Chromatin Remodeling

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Chromatin Remodeling

• DNA is wrapped around histones to form
  nucleosomes
• Chromosome packaging
• Acetylation acetyl groups are added to histones
• Exposes the primer so RNA polymerase can bind and
  transcription can begin
• Deacetylation acetyl groups are removed from
  histones

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(No Transcript)
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RNA Interference

• Occasionally, both DNA strands are transcribed
• Complementary strands bind to one another
• Gene sequence may allow formation of a hairpin
  loop
• RNA strand binds to itself
• Segments of dsRNA attract RNA-induced silencing
  complexes (RISCs)
• Can be used experimentally (clinically?)

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RNA Interference
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Mutations
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What is a Mutation?

• A change in the DNA sequence that is present in
  lt1 of the population
• Mutations can happen at the DNA level or at the
  chromosome level
• Can affect any part of the genome (introns,
  exons, etc.)
• A polymorphism is also a change in a single
  nucleotide but occurs in gt1 of the population
• Change in DNA ?Altered RNA ?Messed up protein
• Mutation refers to genotype while mutant refers
  to phenotype

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Types of Mutations

• Point mutations
• Splice site mutations
• Deletions and insertions
• Pseudogenes and transposons
• Expanding repeats
• Copy variants

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Point Mutations

• Base substitution may be good, bad, or neutral
• Transition
• Purine replaces purine (A?G or G?A)
• Pyrimidine replaces pyrimidine (C?T or T?C)
• Transversion
• Purine exchanged for pyrimidine (or vice versa)
• Missense
• Mutation causes change from one amino acid to
  another
• Nonsense
• Mutation causes change from an amino acid codon
  into a STOP codon
• Mutation in the promoter region
• Protein is normal but less protein is produced

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Base Substitution
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Base Substitution Sickle Cell Anemia
Genotype
Phenotype
Normal Red Blood Cell
Sickle-shaped Red Blood Cell
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Splice Site Mutations

• A type of point mutation that alters the way
  introns and exons are spliced
• Intron is translated or
• exon is skipped

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Deletions and Insertions

• Often cause a frameshift mutation
• Shift the entire reading frame (this is almost
  always REALLY BAD)
• May involve a single nucleotide or an entire
  piece of chromosome
• Tandem duplication
• An insertion mutation that repeats part of a
  genes sequence

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Pseudogenes and Transposons

• Pseudogene
• DNA sequence that is very similar to that of a
  protein-encoding gene
• Sometimes transcribed but not translated
• May interfere with the normal gene, especially
  during crossing over
• Transposons
• Jumping genes
• May disrupt the site they jump from or the one
  they jump to

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Expanding Repeats

• Gene expands
• lt40 copies of the repeated segment is transmitted
  normally but gt40 are unstable
• Cause anticipation
• Phenotype gets worse and has younger onset with
  each generation

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Copy Variants

• Sequences that are present in more than one place
  in the genome
• Two individuals may have similar DNA sequences
  but very different s of copies of those
  sequences
• Copies may be next to each other or on different
  chromosomes

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Effects of Mutations

• Loss of function
• Genes product is reduced or absent
• Tend to be recessive
• Gain of function
• The action of the gene product changes
• Tend to be dominant

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Germline vs. Somatic Mutations

• Germline mutation
• Change occurs during DNA replication before
  meiosis
• Resulting gamete and all cells that descend from
  it following fertilization have the mutation (all
  cells in the body)
• Somatic mutation
• Change occurs during DNA replication before
  mitosis
• All cells that descend from the changed cell are
  mutated (a subset of cells in the body)

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Spontaneous Mutations

• Usually an error in DNA replication
• Each gene has a 1/100,000 chance of mutating
• We all likely have several mutations in our DNA
  but most DNA is non-coding

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Mutational Hotspots

• Regions in the DNA where mutations are more
  likely to occur
• Usually, repetitive sequences
• Mississsippii

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Induced Mutations

• A mutagen is an agent that causes mutation
• Ex Ionizing radiation breaks the DNA
  sugar-phosphate backbone

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Conditional Mutations

• Ex The gene for glucose 6-phosphate
  dehydrogenase
• Used by red blood cells to extract energy from
  glucose
• Mutated in 100 million people
• The mutation can cause severe anemia but ONLY
  following exposure to
• Fava beans
• Pollen in Baghdad
• Or certain anti-malaria drugs