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Unit 5: Gene Expression and Mutation
Genetics 2013 - 2014
Gene Expression through Time and Tissue
 Changes in gene expression may occur _____________________________ and in different cell types
 This may occur at the ____________________________________________/gland level
 _________________________ changes
- Changes to the chemical groups that __________________________________________ DNA that are transmitted to
daughter cells after cell division
 Adult hemoglobin has _____________ globular polypeptide chains
- Two alpha (α) chains = ____________ amino acids
- Encoded on chromosome _________
- Two beta (β) chains = ____________ amino acids
- Encoded on chromosome ___________
 Each globin surrounds an iron-containing ______________ group
Globin Chain Switching
 Subunits change in response to ____________________ levels
 Subunit makeup ______________ over lifetime
- ______________________ = Two epsilon () + two zeta ()
- ______________________ = Two gamma () + two alpha ()
- ______________________ = Two beta (β) + two alpha ()
- The adult type is about 99% of hemoglobins by _______________ years of age
Changing Gene Expression in Blood Plasma
 Blood plasma contains about __________________________ different types of proteins
 Changing conditions cause a change in the ____________________________________________ of the plasma
 ____________________________________ biology is shedding light on how genes are turned on and off
 The pancreas is a ______________ gland
- _______________________ part releases digestive enzymes into ducts
- _______________________ part secretes polypeptide hormones directly into the bloodstream
 ___________________________________________________________________________ produces either endocrine or exocrine cells
 If transcription factor pdx-1 is activated, some ___________________________________________ follow the exocrine pathway
 Other progenitor cells respond to different ________________________ and yield daughter cells that follow the endocrine
 Proteomics tracks _____________________________________ made in a cell, tissue, gland, organ or entire body
 Proteins can be charted based on the relative abundance of each class at different _____________ of development
 There are _________________________________ categories of proteins
- Including the __________________________________________________, which are activated after birth
Figure 11.4: My summary____________________________________________________________________________________________
Control of Gene Expression
 A protein-encoding gene contains some controls over its ___________________ expression level
- _________________________________ sequence (mutations)
- _________________________________ of gene
 Much of the control of gene expression occurs in two general processes
1) Chromatin __________________________________ = “On/off” switch
2) microRNAs = ___________________________” switch
Chromatin Remodeling
 _______________________________ play major role in gene expression
- ______________________ DNA when and where it is to be transcribed and ___________________ it when it is to be silenced
 The three major types of small molecules that bind to histones are:
- ____________________________ group
- ____________________________ groups
- ____________________________ groups
______________________________________ can subtly shift
histone interactions in a way that eases transcription
Chromatin Remodeling Table Summary: ________________________________________________________________________________________
 MicroRNAs belong to a class of molecules called _________________________________
 They are ______________________ bases long
 The human genome has about 1,000 distinct microRNAs that ____________________ at least 1/3rd of the protein-encoding
 When a microRNA binds to a “target” mRNA, it ________________________________________
____________________________________ provides a practical application of microRNAs because certain microRNAs are
more or less abundant in cancer cells than in healthy ones
A related technology is called _____________________________________________________
- Small synthetic, double-stranded RNA molecules are introduced into selected cells to ______________gene expression
Animation Summary: __________________________________________________________________________________________________________
Maximizing Genetic Information
 The human genome contains about ________________________________ genes
- However, these encode about ____________________________ mRNAs, which in turn specify more than a
_____________________ proteins
 Several events account for the fact that __________________________ outnumber genes
The “genes in pieces” pattern of exons and introns and ______________________________ help to greatly expand the gene
An ___________________________ in one gene’s template strand may encode a protein on the coding strand
Information is also maximized when a protein undergoes _________________________________________ modifications
- Addition of sugars and lipids to create __________________________________ and lipoproteins
Another way that one gene can encode more than one protein is if the protein is _____________ to yield two products
This happens in ______________________________________ imperfect (Yep, fairly gross)
- Caused by a deficiency in the _________________________________ DPP and DSP
- Both are cut from the ________________________ DSPP protein
Most of the Human Genome Does Not Encode Protein
 Only _____________ of human DNA encodes protein
 Rest of genome includes:
- ______________ DNA
- Noncoding ____________
- ____________________
