L1 intro biology-pdf
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www.cbrg.ethz.ch/education/CompBiol/L1-Intro_Biology-PDF.pdf great one!
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L1 intro biology-pdf
- 1. Computational Biology Nives Skunca Slides prepared by Dr. Christophe Dessimoz Q Introduction, Basic Biology 19/21 September 2012
- 2. This week Course introduction Basic Biology
- 3. Reality Nature observation observation observation perturbation take it apart “in vitro” recreate life “synthetic biology” obs. obs. perturb. obs. obs. perturb. Catalogue Georg Dionysius Ehret's illustration of Linnaeus's sexual system of plant classification, 1736 Model f(x) formulate/select Validate by simulation Validate on real data prediction Estimate
- 4. Learning Outcomes • Understand basic concepts of molecular biology • Understand and apply fundamental models, algorithms, data structures, and computational techniques to answer biological questions • Wide range of topics, but special focus on biological sequences and their evolutionary context.
- 5. Topics Molecular Genetics Gene Evolution Genome Evolution Mass Spectrometry Codon Bias Modeling Dynamic programming Markov models Least squares Maximum Likelihood Optimization Heuristics Simulation x
- 6. Organization • Lecture • Wed 13-14 (CAB G52), Fri 13-15 (ML F34) • Prof. Gonnet will hold the lectures • Exercises: • Thu 14-16 (CAB H56), starting this week • If you do not have a nethz account, ask Stefan Zoller as soon as possible.
- 7. Teaching Assistants • Stefan Zoller • Nives Skunca
- 8. Date Topic Lecturer Sept. 19/21 Course Introduction; Basic Molecular Biology NS Sept. 26/28 Markov models/String Alignment I GHG Oct. 3/5 String Alignment II (indels, estimating distances) GHG Oct. 10/12 Substitution Matrices GHG Oct. 17/19 Approximate Alignment Methods; Statistics of Pairwise Alignments GHG Oct. 24/26 Phylogeny I GHG Oct.31/Nov.2 Phylogeny II GHG Nov. 7/9 Phylogeny III GHG Nov. 14/16 Multiple Sequence Alignments AS Nov. 21/23 Synthetic Evolution; Evaluation of Estimators DD/GHG Nov. 28/30 Current research; Mass profiling Guests/ GHG Dec. 5/7 Orthology/Lateral Gene Transfer NS Dec. 12/14 Codon bias SZ Dec. 19/21 Genome Rearrangements GHG
- 9. Course Grade & Credits • Participation in the exercises is strongly encouraged, but not mandatory • Written Exam • During winter session • 3 hours • Only support materials are 2 A4 pages (4 sides), personally handwritten.
- 10. Course Homepage • Course details • Schedule • Slides • Exercises http://www.cbrg.ethz.ch/education/CompBiol
- 11. Darwin • Interpreted language based on Maple • Environment for bioinformatics, can do sequence management, mathematics, alignments, trees, drawing, etc. • Available for download mac and linux (http://www.cbrg.ethz.ch/darwin)
- 12. Biorecipes • A collection of real problems with coded solutions in the Darwin language • Darwin input in green • Darwin output in red www.biorecipes.com
- 13. Other materials • Slides can be downloaded from the course homepage. • Additional notes and references will be made available as well.
- 14. Basic Biology Slides of this part are largely based on material from Dr. Gina Cannarozzi
- 15. Basic Principles • Universality of life on earth: water, carbon-based biochemistry; genetic material; genetic code (largely) universal. → common origin! • Life is compartmentalized: cells are fundamental units of structure, function, organization • Self-replicating • Capable of Darwinian evolution 10 µm Cryptomonadales Encyclopedia of Life (eol.org)
- 16. So what is life? • What about endospores? viruses? mules? priests? prions? computer viruses? • In biology, there are exceptions to almost every rule. “Living organisms undergo metabolism, maintain homeostasis, possess a capacity to grow, respond to stimuli, reproduce and, through natural selection, adapt to their environment in successive generations.”
- 17. Inside a Cell http://www.osovo.com/diagram/prokaryoticcelldiagram.htm http://www.biologycorner.com/resources/cell.gif EukaryoteProkaryote 10-30 µm~2 µm
- 18. Relevant components • Ribosomes translate mRNA into proteins. • Mitochondria (eukaryotes) have their own DNA and are a result of early inclusion of α- proteobacteria into a eukaryotic cell. • Chloroplasts (plants, protists) have their own DNA as a result of early inclusion of cyanobacteria into a eukaryotic cell. • Plasmids (bacteria) are short pieces of circular DNA in multiple copies; nonessential; get transferred between bacteria.
