20
New Drugs R&D spendings
10 20 30 40 50 60 70 80 60 65 70 75 80 85 90 95 Year New drugs per year 5 10 15 20
New Drugs R&D spendings
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Genetic Code
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Actinidin and Papain
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50% sequence ID, same structure
Cystein proteases in kiwi and papaya, respectively Tenderises meat and breaks down casein (milk)
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11% sequence ID, same structure
Hemoglobin and Leghemoglobin
7 Oxygen transport in red blood cells and legumes, respectively
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Sequence-Structure Relation
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Similar sequences hint for…
§ common ancestry and § possibly similar function
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Similar sequence, similar function?
§ Monkey V-sys and human PDGF 85% similar
Doolittle et al., Science, 1983 Simian sarcoma virus onco gene, v-sys, is derived from the gene encoding a platelet-derived growth factor.
§ Hypothesis: Cancer = deregulated growth factor
Alignment from: http://pdf.aminer.org/000/244/500/design_and_implementation_of_a_dna_sequence_processor.pdf
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>sp|P00674|RNP_HORSE Ribonuclease pancreatic Horse KESPAMKFERQHMDSGSTSSSNPTYCNQMMKRRNMTQGWCKPVNTFVHEPLADVQAICLQ… >sp|P00673|RNP_BALAC Ribonuclease pancreatic Minke whale RESPAMKFQRQHMDSGNSPGNNPNYCNQMMMRRKMTQGRCKPVNTFVHESLEDVKAVCSQ… >sp|P00686|RNP_MACRU Ribonuclease pancreatic Red kangaroo ETPAEKFQRQHMDTEHSTASSSNYCNLMMKARDMTSGRCKPLNTFIHEPKSVVDAVCHQE…
Similar sequence, common ancestry?
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Alignment
CLUSTAL 2.1 multiple sequence alignment sp|P00674|RNP_HORSE sp|P00673|RNP_BALAC sp|P00686|RNP_MACRU KESPAMKFERQHMDSGSTSSSNPTYCNQMMKRRNMTQGWCKPVNTFVHEPLADVQAICLQ 60 RESPAMKFQRQHMDSGNSPGNNPNYCNQMMMRRKMTQGRCKPVNTFVHESLEDVKAVCSQ 60
- ETPAEKFQRQHMDTEHSTASSSNYCNLMMKARDMTSGRCKPLNTFIHEPKSVVDAVCHQ 59
*:** **:*****: :......*** ** *.**.* ***:***:**. *.*:* * KNITCKNGQSNCYQSSSSMHITDCRLTSGSKYPNCAYQTSQKERHIIVACEGNPYVPVHF 120 KNVLCKNGRTNCYESNSTMHITDCRQTGSSKYPNCAYKTSQKEKHIIVACEGNPYVPVHF 120 ENVTCKNGRTNCYKSNSRLSITNCRQTGASKYPNCQYETSNLNKQIIVACEG-QYVPVHF 118 :*: ****::***:*.* : **:** *..****** *:**: :::******* ****** DASVEVST 128 DNSV---- 124 DAYV---- 122 * *
http://www.genome.jp/tools/clustalw
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Number of aligned residues § Horse and Minke whale: 95 § Minke whale and Red kangoroo: 82 § Horse and Red kangoroo: 75
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Similar sequence, common ancestry?
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African elephant: sp|O47885|CYB_ELEMA Mammoth: sp|P92658|CYB_MAMPR Indian elephant: sp|P24958|CYB_LOXAF
African elephant: sp|O47885|CYB_ELEMA Mammoth: sp|P92658|CYB_MAMPR Indian elephant: sp|P24958|CYB_LOXAF
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Elephant and Mammoth
Mammoth-African elephant 10 mismatches Mammoth-Indian elephant 14 mismatches Significant?
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Similarity implies homology
Sequence similarity is not equal to homology
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Similarity usually implies homology
§ Conservation: Sequences similar in many species § Convergent evolution § Mutation rate varied § Horizontal gene transfer
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Homologue Orthologue Paralogue
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Darwin‘s Tree of Life
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Tree of Life with 2.3 Mio Species
- pentreeoflife.org
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Sequence Alignments
§ Why to compare and align sequences? § How to judge an alignment? § How to compute an alignment? § How to compute an alignment fast?
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How to judge an alignment
§ Scoring scheme
§ number of matches, mismatches, gaps § substitution matrices
§ Significance
§ E-value, P-value, Z-score
§ Structure
§ Benchmark sequence against structure alignment
§ Function
§ Benchmark sequence alignment implies similar function?
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Sequence Alignments
§ Why to compare and align sequences? § How to judge an alignment? § How to compute an alignment? § How to compute an alignment fast?
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Levenshtein (or Edit) Distance
Minimum number of insertions, deletions, and replacements to convert string a into string b
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Levenshtein (or Edit) Distance
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Let a = a1 . . . am and b = b1 . . . bn be strings. Then leva,b = leva,b(m, n) is the Levenshtein distance of a and b, where leva,b(i, j) = 8 > > > > < > > > > : max(i, j) if min(i, j) = 0, min 8 > < > : leva,b(i 1, j) + 1 leva,b(i, j 1) + 1 leva,b(i 1, j 1) + 1(ai6=bj)
- therwise,
and 0 i m and 0 j n and 1(ai6=bj) := ( 1 if (ai 6= bj), if (ai = bj).
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From Distance to Alignment
From lectures.molgen.mpg.de/Alg/Intro/
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Aligning RDISLVKNAGI and RNILVSDAKNVGI R D I S L V - - - K N A G I R N I - L V S D A K N V G I
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Sequence Alignments
§ Why to compare and align sequences? § How to judge an alignment? § How to compute an alignment? § How to compute an alignment fast?
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Computing Alignments fast
compbio.pbworks.com
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Computing multiple sequence alignments
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Computing phylogenetic trees
§ Distance-based
§ Neighbour joining § Hierarchical clustering
§ Character-based
§ Parsimony method § Maximum Likelihood
Saitou, Kyushu Museum, 2002
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