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Welcome to Integrated Bioinformatics Friday, 8 September 2006 • Comparison of genomes – Scenario • Installing and running Blast • Weekend/Monday – How to find differences • Nature of research articles E. coli: What makes it kill? Escherichia coli . . . . . . very small lab rats Courtesy of Kent State University Microbiology E. coli: What makes it kill? Escherichia coli . . . haemorrhagic colitis E. coli: What makes it kill? E. coli K12 TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder E. coli O157:H7 TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder E. coli: What makes it kill? E. coli K12 TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder E. coli O157:H7 TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder E. coli: What makes it kill? Killer protein Killer functions Membrane protein, sodium transporter Iron responsive transcriptional regulator Calcium-dependent protein kinase Unknown protein Unknown protein Similarity finder Unknown protein ... ideas for new antibiotics Welcome to Integrated Bioinformatics Friday, 8 September 2004 TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder TCTACTTATA AAGAGTCTGT TTCTGTCTGC TGGATTTCGG GAACCTTAGT CTCCGTAAAC TGAATAAACT AAGAGTTTAA AAACCTGTAT TTATATATTT CCCCAGCTGT GACAGCACTG GCTGAAATTC CCCTGCACCA ATGAATGACT TTCAATCCAC TGAATGAACA TCTGACCTCT AACTCTAGCC GACTTCTGCT CTCTAACATG TTGTTAAAGG AGTTAAAAAC GGTTACATGA TAAGAAATTA CATTAAAAAG ACCCTCAAGA CGCTGAGAGC GGTCTTTCCT GAACGAACGA AGGGCTACAC CATACATGGT GGCAGCTTTC TGCCCCACTC ATACCAAAGT ATGTCAGCAA TACAAATGAA GAATTGCAGT ACTGCCTAAA ATTGCAATTA AGGCAAATAC AGGCACCGGC AGAGTGGTAC GTGGGCACTG TTGAATGAAA Gene finder Welcome to Integrated Bioinformatics Friday, 8 September 2006 • Nature of research articles • Comparison of genomes - Scenario • Weekend/Monday – How to find differences – Parsing programs – Regular expressions Welcome to Integrated Bioinformatics Friday, 8 September 2006 • Nature of problem sets • Nature of research articles • Comparison of genomes - Scenario • Weekend/Monday – How to find differences • Today – Why differences How do differences arise between genomes? Addition/deletion of DNA Where do they come from? How to distinguish – GC-content from ? How do differences arise between genomes? Addition/deletion of DNA Point mutation organism 1 TTT TCT GAA TCC GTA GAC GTT organism 2 TTT TCT GAA TCA GCA GAC GTG What kind of mutations arise? How do differences arise between genomes? Addition/deletion of DNA Point mutation Keeping track of gene variants – Concepts of ortholog / paralog How do differences arise between genomes? Infection Phage Phage genome Bacterial chromosome Lysogenic Phage genome pathway Death General transduction Lytic pathway How do differences arise between genomes? Infection Phage Phage genome Bacterial chromosome Lysogenic Phage genome pathway Lytic pathway Life! How do differences arise between genomes? Infection Phage Phage genome Bacterial chromosome Lysogenic Phage genome pathway Lytic pathway Life! Specialized transduction The gene encoding diphtheria toxin (tox) is carried on corynephage b b tox – C.d. tox + C.d. Lysogenic conversion by corynephage b confers toxogenicity!! How to distinguish foreign from native genes? GC-content = [G] + [C] [total nucleotides] SQ2: List the two triplets that code for Lys. What proportion of each is used in Borrelia burgdorferi compared to Mycobacterium tuberculosis? Is this finding surprising? Why or why not? Borrelia burgdorferi AAU Asn 0.80 AAC Asn 0.20 AAA Lys 0.80 AAG Lys 0.20 Mycobacterium tuberculosis AAU Asn 0.21 AAC Asn 0.79 AAA Lys 0.26 AAG Lys 0.74 29% GC content 65% GC content How to distinguish foreign from native genes? SQ4: The GC content of Bacillus anthracis is 33.97%. By analysis of codon use, would it likely be easier to detect a foreign gene originating from Borrelia burgdorferi or from Mycobacterium tuberculosis? Borrelia burgdorferi AAU Asn 0.80 AAC Asn 0.20 AAA Lys 0.80 AAG Lys 0.20 Mycobacterium tuberculosis AAU Asn 0.21 AAC Asn 0.79 AAA Lys 0.26 AAG Lys 0.74 29% GC content 65% GC content DNA mutation has multiple causes • Errors during DNA replication • base mis-incorporation • polymerase slippage / repeat amplification • Errors during recombination or cell division • chromosome loss or rearrangement • large insertions or deletions • Environmental factors – mutagens: • radiation – UV or ionizing radiation • chemical – many mechanism of action • Spontaneous events: • tautomerisation • depurination • deamination • Viral infection or transposons How do differences arise between genomes? Addition/deletion of DNA Point mutation organism 1 TTT TCT GAA TCC GTA GAC GTT organism 2 TTT TCT GAA TCA GCA GAC GTG GUU GUC GUA GUG Val Val Val Val GCU GCC GCA GCG Ala Ala Ala Ala How do differences arise between genomes? Addition/deletion of DNA Point mutation organism 1 TTT TCT GAA TCC GTA GAC GTT organism 2 TTT TCT GAA TCA GCA GAC GTG Silent mutation GUU GUC GUA GUG Val Val Val Val GCU GCC GCA GCG Ala Ala Ala Ala Single base mutations Transitions Purine for purine or pyrimidine for pyrimidine Transversions Purine for pyrimidine or pyrimidine for purine How do differences arise between genomes? Addition/deletion of DNA Point mutation organism 1 TTT TCT GAA TCC GTA GAC GTT organism 2 TTT TCT GAA TCA GCA GAC GTG Transition: Transversion: purine pyrimidine purine pyrimidine purine pyrimidine Tautomerization of bases C T G A C* T* A G DNA replication can “lock in” a mutation Mutations can arise as a consequence of misincorporation during replication How to distinguish foreign from native genes? SQ7: There are two codons each for 9 of the amino acids. Choose any one of these 18 codons. • Create a transition mutation in the third position of the codon. What is the result? • Create a transversion mutation in the third position. What is the result? • In the third position, are transition mutations or transversion mutations more likely to result in a change in the amino acid encoded? How do differences arise between genomes? Addition/deletion of DNA Point mutation Keeping track of gene variants – Concepts of ortholog / paralog How do differences arise between genomes? Addition/deletion of DNA Point mutation Keeping track of gene variants – Concepts of ortholog / paralog Orthologs, Paralogs, and Xenologs Speciation event leading to orthologs Horizontal transfer leads to xenologs Gene duplication gives rise to paralogs Orthologs vs Paralogs SQ5: Are genes B1 and C2 orthologs or paralogs? How to predict orthology with imperfect information? A1 AB1 Species A B1 B2 C1 C2 Species B C3 Species C