- 19. • Genome: all the genetic material of an organism. • The genome consists of genes and non-coding regions. • Genes consist of regulatory regions, intron, exons, untranslated regions http://www.scfbio-iitd.res.in/tutorial/geneorganization.html Genome chromosome chromatin histone
- 20. Escherichia coli Homo sapiens 1 circular chromosome 1 plasmid (multiple copies) ~4.6 million base pairs ~3.9 million coding bases (85%) 4132 protein-coding genes 172 RNA (tRNA, rRNA,etc) 578 pseudogenes 23 chromosome pairs ~3 billion base pairs ~50 million coding bases (1.5%) ~21,000 protein-coding genes ~294,000 exons ~60,000 different transcripts ~6,000 pseudogenes ~4,800 RNA genes ~2,900 RNA pseudogenes
- 21. DNA Deoxyribonucleic acid • Double helix • Backbones: phosphate and deoxyribose , directed (5’ → 3’), antiparallel • Connection: 4 bases Adenine, Thymine, Cytosine, Guanine. • A-T and C-G are paired by hydrogen bonds (relatively weak) Wikipedia 34 Å (3.4 nm) 3.3 Å (0.33 nm)
- 22. DNA Bases Wikipedia PuRines PYrimidines C ···· G: 3 H-bonds A ···· T: 2H-bonds
- 23. Hydrogen Bond • X-H ···· Y where X,Y is an electronegative atom (typically N,O,F) • Responsible for high boiling point of water (each H20 can have up to 4 H bonds)
- 24. “Central dogma of molecular biology” Wikipedia
- 25. DNA Replication Wikipedia Polymerase can only add bases from 5’→3’ (DNA is read 3’ → 5’)
- 27. End of day 1
- 28. RNA • Single stranded (can form structure) • Uracil instead of Thymine • mRNA: messenger RNA, for translation • rRNA: subunit of ribosome • tRNA: specific for one amino-acid, selectively bind to codon via ribosome. • microRNA: short nucleotides (~22 nts) which regulate gene function http://www.pdb.org/pdb/static.do? p=education_discussion/ molecule_of_the_month/pdb15_2.html
- 29. Transcription • Transcription factors bind to promoter sites at the 5’ regulatory region. • RNA polymerase, binds to the complex. • Working together, they open the DNA double helix. • Genes can be on either strand, but direction of growing mRNA sequence is always 5’ → 3’
- 30. Roger Kornberg Nobel Prize Chemistry 2006 The chain shown in grey is RNA polymerase, with the portion that clamps on the DNA shaded in yellow.The DNA helix being unwound and transcribed by RNA polymerase is shown in green and blue, and the growing RNA stand is shown in red. http://med.stanford.edu/featured_topics/nobel/kornberg/release.html
- 31. Post-transcriptional modifications (Eukaryotes) • 5’ Cap • Poly-A tail • Splicing (removal of introns) Research questions:Where are the introns? Where are the coding sequences? Where are the stop and start of transcription? Where are the binding sites for the transcription factors that control when transcription takes place?
- 32. Alternative Splicing • Humans: >50% of genes have splice variants. • Dscam gene in D. melanogaster: 95 alternative exons can express 38,016 different mRNAs through alternative splicing.
- 34. The Genetic Code
- 35. Proteins • Participate in most (all?) cellular processes • Made of 20 amino-acids (+ occasionally a cofactor, such as metal ion, heme, ATP, etc.) • Encoded in DNA
- 37. Amino Acids Wikimedia Commons • Only sidechains differ (red) • Sidechains have diverse chemical properties (charge, size, pH, hydrophobicity, ...)
- 39. Proteins have a 3D structure Wikimedia Commons
- 40. Biological sequences How are they identified? Where are they stored?
