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Introduction to Bioinformatics

Introduction to Bioinformatics. Molecular Biology Primer. Genetic Material. DNA (deoxyribonucleic acid) is the genetic material Information stored in DNA the basis of inheritance distinguishes living things from nonliving things Genes

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Introduction to Bioinformatics

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  1. Introduction to Bioinformatics Molecular Biology Primer

  2. Genetic Material • DNA (deoxyribonucleic acid) is the genetic material • Information stored in DNA • the basis of inheritance • distinguishes living things from nonliving things • Genes • various units that govern living thing’s characteristics at the genetic level

  3. Nucleotides • Genes themselves contain their information as a specific sequence of nucleotides found in DNA molecules • Only four different bases in DNA molecules • Guanine (G) • Adenine (A) • Thymine (T) • Cytosine (C) • Each base is attached to a phosphate group and a deoxyribose sugar to form a nucleotide. • The only thing that makes one nucleotide different from another is which nitrogenous base it contains Base P Sugar

  4. Purine: Pyrimidine: Nucleoside

  5. Nucleotides • Complicated genes can be many thousands of nucleotides long • All of an organism’s genetic instructions, its genome, can be maintained in millions or even billions of nucleotides

  6. Orientation • Strings of nucleotides can be attached to each other to make long polynucleotide chains • 5’ (5 prime) end • The end of a string of nucleotides with a 5' carbon not attached to another nucleotide • 3’ (3 prime) end • The other end of the molecule with an unattached 3' carbon

  7. 5’ 1’ 4’ 2’ 3’

  8. Base Pairing • Structure of DNA • Double helix • Seminal paper by Watson and Crick in 1953 • Rosalind Franklin’s contribution • Information content on one of those strands essentially redundant with the information on the other • Not exactly the same—it is complementary • Base pair • G paired with C (G  C) • A paired with T (A = T)

  9. Base Pairing • Reverse complements • 5' end of one strand corresponding to the 3' end of its complementary strand and vice versa • Example • one strand: 5'-GTATCC-3' the other strand: 3'-CATAGG-5'  5'-GGATAC-3' • Upstream: Sequence features that are 5' to a particular reference point • Downstream: Sequence features that are 3' to a particular reference point 5' 3' Upstream Downstream

  10. DNA Structure

  11. DNA Structure

  12. Chromosome • Threadlike "packages" of genes and other DNA in the nucleus of a cell

  13. Chromosome • Different kinds of organisms have different numbers of chromosomes • Humans • 23 pairs • 46 in all

  14. Central Dogma of Molecular Biology • DNA: information storage • Protein: function unit, such as enzyme • Gene: instructions needed to make protein • Central dogma

  15. Central Dogma of Molecular Biology • Central dogma reverse transcription (reverse transcriptase) replication (DNA polymerase) • DNA obtained from reverse transcription is called complementary DNA (cDNA) • Difference between DNA and cDNA will be discussed later

  16. Base Base P P Sugar Sugar Central Dogma of Molecular Biology • RNA (ribonucleic acid) • Single-stranded polynucleotide • Bases • A • G • C • U (uracil), instead of T • Transcription (simplified …) • A  A, G G, C  C, T  U DNA H RNA OH

  17. DNA Replication (DNA  DNA)

  18. DNA Replication (DNA  DNA)

  19. DNA Replication Animation Courtesy of Rob Rutherford, St. Olaf University

  20. Transcription (DNA  RNA) • Messenger RNA (mRNA) • carries information to be translated • Ribosomal RNA (rRNA) • the working “spine” of the ribosome • Transfer RNA (tRNA) • the “decoder keys” that will translate nucleic acids to amino acids

  21. Transcription Animation Courtesy of Rob Rutherford, St. Olaf University

  22. Peptides and Proteins • mRNA  Sequence of amino acids connected by peptide bond • Amino acid sequence • Peptide: < 30 – 50 amino acids • Protein: longer peptide

  23. Genetic Code – Codon Codon: 3-base RNA sequence Stop codons Start codon

  24. List of Amino Acids Amino acid Symbol Codon A Alanine Ala GC* C Cysteine Cys UGU, UGC D Aspartic Acid Asp GAU, GAC E Glutamic Acid Glu GAA, GAG F Phenylalanine Phe UUU, UUC G Glycine Gly GG* H Histidine His CAU, CAC I Isoleucine Ile AUU, AUC, AUA K Lysine Lys AAA, AAG L Leucine Leu UUA, UUG, CU*

