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Department
Biological Sciences
Course
55-213
Professor
Hubberstey
Semester
Winter

Description
Lecture 1 What I would like you to get out of this course: 1. why molecular biology is extremely important for your lives 2. understanding of how your genome is organized and functions 3. how molecular biology processes function in your cells 4. appreciation of how amazing these processes are and the impact new molecular biology technology will have on society Why is molecular biology important to your lives? 5. molecular technology will revolutionize medicine in the next 10-20 years and will affect everyone 6. understanding how diseases are caused 7. susceptibility genes for multigenic diseases (cancer, heart disease, schizophrenia, autism) 8. everyone will have their own genome sequence in the next decade How much DNAdoes each of your cells contain? 9. 1 metre- 3 billion nucleotides 10. All our genomes are roughly the same o About one in every hundred nucleotide are different How long will it take you to read your genome? 11. 57 years! Human Genome project: completedApril, 2003 12. entire nucleotide sequence of our chromosomes 13. 20-25,000 genes 14. cost about $3 billion Personalized medicine: Your individual genome sequence 15. ~$100 within 3-5 years 16. determine susceptibility to disease 17. which medications you will respond to or react to: o 32,000 deaths/year due to adverse side effects of prescription drugs 18. will be used in doctor’s offices in next 10 years 19. important to understand what this information means What can you get today for $99? 20. Not complete genomic sequence 21. Sequences of thousands of genetic markers, >1,000,000 base pairs Personalized medicine: 22. Using genomic information for disease discovery, treatment and drug effectiveness (pharmacogenomics) 23. http://www.youtube.com/watch?v=K0YAeC4oeEY Ethical questions: 24. What to do with this information without treatment for some diseases? 25. Psychological impacts on individuals and their disease risks 26. Impacts on insurance policies and job security Other genome projects How many of your own cells in your body? 27. 20-30 trillion How many total cells in/on your body? 28. 150 trillion Bacterial diversity on the human body 29. Very few bacterial species can be cultured in lab (<10%) 30. New DNAsequencing technologies can now identify many unknown bacterial species without culturing 31. http://www.plosone.org/article/info%3Adoi %2F10.1371%2Fjournal.pone.0047712 Genomes and Evolution 32. 2.7% of genomes are different 33. some genes have been mutated or duplicated 34. FoxP2: differs by two amino acids o involved in speech development Molecular signals: How do our cells respond to environmental signals? 35. http://www.youtube.com/watch?v=CaDgC0h8xYw History of Molecular Biology (Figure 1.1) 36. Very young 37. 1953 finally know the structure of DNA 38. This is the "golden age" of molecular biology ---> still in the primitive stage 39. Used to take a long time to culture e coli. o Now it takes 10mins 40. Now we have different instruments and more knowledge 41. Revolutionary since it helps us discover which bacteria is harmful and causing illnesses o We can sequence the DNAof the viruses faster Other genomes sequenced 42. Platypus o Reptile and mammal 43. Looking into different genomes of Dogs o All are the same species but the breed is different o Many purebred dogs have genetic abnormalities due to their previous inbreeding 5 questions 44. What is a gene? o Asegment of DNAthat has a code to make RNAmolecules (does not have to code for protein) 45. What is an allele? o Aword that describes an alternative form of a gene o In the population there are multiple alleles o Are very common; w share a lot of our genes but the different changes make up the alleles 46. What is transcription? o Uses DNAas a template to produce a single RNAmolecule o RNApolymerase is the enzyme that does this 47. What is translation? o RNAas a template that codes into protein o Ribosome's do this 48. What is a single nucleotide polymorphism? o One nucleotide changes into a different nucleotide o For example: one person hasA-T another persons genome contains a G-C 49. Figure 1.19 DNAreplication: 50. DNApolymerase 51. dsDNA------>dsDNA Transcription: 52. RNApolymerase 53. dsDNA-----> ssRNA Reverse Transcription: 54. Reverse transcriptase 55. ssRNA-----> dsDNA What is the definition of a gene??? 56. sequence of DNAthat encodes a functional RNAmolecule; in protein coding genes, the RNAin turn codes for protein 57. some genes encode RNAthat is not translated into protein o Ribosomal RNA(rRNA) o Transfer RNA(tRNA) o Micro RNAs (miRNA- 26-31 nucl.) o PIWI RNAs (piRNA- 21-24 nucl.) o Small inhibitory RNAS (siRNA) • (miRNA, piRNA, siRNA) much more numerous than first thought- play roles in regulating gene expression Lecture 2 58. DNA= 4 bases (A,T,C,G) o Coded to RNA(A,U,C,G) o Then coded to protein • However some RNAs are not translated into protein  They regulate gene expression  Do not know exactly what they do  However we know microRNAhelps in cancer development  PiWi RNAis a major factor in gene development 59. DNAis the genetic material and can transform cells 60. One of the first experiments to show DNAas a genetic material is by Grifith 61. 