Organization eukaryotic genome
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Organization eukaryotic genome Presentation Transcript

  • 1. Organization of the EukaryoticChromatin StructureNoncoding sequencesLevels of packingGene regulationChemical Modifications
  • 2. Human Genome  20,000-30,000 genes  most of the DNA does NOT encode for a protein or RNA (is not a gene) http://upload.wikimedia.org/wikipedia/commons/6/64/Components_of_the_Human_Genome.jpg
  • 3. Coding & Noncoding Sequences http://www.hhmi.org/biointeractive/dna/DNAi_coding_sequences.html
  • 4. Classes of Noncoding Sequences  Introns  Regulatory sequences  Highly repetitive sequences:  Tandemly repetitive DNA (tandem repeats)  Interspersed repetitive DNA  Telomeres
  • 5. Noncoding DNA Noncoding DNA Introns Repetitive DNA Regulatory sequences Telomere Tandemly Repetitive Interspersed DNA (e.g. VNTRs) Repetitive DNA (e.g. transposon)
  • 6. Tandemly Repetitive DNA Short identical DNA sequences repeated in series Many types, often classified by length of the repeat Variable Number Tandem Repeats (VNTRs)  Number of repeat varies  Sequence can be repeated different number of times
  • 7. Tandemly Repetitive DNAApplication Useful for DNA Fingerprinting and studying evolution OSC Lab: VNTR at the D1S80 locus  Length of repeat: 16 bp  Repeated sequence: GTGGTCCTCCTTCCTG  Number of repeats: 14-41  Total length: 200-700 bp
  • 8. Example: Fragile X Syndrome First triplet repeat identified was the one in Fragile X syndrome Repeat sequence: CGG triplet on X chromosome Normal fragile X allele: repeated 30x in the 5’ untranslated region of the first exon Fragile X syndrome: repeat is over 100x The most common single known cause of intellectual disability and autism
  • 9. Example: Huntington’s Disease  Neurodegenerative Repeats Disease disorder that affects < 27 - muscle coordination and 27 – 35 - Repeat Median Age at leads to cognitive decline 36 – 39 +/- Size Onset * (years) and psychiatric problems 39 66 (72-59) > 39 + 40 59 (61-56)  Repeat sequence: CAG 41 54 (56-52)  Individuals affected with 42 49 (50-48) HD typically have at least 43 44 44 (45-42) 42 (43-40) 36 repeats or greater. 45 37 (39-36) 46 36 (37-35) 47 33 (35-31)Specific numbers of CAG repeat correlates to disease. Walker FO (2007). "Huntingtons disease".Lancet 369 (9557): 218–28. Normal HD gene CAG repeats range from 10 - 27 repeats. A few 48 32 (34-30)normal individuals have intermediate HD gene CAG repeats of 27-35 repeats. 49 28 (32-25)A current review of 1,049 persons (the majority of whom were symptomatic) has provided adetermination of the likelihood of an age-of-onset for a given CAG repeat size for repeats between 50 27 (30-24)39 50 repeats (Brinkman et al., 1997; Am. J. Hum. Genet. 60:1202-1210). *Age by which 50% of individuals will be affected
  • 10. Comparing Prokaryotic andEukaryotic DNA Prokaryote EukaryoteDNA Circular LinearLocation of Not in nucleus Contained inDNA Nucleoid region nucleusDNA bound No. Naked. Yeswith proteins?
  • 11. Chromosome Structure 2 arms, divided at centromere:  p arm – petit arm  q arm – long arm Centromeres:  region where sister chromatids are connected  made up of repetitive sequences
  • 12. Activity: DNA Packing Materials:  Thread  Scissors  pill covers Instructions:  Cut out 20 m of thread  Put the thread in the pill cover
  • 13. DNA Packing Animation Try to ignore the strange music http://www.youtube.com/watch?v=N5zFOScowqo
  • 14. Levels of DNA packing 1st level: nucleosome 2nd level: solenoid / chromatin 3rd level: looped domain 4th level: metaphase chromosome
  • 15. http://www.nature.com/nri/journal/v3/n11/images/nri1225-i2.jpg
  • 16. Histones Proteins around which DNA coils to form chromatin Contain positively charged R-groups which bind to the negatively charged DNA (phosphate groups)  DNA backbone has a negative charge  histones have a positive charge 5 types  Core: H2A, H2B, H3, H4  Linker: H1
  • 17. First level of packing: Nucleosome Nucleosome = DNA + core histones DNA wrapped twice around an octamer of core histones consisting of:  2 of each core histone: H2A, H2B, H3, H4  Note: H1 is not part of the nucleosome, but is attached to the DNA near the nucleosome 10 nm in diameter http://biology.kenyon.edu/courses/biol114/Chap01/chrom1.gif
  • 18. http://bio.research.ucsc.edu/people/boeger/images/research%20interest%20images/nucleosome%20bigger.jpg http://bioweb.wku.edu/courses/Biol566/Images/NucleosomeF09-30A.JPG
  • 19. Beads-on-a-string A nucleosome looks like a bead (histone) with string wrapped around it (DNA) Beads-on-string Consists of histone octamer and DNA http://219.221.200.61/ywwy/zbsw(E)/pic/ech9-19.jpg
  • 20. SUPERCOILING BEGINS!!!http://www.nature.com/nri/journal/v3/n11/images/nri1225-i2.jpg