- Promoters and other ______________________ sequences
- _________________________________ sequences
Viral DNA
 About _____________ of our genome is derived from RNA viruses called _______________________________
- This is evidence of ____________________________________________
- Sequences tend to ____________________ over time
Noncoding RNAs
 Nearly all of the human genome can be ______________________________, and much of it is in the form of noncoding RNAs
 This includes ________________ and _____________________
 However, there are hundreds of thousands of other ncRNAs
- These are transcribed from ____________________________
- But are not _____________________________into protein
 ___________________________ are the most abundant type of repeat
- Sequences that ________________ about the genome
- ____________ repeats can copy themselves
- Comprise about _____________ of the genome
 Rarer classes of repeats include those that comprise _________________________________________, and rRNA gene clusters
Transposon Animation Summary: ______________________________________________________________________________________________
Be sure to pay attention to types of noncoding regions and their characteristics in Table 11.2
The Nature of Mutations
 A mutation is change in a DNA sequence that is present in ___________________ of a population
 May occur at the __________________________________________________ level
 A _____________________________________ is a genetic change that is present in > 1% of a population
 The effect of mutations vary
o “Loss-of-function” mutations – ________________________
o “Gain-of-function” mutations – _______________________
 The term mutant refers to ___________________
- Usually connotes an abnormal or unusual, or even uncommon variant that is nevertheless ________________________
 Mutations are important to __________________________
 Our evolutionary _____________________________ to other species allows us to study many mutations in non-human
 Germline mutations
- Originate in ____________________________
- Affect ______________________ of an individual
 Somatic mutations
- Originate in ______________________
- Affect only cells that __________________________ from changed cell
Mutations Alter Proteins
 Identifying how a mutation _____________________________________ has clinical applications
 Examples of mutations that cause disease:
- _____________________________ gene
- _____________________________ genes
Sickle Cell Anemia
 Results from a __________________________________________________
-globin gene, which replaces glutamic acid (6th
position) with valine
 Phenotype associated with _______________________________
 Altered surface of hemoglobin allows molecules to link in ___________________________ conditions
 Creates __________________________________ of RBC
 Sickling causes ______________________________________________________________________________________ when RBC
become lodged in small blood vessels
 Caused by another _________________________________________ mutation
 Too _______________ beta globin chains
 Excess of alpha globin __________________________ formation of hemoglobin molecules
 So RBCs die
 Liberated _______________ slowly damages heart, liver, and endocrine glands
 Two forms
o Thalassemia ______________ (heterozygous)
o Thalassemia ______________ (homozygous for mutation and more severe)
 A major component of _________________________________________
- Bone, _________________________, skin, ligament, tendon, and tooth dentin
 More than ____________ collagen genes encode more than ___________ types of collagen molecules
 Mutations in these genes lead to a variety of ___________________________ problems
 Collagen has a _____________________ structure
- Triple helix of two _________________________ polypeptides
- Longer ________________________________, procollagen is trimmed to form collagen
Collagen Disorders
 Be familiar with what these are; you will not be asked details
Ehler-Danos Syndrome
 A mutation prevents _________________________ chains from being cut
 Collagen molecules cannot assemble, and so _________________ becomes stretchy
How Mutations Cause Disease
 Mutations in a gene may cause either ____________________________________ of the same disease or distinct illnesses
 Table 12.2 lists several examples of mutations and the diseases they produce
o You should be able to describe and explain two of these
o You should be familiar with the name and ____________________________of the remainder
Causes of Mutations
 Mutations may occur ______________________________ or by exposure to a chemical or radiation
 An agent that causes a mutation is called a __________________________________________
Spontaneous Mutation
 ________________________ or new mutations
 Not caused by _____________________________ to known mutagen
 Result from errors in __________________________________________
 DNA bases have slight _______________________________________
 Exist in alternating forms called ________________________________
 As replication fork encounters unstable tautomers, ________________________ can occur
Tautomer Mispairing Animation Summary: _____________________________________________________________________________________
Spontaneous Mutation Rate
 Rate ______________________ between genes
- _____________________________ usually have higher mutation rates
 Each human gene has about ____________________________ chance of mutating
 Each individual has ___________________________________ mutations
 Mitochondrial genes mutate at a _______________________ than nuclear genes because they cannot ________________their
Mutation Rates
 Do not memorize rates!