1928: Griffith experiment using Pneumococcus 62. Proved that virulence can be passed between cells via DNAtransformation 63. He found that a "cell" had the ability to take one cell with another cell to create a new cell 64. Transformation of DNA 65. Avirulent (nonlethal) R type bacteria could be converted to lethal S (smooth) bacteria when cells were mixed together o Figure 1.3 & 1.4 66. Heat kills cell but does not kill DNAso the R cell can pick up the DNAand The R strain becomes an S strain DNAis the transforming principle 67. Most experiments were done with bacteria and viruses 68. 1st technique was radioactivity o Biologist could use the radioisotopes to visually see what was going on DNAis Genetic Material of Viruses 69. Hersey and Chase experiment (1952) o used radioactive compounds to tag DNA( P) and protein ( S) of viruses (Phage T2) o infected bacteria and recovered viral progeny and measured radioactivity amounts o new viruses had high levels of P and not S 35 70. These viruses could only infect bacteria 32 71. New viruses --> high level of P --> low levels of 35S o DNAis genetic material of viruses 72. Figure 1.6 73. 74. 2 critical experiments 75. We were able to develop genetic engineering techniques 76. DNAcan be introduced into all cells o when DNAis put into eukaryotic cells it is termed transfection which is the same as transformation into bacteria o DNAtransforms at LOW efficiency o need a way to select for cells that have taken up DNA • Selectable markers • Antibiotic resistance in bacteria 77. Transfection - DNAfrom outside into a new cell 78. Transformation - transforming into a different form o Ex. Taking DNAinto bacteria cell 79. Need to pre-treat the DNAto make it more competent o Still low efficiency 80. What do you do to select the cells that have taken up the DNA o Therefore you need selective markers • Allows bacteria to grow • It can block  Makes an enzyme that degrade the antibiotic to enter cell 81. Figure 1.7 82. Craig Venter o Creating synthetic life forms o Creating the 1st synthetic cell o Decides what genes will be in it o Working on the 1st synthetic life forms to see if they cells will replicate and divide DNAStructure 83. DNAis double helix with an average of 10 bp/turn 84. overwound DNAhas more bp/turn and underwound has less 85. the two strands of helix run antiparallel 86. DNAhas minor and major grooves Figure 1.8:Apolynucleotide has a repeating structure. Figure 1.12: Flat base pairs connect the DNAstrands. DNASupercoiling: 87. DNAcan coil around its axis if it is closed with no free ends (e.g. plasmid- closed circular DNA) 88. SupercoilingAffects the Structure of DNA o Aclosed DNAcan be a circular DNAmolecule or a linear molecule where both ends are anchored in a protein structure. 89. Creates tension 90. Difference between relaxed and supercoiled --> relaxed has one cut strand 91. Positive supercoiling: o twisting of the DNAhelix in the same direction as the two strands; causes increase in the number of bases /turn 92. Negative supercoiling: o twisting of the DNAhelix in the opposite direction as the two strands; causes decrease in the number of bases /turn o causes strand separation-denaturation 93. Why is this important?? o DNAstrands have to separate during replication, transcription and recombination 94. How does the torsional stress get relieved? o a nick (break) is generated in one of the strands which allows it to rotate to relieve tension o nick is resealed (ligated) after it is rotated around the intact strand o many proteins (enzymes) are involved in this process 95. Only way to relieve tension is to cut DNA 96. Problem: supercoiling affects the bp per turn 97. Twisting causes box pairs to come closer together 98. If you stretch it out too much the strand will separate o Cannot happen in (+) because the DNAis wound together tighter 99. Why is this important? o Because we have 3 billion bases and the DNAstructure is always under pressure due to these tensions & the supercoiling due to the separation o Causes problems during DNAreplication due to the separation o Causes problems during transcription & replication since the DNAneed to be separated 100. How does the torsional stress get relieved o DNAneeds to be cut • This frees up one of the ends which relieves the stress • When it is complete then it can be reattached  Takes many proteins o Make sure knots aren't formed in the DNA 101. 