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Chromatin Remodeling DNA is wrapped around histones to form nucleosomes DNA is wrapped around...

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

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?)

RNA InterferenceRNA Interference

Mutations

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

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


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