Ch. 19: The Organization and Control of Eukaryotic Genomes

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Ch. 19 The Organization and Control of
Eukaryotic Genomes
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The Structure of Chromatin

• Each Chromosome about 6 cm long, 1000x longer
  than width of cell
• Eukaryotic DNA associated w/ proteins
• Chromatin undergoes changes in the course of the
  cell cycle.
• During Interphase, chromatin fibers are diffused
  within the nucleus.
• Various levels of packing of DNA

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• Histones proteins DNA wrap around.
• Positive charge, DNA negative charge
• 5 types of histones (gene highly conserved)
• Mass of Histone Mass of DNA
• Nucleosome (DNA/Histone) complex stays together
  except during DNA Replication
• Nucleosome can change shape

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Higher levels of DNA Packing

• Heterochromatin-
• nontranscribed eukaryotic chromatin
• highly compacted
• visible with a light microscope during
  Interphase.
• Not transcribed
• Euchromatin- (True Chromatin) less compacted
  than heterochromatin.

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Tandemly Repetitive DNA

• Short sequences repeated in a series
  (GTTACGTTACGTTAC).
• 10-15 of genome
• Up to 10 bp long
• Several hundred thousand repeats long
• Have a different density (lower)
• Satellite DNA
• Fragile X Syndrome
• CGG repeat 30x ? Normal
• CGG repeat 1000x ? Fragile X
• Huntingtons Disease
• CAG repeated
• Translated to glutamine
• Different protein
• Satellite DNA located at telomeres

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INTERSPERSED REPETITIVE DNA

• Scattered about the genome.
• thousands of base pairs long.
• Copies are not identical.
• 25-40 in mammalian genomes.
• 5 are in a family of sequences called Alu
  Elements
• Made into RNA but function unknown
• Transposons (jumping genes)

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Gene Family Duplication

• Most Euk. Genes have unique sequence, one copy
  per haploid cell.
• Some present in more than one copy, or resemble
  sequence.
• Multigene families
• identical gene, clustered tandemly,
• mostly RNA products (rRNA).
• Single transcription unit repeated 100x
• Gene for Histones

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Non-identical gene families

• Two related Families of Genes
• Globins alpha and beta code for
• Hemoglobin
• Chromosome 16 codes for a globin
• Chromosome 11 codes for ß globin
• Both genes have similar sequence
• Possibly from common ancestor?
• Different version of hemoglobin expressed at
  different times
• Fetal Hgb has higher affinity to O2 than adult
  form
• Difference b/c of possible mutations that
  accumulate
• Evidence.pseudogenes
• Similar genes w/no product

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GENE AMPLIFICATION REARRANGEMENT

• Gene Amplification- number of copies of a gene
  temporarily increases during a stage in
  development. (rRNA in ovum, cancer cells, does
  not affect gametes
• DNA Rearrangements or Loss
• Gene loci changes
• Retrotransposons (DNA? RNA?DNA)
• Reverse Transcriptase
• Transposons (jumping genes)
• McClintock purple gene in corn

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Immunoglobin Genes

• Example of gene rearrangment
• Immune System needs to recognize many different
  foreign invaders
• Function pieces of DNA spliced together to form
  functional antibody
• Undifferentiated cell DNA is different from
  Differentiated cells DNA
• Various polypeptides from the gene are used
• Constant Region (C) consistent in all Abs
• Variable Region (V) changes per Abs
• Increases Antibody diversity

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THE CONTROL OF GENE EXPRESSION

• Eukaryotic genomes may contain thousands of
  genes.
• Gene expression is controlled on a long term
  basis for cellular differentiation.
• Highly specialized cells, (muscles or nervous
  tissues) express only a fraction of their genes.
• Gene expression is regulated at the level of
  transcription by DNA-binding proteins that
  interact with other protein and external signals.

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ORGANIZATION OF A TYPICAL EUKARYOTIC GENE

• Coordinate gene expression depends on the
  association of a specific control element with
  every gene of a dispersed group.
• Genes with the same control elements are
  activated by the same chemical signals.

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Transcriptional Control

• Typical EuK Gene
• Enhancers (distal)
• Control Elements (proximal)
• Promoter
• Gene (intron/exons
• Terminator
• Control Elements
• Noncoding DNA
• Regulate transcription
• Binds to Transcription Factors
• Enhancers need Activators to bind b4 working

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Post-Transcriptional Control

• Expression of functional protein regulates
  synthesis of RNA transcript.
• Regulation of RNA degradation
• Control of translation regulatory proteins block
  leading region prevents ribosomes to attach.
• Protein Processing/Degredation
• Alternative RNA Splicing produces different RNA
  molecules from same primary target.

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Alternative RNA Splicing
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Degradation of Protein

• Polypeptide needs to be transported for function
  and destruction
• Ubiquitin targets p.p. for destruction
• Proteasomes recognize ubiquitin and degrade
  tagged protein
• Mutation in proteasome may cause cancer

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THE MOLECULAR BIOLOGY OF CANCER

• Mutations that alter genes in somatic cells can
  lead to cancer.
• Oncogenes- cancer causing genes.
• Proto-oncogenes- normal cellular genes that code
  for proteins that stimulate normal cell growth
  and divisions.

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Genetic changes
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Normal Signaling Pathways
Growth Stimulatory Growth Inhibitory

• P53 gene
• Guardian Angel of the Genome
• Damage to DNA causes p53 to turn on
• Triggers apoptosis or cell death
• Mutation in p53
• No cell death
• Cell cycle not inhibited

• Ras gene codes for G protein
• Stimulates cell cycle
• Increase Mitosis
• Proto-oncogene
• Mutation in Ras may cause hyperactive G protein
• Excessive cell growth

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• Multiple Mutation needed to produce cancer
• Incidence of cancer increases with age as
  mutations accumulate in cells

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Operons

• Pg 347-350

• Multiple genes coding for an enzyme
• Clustered together
• Single promoter
• Operator on/off switch for all genes within the
  promoter (always in on position)
• Regulatory Gene produces protein that can
  potentially blocks Operator but must be activated
• Corepressor small molecule that activates the
  regulatory protein
• Causes gene to be turned off
• Corepressors can activate or deactivate genes as
  needed