102. Topoisomerases o Critical o Done at remarkable speeds o can relax OR create supercoils in DNA o Break bonds in DNA • Type I: single strand breaks • Type II: double strand breaks o Gyrases can also affect supercoiling 103. Enzymes involved in DNAdegradation: o Deoxyribonucleases (DNases) degrade DNA o Ribonucleases (RNases) degrade RNA o Endonucleases: break bonds within nucleic acid 104. Believe these enzymes evolved with eukaryotic cells 105. Used to fight off foreign cells 106. Figure 1.17 107. Which are used o Restriction enzymes • Isolated from bacteria o (our cells do not produce restriction enzymes) o Help scientist manipulate DNA 108. Which endonucleases are used in molecular biology? o Exonucleases: break bonds at ends of nucleic acid- (5’OR 3’ends) o Cut at the end DNAreplication is semi-conservative 109. Each original strand of the DNAduplex serves as a template for the production of a new strand 110. Meselson-Stah15Expt (1958) labelled DNAwith ‘heavy’ 111. isotope of N ( N) and watched generation of new strands 112. measured the weight of DNAusing density centrifugation 113. One strand at as a template for the daughter cell/strain 114. 1N is heavier than N o Figure 1.15 --> shows the experiment o Isolated DNAfrom each round o Therefore the "mother strand" produces template to "daughter strand" o DNA needed to be separate in these stages to produce results 115. DNAcan be hybridized with its complementary bases 116. (Figure 1.15 Meselson-Stahl) NucleicAcid Hybridization 117. all nucleic acids can hybridize (form H bonds) with each other using complementary sequences 118. DNA-DNA, RNA-DNA, RNA-RNA 119. intra- or intermolecular bonds o Intra - normally in RNA 120. heating can lead to strand separation or denaturation of DNADuplex (‘melting’of DNA) 121. melting point (T ) is the midpoint of the range over which DNAstrands separate M 122. T Ms dependent on the length of DNAand G-C content o typical 40% GC DNAhas T of M7 C o 123. DNAis very stable o However when you heat it you can separate the H-bonds o More bonds = higher melting point • G ≡ C --> higher melting point then A=T 124. Figure 1.22 = different types **need to know** 125. Figure 1.23 o Process of ripping apart DNAby heating it (denaturation) o Then renaturing DNA o Critical experiment • You can take differnet single stranded DNAmolecules to denature and renature together to form double stranded DNA • Helps to show whether these DNAstructures are similar 126. Renaturation of nucleic acid strands o any two strands with complementary sequences can anneal, or renature (or hybridize) o ability of two strands to hybridize is directly related to their complementarity o can still get hybridization with sequences that are not 100% homologous 127. Many molecular biology techniques rely on hybridization o Important because many techniques rely on hybridization o allows for detection of specific DNAor RNA sequences • Southern blotting- DNAdetection • Northern blotting- RNAdetection • Western blotting - Protein detection • (southern comes from J.M Southerns) • There are also north-western and south-western blotting 128. NucleicAcid hybridiation o Very critical to technology o Major techniques = Southern and Northern Blotting o Because of the nature of nucleic acid coming together, you can take one nucleic acid from one organism and put it together with a nucleic acid fro another organism 129. Figure 1.24 o For any hybridizing technique the probes need to be single stranded • Therefore you need to denature the DNA • You blot one on a filter • Then you put the two single strands together and heat them up for redenaturization • (higher temp. = higher complimentary between DNAsamples) o DNAusually gets labelled through radioisotopes o Both probe and target have to be single stranded (DNAor RNA) 130. Do not use radioisotopes as much as we used to o (pain to work with & all the safety procedures) 131. Now use CCE cameras that can detect light coming off (Chemo luminescence) o Used for visual detection 132. DNAis usually radioactively labeled so detection can be performed using X-ray film (autoradiography) 133. Both probe and target have to be single-stranded (DNAand/or