  • 21. Second level of packing: Solenoids / chromatin Solenoid: H1 histones aggregate causing 6 nucleosomes to coil together 30 nm in diameter stack on top of each other forming the chromatin fiber http://www.bio.miami.edu/dana/104/nucleosome.jpg
  • 22. http://www.nature.com/nri/journal/v3/n11/images/nri1225-i2.jpg
  • 23. Third level of packing:looped domains Chromatin fibers forms loops which attach to nonhistone proteins Nonhistone proteins form a scaffold 300 nm in diameter http://bioweb.wku.edu/courses/Biol566/Images/ChromatinF09-35.JPG
  • 24. http://www.nature.com/nri/journal/v3/n11/images/nri1225-i2.jpg
  • 25. Fourth level of packing:Metaphase Chromosome Looped domains coil and fold, further compacting chromatin Result in the characteristic metaphase chromosome seen in karyotypes Such packing occurs during mitosis
  • 26. DNA Packing Video http://www.dnai.org/c/index.html http://www.youtube.com/watch?v=bwVjYxcDQ5I http://www.hhmi.org/biointeractive/dna/DNAi_packaging_vo2.html
  • 27. Tutorial Discovery of chromosome packaging http://www.dnaftb.org/dnaftb/29/concept/index.html
  • 28. Gene Regulation Topics Review cell cycle Metaphase chromosome in mitosis Interphase chromatin in G1, S, G2  DNA replication  transcription
  • 29. Gene Regulation Defined The ability to control whether a gene is actively being transcribed or not This regulation can occur at the:  Structural level (e.g. supercoiling of DNA)  Molecular level (e.g. negative feedback to suppress enzymatic activity)
  • 30. Cell Cycle http://www.biologycorner.com/resources/cellcycle2.jpg
  • 31. Supercoiling For a gene to be expressed (transcribed), the chromosome at that region must be uncoiled Different levels of supercoiling affects transcription Allows control over which genes are expressed
  • 32. Mitosis: PMAT  DNA is “inactive” because it is in the most condensed form (metaphase chromosome)  thus information is inaccessiblehttp://upload.wikimedia.org/wikipedia/commons/4/4b/Chromatin_Structures.png
  • 33. Interphase Chromatin Much less condensed than during mitosis Scaffold may be less defined (e.g. attach to inside of nuclear envelope) But order still exists:  Each chromosome occupies a restricted area with the nucleus  Nucleosome structure stays intact throughout cell cycle  Most still maintain the solenoid and looped domain structures
  • 34. Interphase Chromatin  Different levels of packing on various regions of the same chromosome  Euchromatin: loosely packed region on chromatin, active transcription  Heterochromatin: densely packed region on chromatin, inactivatedEu = true; Hetero = different
  • 35. Chromatin Structure duringTranscription http://upload.wikimedia.org/wikipedia/commons/4/4b/Chromatin_Structures.png
  • 36. http://upload.wikimedia.org/wikipedia/commons/4/4b/Chromatin_Structures.png
  • 37. MaCS onlyThe following sections are for the MaCS grade 12 biology class only
  • 38. Epigenetics Study of heritable changes in gene expression caused by mechanisms other than the DNA sequence Modifications often affect both chromatin structure and gene regulation Modifications include:  DNA methylation  Histone acetylation http://cerch.org/wp-content/uploads/2011/02/DNA-methylation-image.jpg
  • 39. Methylation Attachment of methyl groups (-CH3) to DNA bases, usually at cytosine Occurs after DNA is replicated (S-phase) In general, methylation occurs on genes that are not expressed  Methylation suppresses gene expression  Removing methylation turns genes “on”
  • 40. Histone AcetylationAttachment of acetyl group (-COCH3) to histones Acetylation changes histone shape reducing its grip on the DNA Results in more loosely packed DNA, available for transcription  Acetylation activates gene expression  Deacetylation suppresses gene expression
  • 41. Summary of Modificationsaffecting chromatin structure and gene regulation http://cnx.org/content/m26565/latest/graphics35.jpg
  • 42. Summary of Modificationsaffecting chromatin structure and gene regulation http://cnx.org/content/m26565/latest/graphics35.jpg
  • 43. Genomic Imprinting Imprinting: suppression of genes so that only 1 allele is expressed  Established in germline cells  Maintained in all somatic cells derived from the parent cell Most genes are not imprinted: both alleles are expressed Imprinted genes:  Expressions regulated by epigenetic factors  Inactivated gene can be either maternal or paternal  Genes are expressed from the non-imprinted allele
  • 44. http://www.fluorous.com/images/epigenetics.jpg
  • 45. Epigenetics Videos PBS NOVA Now “Epigenetics” (13:03) http://www.youtube.com/watch?v=7WEHoCA1hpo BeginBeforeBirth “What makes us who we are?” (4:11) http://www.youtube.com/watch?v=9AfBsTAQ8zs BBC Horizon “The Ghost in Your Genes” (49:06) http://www.youtube.com/watch?v=Q6cQSR3mPm8