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Statistics for Microarrays Biological background: Molecular Biology Class web site: http://statwww.epfl.ch/davison/teaching/Microarrays/ Acknowledgements • http://www.accessexcellence.org/AB/GG •http://www.oup.co.uk/best.textbooks/bioch emistry/genesvii • Sandrine Dudoit, UC Berkeley Biostatistics • Yee Hwa Yang, UC Berkeley Statistics • Terry Speed, UC Berkeley Statistics and WEHI, Melbourne, Australia Two types of organisms* * Every biological ‘rule’ has exceptions! Timeline of Genetics Highlights Mendelian Genetics http://www.stg.brown.edu/webs/MendelWeb/MWtoc.html Human Chromosomes Human Chromosome Banding Patterns Chromosomes and DNA Cell Division -- Mitosis Cell Division -- Meiosis Crossing over and Recombination Mitosis and Meiosis Compared (BREAK) DNA Structure Discovery Nature (1953), 171:737 “We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.” DNA • A deoxyribonucleic acid or DNA molecule is a double-stranded linear polymer composed of four molecular subunits called nucleotides • Each nucleotide comprises a phosphate group, a deoxyribose sugar, and one of four nitrogen bases: adenine (A), guanine (G), cytosine (C), or thymine (T) • The two strands are held together by weak hydrogen bonds between complementary bases • Base-pairing occurs according to the rule: G pairs with C, and A pairs with T Polymorphic DNA Tertiary Structures DNA B-type (7BNA) (Watson-Crick form) DNA A-type (140D) DNA Z-type (2ZNA) (low water content) (high salt concentration) Genes are linearly arranged along chromosomes DNA Structure (overview) DNA Structure The monomeric units of nucleic acids are called nucleotides. A nucleotide is a phospate, a sugar, and a purine (A, G) or a pyramidine (T, C) base. Nucleotide Bases Adenine (A) Guanine (G) Thymine (T) Cytosine (C) (DNA) (Pyrimidines) (Purines) Uracil (U) (RNA) Nucleotide codes A Adenine W Weak (A or T) G Guanine S Strong (G or C) C Cytosine M Amino (A or C) T Thymine K Keto (G or T) U Uracil B Not A (G or C or T) R Purine ( A or G) H Not G (A or C or T) Y Pyrimidin e (C or T) D Not C (A or G or T) N Any nucleotide V Not T (A or G or C) Base Pairing Proteins • Proteins: macromolecules composed of one or more chains of amino acids • Amino acids: class of 20 different organic compounds containing a basic amino group (NH2) and an acidic carboxyl group (-COOH) • The order of amino acids is determined by the base sequence of nucleotides in the gene coding for the protein • Proteins function as enzymes, antibodies, structures, etc. Amino acid codes Ala Arg Asn Asp Cys Gln Glu Gly His Ile Leu Lys Met Phe Pro Ser Thr Trp Tyr Val Asx Glx Sec Unk A R N D C Q E G H I L K M F P S T W Y V B Z U X Alanin e Arginin e Asparagin e Aspartic acid Cysteine Glut amin e Glut amic acid Glycine Histidin e Isoleucine Leucine Lysine Methionine Phenylalanin e Prolin e Serin e Threonine Tryptophan Tyrosine Valin e Asn or Asp Gln or Glu Selenocysteine Unknown Primary Protein Structure Multiple Levels of Protein Strucure ( Protein folding) Tertiary Structure of Sperm whale myoglobin (1MBN) (RT) DNA Replication Nature (1953), 171:737 “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” DNA Replication • The DNA strand that is copied to form a new strand is called a template • In the replication of a double-stranded or duplex DNA molecule, both original (parental) DNA strands are copied • When copying is finished, the two new duplexes, each consisting of one of the original strands plus its copy, separate from each other (semiconservative replication) Semiconservative Replication DNA Replication, ctd • DNA synthesis occurs in the chemical direction 5’3’ • Nucleic acid chains are assembled from 5’ triphosphates of deoxyribonucleosides (the triphosphates supply energy) • DNA polymerases are enzymes that copy (replicate) DNA • DNA polymerases require a short preexisting DNA strand (primer) to begin chain growth. With a primer base-paired to the template strand, a DNA polymerase adds nucleotides to the free hydroxyl group at the 3’ end of the primer. • DNA replication requires assembly of many proteins (at least 30) at a growing replication fork: helicases to unwind, primases to prime, ligases to ligate (join), topisomerases to remove supercoils, RNA polymerase, etc. DNA Replication Fork DNA Synthesis DNA is unwinding RNA • RNA, or ribonucleic acid, is similar to DNA, but -- RNA is single-stranded -- the sugar is ribose rather than deoxyribose -- uracil (U) is used instead of thymine • RNA is important for protein synthesis and other cell activities • There are several classes of RNA molecules, including messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), and other small RNAs The Genetic Code • DNA: sequence of four different nucleotides • Protein: sequence of twenty different amino acids • The correspondence between the fourletter DNA alphabet and the twenty-letter protein alphabet is specified by the genetic code, which relates nucleotide triplets, or codons, to amino acids Standard Genetic Code Variation of genetic codes T1 T2 T3 T4 T5 T6 T9 T10 T12 T13 T14 T15 CUU CUC CUA CUG Leu Leu Leu Leu - Thr Thr Thr Thr - - - - - Ser - - - AUU AUC AUA AUG Ile Ile Ile Met Met - Met - - Met - - - - - Met - - - UAU UAC UAA UAG Tyr Tyr Stop Stop - - - - Gln Gln - - - - Tyr - Gln AAU AAC AAA AAG Asn Asn Lys Lys - - - - - Asn - - - - Asn - - UGU UCG UGA UGG Cys Cys Stop Trp Trp - Trp - Trp - Trp - - Trp - Cys - - Trp - Trp - - AGU AGC AGA AGG Ser Ser Arg Arg Stop Stop - - Ser Ser - Ser Ser - - Gly Gly Ser Ser - T1: standard T2: vert mt T3: yeast mt T4: other mt T5: invert. mt T6: cil. etc nuc. T9: ech. mt T10: eup. nuc. T12:alt yeast nuc T13: asc. mt T14: flat. mt T15: bleph. nuc. Protein Synthesis