RNA) 134. Hybridization techniques aren't used enough anymore since most of the genomes are already found DNAMutation: 135. change in the genomic DNAsequence 136. not all mutations are detrimental or affect phenotype of organisms; some may be beneficial and lead to evolution o Spontaneous mutation: result from random cellular events; extremely rare o Mutagens: chemicals or compounds that increase background level of mutation- induced mutations • normally act directly to change DNA base pairs • More mutagens you are exposed to---> more mutations 137. Is good and bad 138. Without mutation we wouldn't be here 139. Mutation is a change in the genomic sequence (1 or more changes) 140. We have 3 billion sequences ~0.3% are different within people in the world (99.7% are the same) 141. If there is a mutation that changes the function -- that mutation is normally bad o However we know in specific cases where a gene changes a function and allows the organism to survive 142. Important to remember more inherited traits are homozygous recessive DNAMutation and disease: 143. if mutations occur in germ line cells- passed on to next generation 144. estimated over 1000 genetic diseases that result from mutation in single genes 145. some mutations occur spontaneously in an individual-did not inherit from parents o Is cystic fibrosis hereditary? • Yes, 28 different mutations in the CTFR gene are known to cause the disease • Most common hereditary disease in NorthAmerica from people originating from Europe • 1 in 20 • Depending in the mutation depends on the severity of the disease o Is liver cancer hereditary? • In 95% of cases = NO • Mutations can happen in somatic cells- not passed on 146. Ex. If you smoke 2 packs a day your mutated cells that cause lung cancer will only harm you o However there are mutated genes that get passed on from generation to generation 147. As we learn more about the genome we can compare it more and find more diseases 148. Happen early in the gametes or early in development when the mutation is not from parents 149. Rate of mutation o Mutations can be detected and repaired in cells o Mutation rate of genes is dependent on genome size and selective pressure applied on organism o Genome sizes vary dramatically between species!! • has major impact on evolution of species o When mutation is detected then the cell is initiated to a suicide pathway o Rate of mutation is based on genome size o Bacteria can pick up mutations so easily since their genes are packed so tightly together Beneficial mutations: 2. some mutations provide benefit for survival 3. Example: CCR5 gene (CCR5Δ32 mutation) -- >Encodes chemokine receptor 5 ---> Non -Functional 4. found that patients homozygous for CCR5Δ32 were resistant to HIV infection (mostly of European origin) 5. HIV uses receptor to infect white blood cells 6. Why does this mutation exist in the population? o Bubonic plague (Black plague) (14 century Europe)- caused by bacteria 7. CCR5Δ32 leads to plague resistance 8. CCR5Δ32 (the delta symbol means there is something missing) o Does not make you sicker or harm your immune system Beneficial mutations: 9. Disease causing genes with benefits depending on gene allele copy number (homo vs. heterozygous) o Cystic fibrosis: • homozygous recessive alleles for CFTR mutation • causes mucus to form in lungs and intestines o Heterozygote advantage: • one copy of recessive allele provides resistance to diarrhea (caused by cholera) and resistance to tuberculosis  tuberculosis responsible for 20% of European deaths between 1600-1900 Questions about mutations and populations: 2. What has to occur in the population for beneficial mutations to be successful and become heritable? o Some selective pressures and advantages o Must be heritable 3. Why are serious mutations not generally observed in the population? o Dies before they are born in the fetus o They are very selective o % of spontaneous abortions = ~60% • Aborted during development • Happens naturally • Fertilized eggs that actually go into term = ~40%  Majority don't make it! Types of Mutation: 4. Point mutation: change in single base pair o Transition: replaces pyrimidine with pyrimidine and purine with purine o Transversion: purine replaced by pyrimidine and vice versa 5. mutations can be induced by chemical modification of bases or incorporation of base analogs into DNA 6. Can occur naturally or through mutagens/ chemicals that can increase process 7. Figure 1.26 - Mutagens --> happens in the same gene 8. Figure 1.27 -Analogs --> happens in a separate gene Mutagens (figure 1.26) Analogs (Figure 1.27) BaseAnalogs: Uses 9. Chemotherapy (anti-metabolites): cancer cells take up analogs and blocks division and DNAreplication o PurineAnalogs: Mercaptoguanine o PyrimidineAnalogs: Fluorouracil 10. eventually, cancer cells die but also normal cells can die too 11. causes side effects of chemotherapy o targets actively dividing normal cells (e.g. hair, skin, epithelial) 12. Can kill cells when used excessively o Used in medicine o Analogs are very toxic (very potent) 13. Pharmical genomics --> how people react differently to drugs Types of Mutation: 14. Insertion: addition of more than one bp into genome 15. Deletion: removal of base pairs from genome 16. Transposons: sequence of DNAthat can duplicate and insert into new location in genome Mutation Reversion: 17. Point mutations and insertions can be reverted back to wild type sequence; deletions cannot 18. Forward mutations: inactivate a gene 19. Backward mutations: restores inactive gene to wild-type o Exact base reversal is true reversion o Base reversal somewhere else in gene compensates for initial mutation: second site reversion 20. Suppressor mutation: second mutation in another gene that compensates for or restores effects of primary mutation o Happens in the same gene 21. Second mutation in a tRNAgene causes the tRNAto recognize the mutated codon from first mutation o Occurs in a separate gene Mutation Hotspots: 22. regions in the genome have higher rates of mutation than others 23. can be affected by particular mutagens or by specific DNAsequences 24. There are certain regions tat are more sensitive in picking up mutations Genome Differences: 25. Genome: collection of all the DNAin an organism 26. All cells have dsDNAgenomes, some viruses have RNAgenomes or DNA genomes 27. all genomes code for the production of all the protein for a cell in an organism 28. the proteins (proteome) provides all the necessary functions for survival of the organism 29. Our genome does not change between cell types 30. What is larger, genome or proteome? o Proteome • There are more proteins then there are genes Lecture 3 Why do plants have more DNA& more genes than mammals? o Plants are polyploidy genomes • This increases genome size o Plants need more genes since they need to adapt to environment due to their inability to move around o Need to survive different environments o Ex. Sunflower vs. polar tree(first tree to be sequenced • Need mechanisms to survive from environment and predators 31. Viroids: unique type of plant infectious agent that does not contain any protein associated with it (ssRNAwith high intramolecular complementarity) o viroids do not encode any protein • Therefore naked RNAmolecules o Virus have a protein coat to protect their genes • However some virus do not have any protein o Viroids do not have any genes • However they are infectious • Single stranded RNAthat produce intra bonds 32. How are they pathogenic?? o may act as a ribozyme or inhibit translation of normal genes in plants • Ribozyme are catalytic o some are transcribed by RNApolII into rolling circle RNA o The sequence of the RNAmolecule is targeted to certain genes and knocks out those genes o Examples: • Potato spindle tuber viroid (PSTV) • Cadang cadang viroid (242 base ssRNA)  Coconuts 33. Figure 1.32 o Shows PSTV viroid o Single stranded & folds on itself to form intramolecular bonds o Sequence is very important 34. Prions:infectious agents that do not contain DNAor RNA o 28kDa hydrophobic glycoprotein (PrP) encoded by normal gene in brain (in mammals) o Opposite of Viroids • Just protein o Prion research area us stil highly debated and how they work o Two forms: • PrP : normal and degraded by proteases in cell sc • PrP : resistant to degradation  Mutant  Does not degrade  Works through mechanisms that are not completely understood  Happens in your brain cells  Happens quickly • Die within a year o PrP is converted to PrP to cause disease 35. Examples of Prion Diseases o Human Prion Diseases • Creutzfeldt-Jakob Disease (CJD)  Naturally occurring  Very rare  85% are caused from spontaneous mutation  Not contagious • Variant Creutzfeldt-Jakob Disease (vCJD) • Gerstmann-Straussler-Scheinker Syndrome • Fatal Familial Insomnia • Kuru o Animal Prion Diseases o Bovine Spongiform Encephalopathy (BSE) o Chronic Wasting Disease (CWD) o Scrapie o Transmissible mink encephalopathy o Feline spongiform encephalopathy o Ungulate spongiform encephalopathy Chapter 2 Genes code for Proteins Figure 2.1 o Achromosome contains a very long stretch of DNAthat contains many genes 36. Only ~5% of our genome encodes for genes --> therefore 95% is really nothing in our chromosomes 37. We roughly