- 43. e MDISTLTASEEIE MEIDAEEIEIMAT IDLAEDLISLFM DDMFSSIDLESI NFEIFNSSDIDSI NIDLESIEEIEIMF EEIEIMATIFNSS DIDIMMDIMMD SINFEIFNSSDIDI MMDATIDLAED LISLFMDDMFSS IDLESINFEIFNSS Sequence Database ...AEDLISLFMDDM ... Protein Identified Unidentified protein extracted from gel Split into fragments of 5-10 amino acids Determine mass using MS (Mass Spectrometry) Determine amino acid sequence and compare with sequ- ence database Proteomics Jiang Long, Science Creative Quarterly Image Bank
- 44. Growth of sequence databases 0 0.5 1.0 1.5 2.0 2000 2002 2004 2006 2008 2010 2012 Year Numberofsequencesx10^7 Protein Data Bank UniProtKB/TrEmbl
- 49. Evolution
- 51. Darwinian Evolution • Start from an initial population • Repeat: • reproduce and “mutate” randomly • natural selection: fittest individuals survive and have descendants → selects “good” mutations • sometimes: a “branching” occurs (e.g. speciation, duplication)
- 52. Not only the “good” characters survive • Genetic drift (random sampling) • Population bottleneck • Founder effect • Genetic hitchhiking (neutral or mildly deleterious alleles linked to positively selected gene)
- 53. Species Evolution • Speciation: the evolutionary process by which new species arise • Can occur from geographic isolation or barriers, new niche entered, animal husbandry Diane Dodd’s fruit fly experiment http://evolution.berkeley.edu/evolibrary/article/_0_0/evo_45
- 54. Krzywinski et al. Circos: an information aesthetic for comparative genomics. Genome Research (2009) vol. 19 (9) pp. 1639-45 Genome Rearrangements e.g. Human vs. Dog
- 55. Example: recombination among E. coli strains Mau et al. Genome Biology 2006 7:R44
- 57. Gene Evolution
- 58. Kunkel, 2004,The Journal of Biological Chemistry Point mutations
- 63. Recombination
- 64. Gene Evolution • Mutation (base substitution) • Insertion/Deletion • Transposition (horizontal transfer) • Recombination • Gene loss or gene duplication • Splicing pattern mutations
- 65. Evolutionary Distances • Time since divergence • Number of common traits. • Edit distance (minimum # of elementary operations to transform one object into the other) • ... • Desirable properties • distance estimable without knowing history • metric properties (e.g. triangle inequality) How can we quantify the amount of evolution between two subjects?
- 66. Markovian Evolution Markov Model: every site evolves independently, probability of mutation only depends on present state (no memory), probabilities of mutation are expressed by transition matrix. A C G T A 0.900 0.033 0.033 0.033 C 0.033 0.900 0.033 0.033 G 0.033 0.033 0.900 0.033 T 0.033 0.033 0.033 0.900 M1= After “one unit” of evolution, the probability that an A mutates into a C is given by the corresponding entry in the matrix: p(A→C | d=1) = M1[A→C] = 0.033
- 70. Lamarck, Philosophie Zoologique , 1809
- 71. Darwin, Notebook B, 1837
- 72. Edward Hitchcock, Elementary Geology, 1840
- 73. Haeckel,The Evolution of Man, 1879
- 74. rRNA was used by Woese (1987) to group early life forms into three kingdoms
