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Chromatin RemodelingChromatin Remodeling
DNA is wrapped around histones to form DNA is wrapped around histones to form nucleosomesnucleosomes Chromosome packagingChromosome packaging
Acetylation =acetyl groups are added to Acetylation =acetyl groups are added to histones histones Exposes the primer so RNA polymerase can bind Exposes the primer so RNA polymerase can bind
and transcription can beginand transcription can begin Deacetylation =acetyl groups are removed Deacetylation =acetyl groups are removed
from histonesfrom histones
RNA InterferenceRNA Interference
Occasionally, both DNA strands are Occasionally, both DNA strands are transcribedtranscribed
Complementary strands bind to one anotherComplementary strands bind to one another Gene sequence may allow formation of a Gene sequence may allow formation of a
“hairpin loop”“hairpin loop” RNA strand binds to itselfRNA strand binds to itself
Segments of dsRNA attract RNA-induced Segments of dsRNA attract RNA-induced silencing complexes (RISCs)silencing complexes (RISCs)
Can be used experimentally (clinically?)Can be used experimentally (clinically?)
What is a Mutation? A change in the DNA sequence that is present in <1% 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 >1% of the population Change in DNA Altered RNA Messed up protein Mutation refers to genotype while “mutant” refers to
phenotype
Types of Mutations Point mutations Splice site mutations Deletions and insertions Pseudogenes and transposons Expanding repeats Copy # variants
Point Mutations Base substitution –may be good, bad, or neutral
Transition Purine replaces purine (AG or GA) Pyrimidine replaces pyrimidine (CT or TC)
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
Base Substitution
Normal gene
mRNA
Protein
A
Lys Phe Gly Ala
A A ACC GGGG U U UUU G
Met
Base substitution
Met Lys Phe Ser Ala
UA G CA A AU U UG G AG C
Base Substitution –Sickle Cell AnemiaNormal hemoglobin DNA
Normal hemoglobin
Glu
mRNA
C
G A A
TT
Mutant hemoglobin DNA
Sickle-cell hemoglobin
Val
mRNA
C
G
A T
AU
Normal Red Blood Cell
Sickle-shaped Red Blood Cell
Genotype
Phenotype
Splice Site Mutations A type of point mutation that alters the way introns
and exons are spliced Intron is translated or
exon is skipped
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 gene’s
sequence
Normal gene
mRNA
Protein
A
Lys Phe Gly Ala
A A ACC GGGG U U UUU G
Met
Base deletion Missing
A
Lys Leu Ala His
U G CA A G U U UG G C G
U
A
Met
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
Expanding Repeats Gene expands <40 copies of the repeated segment is
transmitted normally but >40 are unstable Cause “anticipation”
Phenotype gets worse and has younger onset with each generation
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
Effects of Mutations Loss of function
Gene’s product is reduced or absent Tend to be recessive
Gain of function The action of the gene product changes Tend to be dominant
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)
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
Mutational Hotspots Regions in the DNA where
mutations are more likely to occur Usually, repetitive sequences
“Mississsippii”
Induced Mutations
A mutagen is an agent that causes mutation Ex: Ionizing radiation breaks the DNA sugar-
phosphate backbone