 MIM means: _________________________________________________________________________________________________________
Determining Mutation Rate
 Estimates of spontaneous mutation rate can be derived from _______________________________, dominant traits
 For _________________________ genes,
mutation rate = # of ____________ cases/2X
where X = # of individuals examined
Types of Mutations Table 12.4
 Recognize each of these mutation types
Mutational Hot Spots
 In some genes, mutations are more likely to occur in regions called _____________________
 Short ______________________________ sequences
o Pairing of repeats may interfere with _____________________________________ enzymes
 _____________________________________________
o Often associated with _____________________________________________________
DNA symmetry increases the likelihood of mutation: Figure 12.6
Repeated genes are prone to mutation by mispairing during meiosis
Induced Mutations
 Caused by mutagens, many are also ____________________________________ and cause cancer
 Examples:
- ____________________________ agents: remove a base
- ______________________________ dyes: add or remove base
- ___________________________________: break chromosomes
- ___________________________________: creates thymine dimers
 Site-directed mutagenesis: Changes a gene in a __________________________ way
Ames Test
 An ___________________________ test of the mutagenicity of a substance
 One version uses Salmonella bacteria with mutation in gene for ____________________________
- ____________________________ are exposed to test substance
- Growth on media ________________________________ is recorded
- Bacteria ____________________ grow if mutations have occurred
- Substance can be mixed with _______________________________________________________________ prior to testing
to mimic toxin processing in humans
Exposure to Mutagens
 Some mutagen exposure is __________________________________
- Workplace
- Industrial accidents
- ______________________________
- Medical _____________________________
- Weapons
- ____________________ sources
- Cosmic rays, sunlight, earth’s crust
Types of Mutations
 Mutations can be classified in several ways
- By whether they ___________________________________________________ a function
- By exactly how they ________________________________ DNA
Point Mutations
 A change of a ____________________ nucleotide
 _________________ = Purine replaces purine or pyrimidine replaces pyrimidine
A to G or G to A
C to T or T to C
 _________________ = Purine replaces pyrimidine or pyrimidine replaces purine
A or G to T or C
T or C to A or G
Consequences of Point Mutations
 ______________________________ mutation = Replaces one amino acid with another
 ______________________________ mutation = Changes a codon for an amino acid into a stop codon
- Creates _______________________________ proteins that are often non-functional
 A stop codon that is changed to a coding codon ___________________________ the protein
Splice Site Mutations
 Alters a site where an intron is normally ________________________ from mRNA
 Can affect the phenotype if:
1) Intron is __________________ or exon skipped
- Example: _____________________________________
2) Exon is __________________________
- Example: Familial dysautonomia (FD)
Deletions and Insertions
 The genetic code is read in _______________________
 Nucleotides changes __________________ in multiples of 3 lead to disruptions of the reading frame
 Cause a __________________________________________ and alter amino acids after mutation
 Nucleotide changes in multiples of 3 will _________________ cause a frame-shift
- But they can still __________________________ the phenotype
 A _____________________________ removes genetic material
- __________________infertility: Tiny deletions in the Y
 An ___________________________ adds genetic material
- Gaucher disease: Insertion of one base
 A __________________________________________ is an insertion of identical sequences side by side
- Charcot-Marie-Tooth disease: Tandem duplication of _____________________________ bases
Deletion/Insertion Animation Summary: _____________________________________________________________________________________
Note: ______________________________________ of mutations can cause the ___________________ single-gene disorder
- Example: Familial ________________________________________________
 A DNA sequence similar to a gene but which is _________________________________________
 May not even be __________________________ into RNA
 May have evolved from original gene by _________________________________________________________ mutation
 __________________________________ between a pseudogene and functional gene can disrupt gene expression
Expanding Repeats
 Insertion of ____________________________________ leads to extra amino acids
- The longer proteins ________________________ the cells
 Some genes are particularly prone to _____________________________ of repeats
 Number of repeats correlates with _____________________________________________ and more severe phenotype
 ___________________________________ is the expansion of the triplet repeat with an increase in severity of phenotype with
subsequent generations
Myotonic Dystrophy: A Triplet Repeat Disease
Copy Number Variants (CNV)
 Are sequences that ______________________________________________ from person to person
 Range in size from a __________________________________ to millions
 Account for about _____________ of our genome