- 76. THEMA CENSY METKAMETJAMETMP METTHMETS3 METST ARCFU METHJ METMJ METLZ UNCMA METAC METMAMETBF METBU METTP HALWD NATPDHALMAHALSA PYRHOPYRABPYRFUPYRKO THEPD PYRCJPYRIL PYRAEPYRARSULSOSULAC SULTO STAMF AERPE HYPBU NANEQ PICTO THEACTHEVO RUBXD MYCPA MYCA1MYCUA MYCLE MYCBP MYCBO MYCTF MYCTU MYCTA MYCS2M YCSS M YCSK M YCSJM YCVP NO CFA RHO SR SACEN CO RG L CO RG B CO REF CO R D I C O R JK NO CSJ THEFY STRAW STRCO ACIC1 FRAAA FRASC CLAM 3 LEIXX ARTAT ARTS2 PROAC TROW T TROW 8 BIFLO BIFAA THET2 THET8DEIRA DEIGD RHOBA CHLMU CHLTR CHLTA CHLPN CHLCV CHLFF CHLAB PARUW LEPIN LEPIC LEPBL LEPBJCARRP MAGSM ERYLH NOVAD SPHAL ZYMMORHORT MAGMM GRABCGLUOX RHIMERHIL3 RHIEC AGRT5 RHILO MESSB BRUSUBRUMEBRUABBRUA2 BRUO2 BARHE BARQU BARBK BRAJABRASO BRASBRHOPA RHOP2 RHOPS RHOP5 RHOPB NITWN NITHX PARDP RHOS1RHOS4 JANSC SILPO SILST ROSDO HYPNA MARMM CAUCR PELUB WOLPM WOLTR EHRRW EHRRG EHRCJ EHRCR ANAPZ ANAMM NEOSM RICCN RICFE RICTY RICPR RICBR ORITB DICNV VESOH RUTMC LEGPA LEGPC LEGPH LEGPL COXBU PSYAR PSYCK ACIBT ACIAD WIGBR BUCBP BUCCC BUCAP BUCAI BLOPB BLOFL IDILO AERS4 AERHH ECOUT ECOK1 ECOL6 ECOL5 ECO57 ECOLI SHIDS SHIFL SHIF8 SHISS SHIBS SALTI SALCH SALTY SALPA PHO LL YERPE YER PA YER PN YER PP YER PS YER E8 ER W C TSO D G M BAUCH HAES1 PASM U HAEIN HAEIG HAEI8 HAEIE M ANSM ACTP2 HAEDU PSYINVIBVY VIBVUVIBPAVIBCHVIBF1PHOPR SHEAM SHELP SHEDOSHEFN SHEON SHESM SHESR SHESASHESW COLP3 PSEHT PSEA6 PSEAE PSEAB PSEPKPSEE4 PSEU2PSE14PSESMPSEF5PSEPF PSEU5 ALCBSMARAV HAHCHSACD2CHRSD THICR NITOCMETCAHALHLALHEH XYLFTXYLFAXANCP XANC8XANC5XANACXANOR XANOM NEIMFNEIMANEIMBNEIG1 CHRVOAZOSBAZOSE DECAR BORPEBORBRBORPA BORA1 RALEH RALEJRALMERALSO BURPSBURP1BURP0BURMA BURTA BURCM BURCABURCHBURS3 BURXLJANMA HERAR VEREI ACIAC ACISJ RHOFD POLNA POLSJ METPPTHIDA NITEU NITEC NITMU METFK FRATOFRATH FRATTFRAT1FRATWFRATN MYXXD ANADE DESPS DESVH DESVV DESDG LAWIP SYNFM SYNAS GEOSL GEOMG PELPD PELCD BDEBA CAMJJ CAMJR CAMJE CAMFF HELHP HELPY HELPH HELPJ HELAH WOLSU NITSB SULNB THIDN ACIBL SOLUE SALRD BACTN BACFR BACFN BACV8 PARD8 PORGI CYTH3 G RAFK FLAPJ CHLCH CHLPD PELLDCHLTE SYNP6 ANASP AN AVT TRIEISYNY3SYNELSYNJA SYNJBGLOVI PROM P PROM 5 PROM S PROM0 PROM9 PROMA PROM1 PROMTSYNPX SYNSCSYNS9 SYNPWSYNS3PROMM PROM3 SYNR3 GUITH ENCCU TRYBB LEIMALEIIN LEIBR OSTLU ORYSA ARATHPOPTR BOTCI MAGGR PHANO ASPFU YARLI ASHGO KLULA YEASTCANGA PICSTDEBHACANALLODEL SCHPO CRYNE USTMA APIME DROMEDROPSANOGA AEDAE CHICKORNAN LOXAF ECHTE DASNO MYOLU CANFAFELCA BOVIN TUPGB OTOGA HUMAN PANTR MACMU RABIT SPETR CAVPO MOUSERATNO ERIEU SORAR MONDOXENTR DANRE GASAC TETNG FUGRU ORYLA CIOSACIOIN CAEEL CAERE CAEBR DICDI CRYPV PLAF7 AQUAE TREPA TREDEBORGABORAP BORBU MOOTACARHZDESHYSYNWW FUSNN LACLALACLS LACLM STRPN STRR6 STRP2STRSV STRS2 STRSYSTRMU STRPD STRP1 STRP3 STRPG STRP8 STRP6 STRPM STRPC STRPB STRPF STRA5 STRA1 STRA3 STRT1 STRTD STRT2 ENTFA LEUM M O ENO B LACC3 LACSSLAC S1 PED PA LAC PL LACBA LACJO LACG A LACAC LACDB LACDA BACHD BACSK BACSU BACLD GEOKA GEOTN BACAN BACHK BACAH BACCZ BACC1 BACCR OCEIH LISMO LISMF LISIN LISW6 STAS1 STAHJ STAAR STAAM STAAN STAAW STAAS STAA3 STAAC STAA8 STAAB STAEQ STAES ONYPE AYWBP MESFL MYCMS MYCCT MYCPE UREPA MYCGE MYCPN MYCGA MYCH2MYCHJMYCH7 MYCMO MYCPU MYCS5 THETN CLOPECLOP1CLOPS CLONN CLOTE CLOABCLOD6CLOTH SYMTH DEHE1 DEHSC Archaea Bacteria Eukaryota Proteobacteria Actinobacteria Lactobacillales Bacilli Clostridia Cyanobacteria Tenericutes Spirochaetes Bacteroidetes Chlorobi Chlamydiae Chloroflexi Thermotogae Deinococcus-Thermus Acidobacteria Aquificae Verrucomicrobia Dictyoglomi candidate division TG1 Fusobacteria Planctomycetes