  25. List of Amino Acids Amino acid Symbol Codon M Methionine Met AUG N Asparagine Asn AAU, AAC P Proline Pro CC* Q Glutamine Gln CAA, CAG R Arginine Arg CG*, AGA, AGG S Serine Ser UC*, AGU, AGC T Threonine Thr AC* V Valine Val GU* W Tryptophan Trp UGG Y Tyrosine Tyr UAU, UAC 20 letters, no B J O U X Z

  26. Codon and Reading Frame • 4 AA letters  43 = 64 triplet possibilities • 20 (< 64) known amino acids • Wobbling 3rd base • Redundant  Resistant to mutation • Reading frame: linear sequence of codons in a gene • Open Reading Frame (ORF), definition varies: • a reading frame that begins with a start codon and end at a stop codon • a series of codons in a DNA sequence uninterrupted by the presence of a stop codon  a potential protein-coding region of DNA sequence

  27. Open Reading Frame • Given a nucleotide sequence • How many reading frames? __ • __ forward and __ backward • Example: Given a DNA sequence, 5’-ATGACCGTGGGCTCTTAA-3’ • ATG ACC GTG GGC TCT TAA  M T V G S * • TGA CCG TGG GCT CTT AA  * P W A L • GAC CGT GGG CTC TTA A  D R G L L • Figure out the three backward reading frames • In random sequence, a stop codon will follow a Met in ~20 AAs • Substantially longer ORFs are often genes or parts of them

  28. Translation (RNA  Protein)

  29. Translation Animation Courtesy of Rob Rutherford, St. Olaf University

  30. Gene Expression • Gene expression • Process of using the information stored in DNA to make an RNA molecule and then a corresponding protein • Cells controlling gene expression by • reliably distinguishing between those parts of an organism’s genome that correspond to the beginnings of genes and those that do not • determining which genes code for proteins that are needed at any particular time.

  31. Promoter • The probability (P) that a string of nucleotides will occur by chance alone if all nucleotides are present at the same frequency P = (1/4)n, where n is the string’s length • Promoter sequences • Sequences recognized by RNA polymerases as being associated with a gene • Example • Prokaryotic RNA polymerases scan along DNA looking for a specific set of approximately 13 nucleotides marking the beginning of genes • 1 nucleotide that serves as a transcriptional start site • 6 that are 10 nucleotides 5' to the start site, and • 6 more that are 35 nucleotides 5' to the start site • What is the frequency for the sequence to occur?

  32. Gene Regulation • Regulatory proteins • Capable of binding to a cell’s DNA near the promoter of the genes • Control gene expression in some circumstances but not in others • Positive regulation • binding of regulatory proteins makes it easier for an RNA polymerase to initiate transcription • Negative regulation • binding of the regulatory proteins prevents transcription from occurring

  33. Promoter and Regulatory Example • Low tryptophan concentration •  RNA polymerase binds to promoter • genes transcribed • High tryptophan concentration •  repressor protein becomes active and binds to operator •  blocks the binding of RNA polymerase to the promoter • Tryptophan concentration drops •  repressor releases its tryptophan and is released from DNA •  polymerase again transcribes genes

  34. Gene Structure

  35. Exons and Introns

  36. Exons and Introns Example

  37. Protein Structure and Function • Genes encode the recipes for proteins

  38. Protein Structure and Function • Proteins are amino acid polymers

  39. Proteins: Molecular Machines • Proteins in your muscles allows you to move:myosinandactin

  40. Proteins: Molecular Machines • Digestion, catalysis (enzymes) • Structure (collagen)

  41. Proteins: Molecular Machines • Signaling(hormones, kinases) • Transport(energy, oxygen)

  42. Protein Structures

  43. Information Flow in Nucleated Cell

  44. Wild-type hemoglobin DNA 3’----CTT----5’ mRNA 5’----GAA----3’ Normal hemoglobin ------[Glu]------ Mutant hemoglobin DNA 3’----CAT----5’ mRNA 5’----GUA----3’ Mutant hemoglobin ------[Val]------ Point Mutation Example: Sickle-cell Disease

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