 CNVs may have _________________________________ on the phenotype or they can _____________________ a gene’s function
and harm health
 Indeed, CNVs correlated to _______________________________________ might be used to give medical advice
Importance of Position
 The degree that a mutation _____________________ phenotype depends on:
- _____________________ in the gene the change occurs
- How it affects ____________________________ or expression of encoded protein
 Examples – ______________________ and prions
- Certain mutations exert effects while others _____________________
Globin Mutations
Understand that many different mutations in the same gene can occur, each with different effects
Prion Disorders
 A prion disease can be ___________________________________________________
 The prion protein exists in both _______________________________________________________ conformations
- The normal form has a ________________________________ made up of helices
- In a disease-causing form, the helices open into a _________________________
 The amino acid in ____________________ position is key to developing prion disease
 Individuals ____________________________ with valine (VV) or methionine (MM) develop disease
 Heterozygotes have ______________________ function
 Position 178 is also important due to the _______________________ of the protein
Not All Mutations Impact Protein Function
 _________________________________mutations are mutations that do not alter the encoded amino acid
 Example:
- A mutation from CAA to CAG alters the DNA, but the protein sequence __________________________________
- CAA and CAG both code for ___________________________________________
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- These are called _________________________________________________
A ______________________________________ alters the encoded amino acid to another amino acid
- Creates a __________________________________ codon
 Some nonsynonymous mutations are _________________________________________; Encode a chemically similar amino acid
and may not alter function
 The impact of a missense mutation is not _______________________ from protein sequence alone
 A __________________________________mutation produces a phenotype under particular conditions or environments
 Glucose 6-phosphate dehydrogenase enzyme responds to ___________________________________, chemicals that strip
electrons from other molecules
 High levels of oxidants occur when eating _____________________________ or taking certain antimalarial drugs
Individuals with G6PD mutations
Low oxidants
_______________ phenotype
High oxidants
RBCs __________________; Hemolytic anemia
DNA Repair
 Errors in ___________________________________ or damage to DNA create mutations
- May result in _______________________
 Fortunately, most errors and damage are ____________________________
 Type of repair depends upon the type of _________________________ or error
 Organisms vary in their ability to ______________________ DNA
Types of DNA Repair
 In many modern species, _____________________________ of DNA repair peruse the genetic material
1) _____________________________ repair
2) _____________________________ repair
3) _____________________________ repair
Photoreactivation Repair
 Enzymes called _________________________________ use light energy to break the extra bonds in a pyrimidine dimer
 Enables UV-damaged _____________________to recover from exposure to sunlight
 _____________________________ do not have this type of repair
Excision Repair
 Pyrimidine dimers and surrounding bases are ______________________________________________________
 Humans have _______________________________ of excision repair
 ____________________________________ repair
- Replaces up to ______________ bases
- Corrects mutations caused by different insults
 _____________________________________ repair
- Replaces _______________ bases
- Specific to _________________________ damage
Excision Repair
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DNA Repair Animation Summary: _____________________________________________________________________________________
Mismatch Repair
Enzymes detect nucleotides that do not base pair in newly replicated DNA
The incorrect base is excised and replaced
Proofreading is the detection of mismatches
Failure of DNA Repair
If both copies of a repair gene are mutant, a disorder can result
The protein p53 monitors repair of DNA
If damage is too severe, the p53 protein promotes programmed cell death or apoptosis
Mutations may occur in genes encoding DNA repair proteins
Lead to overall increase in mutations
Repair Disorders: Trichothiodystrophy
At least five genes are involved
Symptoms reflect accumulating oxidative damage
Faulty nucleotide excision repair or base excision repair or both
Repair Disorders:
Inherited Colon Cancer
Hereditary nonpolyposis colon cancer
Affects 1/200 individuals
Defect in mismatch repair
HNPCC gene is on chromosome 2
Repair Disorders:
Xeroderma Pigmentosum
Autosomal recessive; Seven genes involved
Malfunction of excision repair
Thymine dimers remain and block replication
Must avoid sunlight
Only 250 cases worldwide
Repair Disorders:
Ataxia Telangiectasis
Autosomal recessive disorder
Defect in cell cycle checkpoint kinase
Cells continue through cell cycle without pausing to inspect DNA
Individuals with AT have 50X the risk of developing over general population
Heterozygotes have a two- to sixfold increase in cancer risk
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