The Organization and Control of Eukaryotic Genomes

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The Organization and Control of Eukaryotic Genomes

• Ch. 19
• AP Biology
• Ms. Haut

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Structure of Chromatin

• Eukaryotes package their chromosomal DNA into
  chromatin
• Based on successive levels of DNA packing

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DNA Packing
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Genome Organization at the DNA Level

• In eukaryotes, most DNA does not encode protein
  or RNA, and sequences may be interrupted by long
  stretches of noncoding DNA (introns)
• Some of sequences may be present in multiple
  copies

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Tandemly Repetitive DNA

• 10-25 of total DNA is satellite DNA, short
  (5-10 nucleotides) sequences that are tandemly
  repeated thousands of times
• Sequences are not transcribed, function unknown
• Associated with telomeres (ends of chromosomes)
• Important in maintaining integrity of the lagging
  strand during DNA replication
• Number of genetic disorders caused by abnormally
  long stretches of tandemly repeated nucleotide
  tripletsfragile X, Huntingtons disease

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Shortening Telomeres

• Telomerase periodically restores the repetitive
  sequence to the ends of chromosomes
• Humans have 250-1500 repetitions of TTAGGG
• Similar among many organisms--Contain blocks of G
  nucleotides

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Interspersed Repetitive DNA

• 25-40 (in mammals) of repeated units scattered
  about the genome
• Alu elements
• There are several presence/absence polymorphisms
  that are diagnostic for different human
  populations
• Can be used to infer time and order of sequence
  duplication events

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Transposons/Retrotransposons

• Jumping genes
• Retrotransposons move within the genome by means
  of an RNA intermediate, a transcript of the
  retrotransposon DNA
• To be reinserted, the RNA retrotransposon is
  converted back to DNA by the enzyme reverse
  transcriptase

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Control of Gene Expression

• Cell differentiation each cell expresses only a
  small fraction of its genes
• Genes are regulated on long term basis
• Transcription enzymes must locate the right genes
  at the right time
• Uncontrolled or incorrect gene action can cause
  serious imbalance and disease, including cancer

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Chromatin Modification affect Availability of
Genes for Transcription

• DNA methylation addition of CH3 to bases of DNA
  after DNA synthesis
• 5 of Cytosine residues are methylated
• Genes not expressed are more heavily methylated
  (e.g. Barr bodies)
• May explain genomic imprinting where the maternal
  or paternal allele of a gene is turned off at the
  start of development

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Chromatin Modification affect Availability of
Genes for Transcription

• Histone acetylation addition of COCH3 to
  certain amino acids of histone proteins
• When acetylated, histones grip DNA less tightly
• Transcription proteins have easier access to the
  genes in acetylated regions

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Roles of Transcription Factors

• Requires protein-protein interactions to initiate
  transcription
• Key to efficient transcription are control
  elements
• Enhancersactivator protein bind to and cause
  activators to be brought closer to the promoter
• Repressorsbind silencers which may affect DNA
  methylation

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Posttranscriptional Mechanisms

• Alternative splicing different mRNA molecules
  are produced from the same primary transcript
  depending on which RNA segments are treated as
  exons and which are treated as introns
• Controlled by regulatory proteins

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Regulation of mRNA Degradation

• Eukaryotic mRNA can exist in the cytoplasm for
  hours or even weeks
• Longevity of a mRNA affects how much protein
  synthesis it directs (longer viability more
  protein) (e.g. hemoglobin)

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Control of Translation

• Binding of repressor protein to 5-end of mRNA
  prevents ribosome attachment
• Translation can be blocked by inactivation of
  certain initiation factors (occurs during
  embryonic development)
• Inactive mRNA can be stored by ovum until
  fertilization triggers initiation factors to
  start translation

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Protein Processing and Degradation

• Polypeptide modification before activation
• Adding phosphate groups or chemical groups such
  as sugars
• Selective degradation
• Cells attach ubiquitin to mark proteins for
  destruction
• Proteasomes recognize the mark and destroy the
  protein
• Mutated cell-cycle cyclins that are impervious to
  proteasome degradation can lead to cancer

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Molecular Biology of Cancer

• Results from genetic changes that affect the cell
  cycle
• Can be random and spontaneous
• Most likely due to environmental influences
• Viral infection
• Exposure to carcinogens (X-rays, chemical agents)
• Leads to activation of oncogenes

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Proto-oncogenes

• Genes that normally code for regulatory proteins
  controlling cell growth, division and adhesion
• Can be transformed by mutation into an oncogene

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Movement of DNA within the Genome

• chromosomal abberationsplacing oncogenes next to
  promoters

Burkitts Lymphoma
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Gene Amplification

• More copies of oncogenes present in a cell than
  normal
• ras gene

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Point Mutation

• Slight change in nucleotide sequence might
  produce a growth-stimulating protein that is more
  active or more resistant to degradation than the
  normal protein

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Tumor-Suppressing Genes

• Changes in such genes can code for proteins that
  normally inhibit growth can promote cancer
• p53 gene
• Normal function
• Cooperate in DNA repair
• Control cell anchorage
• Play role in cell-signaling pathways that inhibit
  the cell cycle

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Tumor-Suppressing Genes

• Faulty tumor-suppressing genes interfere with
  normal signaling pathways

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Multiple Mutations Underlie Cancer Development

• More than one somatic mutation is probably needed
  to transform normal cells into cancerous cells

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Breast Cancer

• 5-10 of all breast cancer cases are believed to
  have a genetic link.
• Of these, 2/3 are caused by mutations in either
  BRCA1 or BRCA2, genes thought to play a role in
  fixing damaged DNA.
• 50-60 of individuals with certain mutations
  in either of these two genes will develop breast
  cancer by age 70.

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Viral Causes

• 15 of human cancer cases worldwide
• Some types of leukemia, liver cancer, cervical
  cancer
• Viruses might
• add oncogenes to cells
• Disrupt tumor-suppressor genes
• Convert proto-oncogenes into oncogenes