know where the genes are located in our genome 38. most genes in the genome code for proteins 39. Alleles: alternate forms of a gene (may be many for a single gene) 40. Locus: region on the chromosome where a gene is located o Physical spot (sight on that chromosome loction 41. genes on a specific chromosome are said to be linked o they do not assort independently during meiosis as do genes that are on different chromosomes 42. recombination can occur between homologous chromosomes during meiosis (crossing over) o causes genetic variation 43. New Discovery 44. you get one maternal and one paternal copy for each gene o However in 2006- New discovery: o compared genome sequences from 270 people from 4 populations (descendants from Europe, Africa, Asia) o You don't always get 1 copy from each parent • Called "Copy Number Variant" • Ex. Play a role in autism 45. CNVS o CNVs: copy number variations (>1000bp) o insertions, duplications and deletions o 1447 CNVs account for ~ 12% of genome (total of 360 megabases) o Large --> 100bp 46. What does this mean? o for some genes we may inherit more or less genes from one parent (genomic copy number) o implications for disease traits (autism, heart disease, Schizophrenia, Parkinson’s, Alzheimer’s) where increase or decrease in gene expression may be a cause o Probably a lot of these CNVs do not make a difference since our genome only encodes for 5% • However the majority are on genes  Therefore it shows that our genes do vary from parent to parent o Disease are hard to detect and cure due to their complexity 47. Charcot-Marie-Tooth (CMT) Disease o Most common nerve related disorders o Leads to myelin sheath damage in peripheral nerves o Diagnosed in mid-childhood and progressively gets worse o Caused by mutation in PMP22 gene (Peripheral Myelin Protein) o Another 43 genes involved in other CMT phenotypes 48. PMP22 Gene copy number and impact on disease o You do not need to mutate the gene to receive CMT Copy number variation for specific genes vary between populations Human evolution and copy number variation: 49. Can copy number variation explain some human phenotypes? o Diet (high vs. low starch) can select for high amylase gene (AMY1) copy number High starch diets = high amylase copy number What is a gene 50. If sequences of gene X are different, they are different alleles of gene X (also SNPs) 51. If gene X is duplicated, creates a CNV History One gene= one enzyme hypothesis (1909/1941) ↓ Some enzymes are produced by >1 gene One gene= single polypeptide (1962) 52. Some genes only encode RNA o Gene is a sequence of DNAthat encodes a functional RNAmolecule (2013) 53. most mutations that affect gene function are recessive (get absence or reduction in protein function) Figure 2.2 Types of gene mutations: 54. Null mutant: eliminates function of a gene (no protein produced) o sometimes these are lethal mutations (organism dies) o Nothing being mae 55. Silent mutation: usually point mutations that change the DNAsequence but not the protein sequence o Contribute to the genetic diversity 56. Neutral mutations: changes in DNAsequence resulting in changed amino acid sequence that does not affect protein activity o Switched amino acids to another amino acid o Nothing happens 57. Leaky mutations: may affect protein function but not enough to change phenotype o Change protein function o Nothing bad happens o No change in phenotype Types of gene mutations: 58. Loss-of-function mutations: leads to loss in gene function o (but not usually complete loss) 59. Gain-of-function mutations: mutation that causes new function for a protein o (rare but usually dominant) Figure 2.4 - summarizes mutations 60. Different mutation and their functions towards protein 61. Different types of mutations o They happen all the time o We have different alleles o Any mutation they have usually has a mall change in the protein function 62. Mutations aren't always bad o Sometimes they can be good & add new functions that benefit the organism MultipleAlleles 63. usually multiple mutations in a gene results in many different alleles 64. Arise due to mutation 65. Sometimes you get a secluded population and any changed that happen get passed down 66. There's usually a "wild" type allele that is higher populated which makes it the "normal" allele 67. Wild type tends to be the dominant allele 68. can have a heterozygote that contains two mutant alleles o Eye color in Drosophila (fly) + • W -iwild type normal (red) • W - white eye (no pigment) • W W – heterozygote is red (dominant) • WW –Homozygote is white (recessive)
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