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Human Genetics
Concepts and ApplicationsNinth Edition
RICKI LEWIS
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display
PowerPoint Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida
12
Gene
Mutation
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The Nature of Mutations
A mutation is change in a DNA sequencethat is present in < 1% of a population
May occur at the DNA or chromosome level
A polymorphism is a genetic change thatis present in > 1% of a population
The effect of mutations varyLoss-of-function mutations Recessive
Gain-of-function mutations Dominant
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The Nature of Mutations
The term mutant refers to phenotype
- Usually connotes an abnormal or
unusual, or even uncommon variant thatis nevertheless normal
Mutations are important to evolution
Our evolutionary relatedness to otherspecies allows us to study manymutations in non-human species
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Figure 12.1
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The Nature of Mutations
Germline mutations
- Originate in meiosis
- Affect all cells of an individual
Somatic mutations
- Originate in mitosis
- Affect only cells that descend fromchanged cell
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Mutations Alter Proteins
Identifying how a mutation causessymptoms has clinical applications
Examples of mutations that causedisease:
- Beta globin gene- Collagen genes
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Sickle Cell Anemia
Results from a single DNA base change in theb-globin gene, which replaces glutamic acid(6th position) with valine
Phenotype associated with homozygotesAltered surface of hemoglobin allows molecules
to link in low oxygen conditions
Creates sickle shape of RBC
Sickling causes anemia, joint pain, and organdamage when RBC become lodged in smallblood vessels
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Figure 12.2
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Thalassemia
Caused by another beta hemoglobin mutation
Too few beta globin chains
Excess of alpha globin prevents formation of
hemoglobin moleculesSo RBCs die
Liberated iron slowly damages heart, liver, and
endocrine glandsThalassemia minor (heterozygous)
Thalassemia major (homozygous for mutationand more severe)
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Collagen
A major component of connective tissue
- Bone, cartilage, skin, ligament, tendon,and tooth dentin
More than 35 collagen genes encode morethan 20 types of collagen molecules
Mutations in these genes lead to a varietyof medical problems
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Collagen Disorders
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Collagen has a precise structure
- Triple helix of two a1 and one a2polypeptides
- Longer precursor, procollagen istrimmed to form collagen Figure 12.3
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Figure 12.4
Ehler-Danos Syndrome
A mutation prevents procollagen chainsfrom being cut
Collagen molecules cannot assemble, and
so skin becomes stretchy
Figure 12.4
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Figure 12.4
How Mutations Cause Disease
Mutations in a gene may cause eitherdifferent versions of the same disease
or distinct illnesses
Table 12.2 lists several examples of
mutations and the diseases theyproduce
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How Mutations Cause Disease
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Figure 12.4
Causes of Mutations
Mutations may occur spontaneously or byexposure to a chemical or radiation
An agent that causes a mutation is calleda mutagen
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Figure 12.4
Spontaneous Mutation
De novoor new mutations
Not caused by exposure to known mutagen
Result from errors in DNA replicationDNA bases have slight chemical instability
Exist in alternating forms called tautomers
As replication fork encounters unstabletautomers, mispairing can occur
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Figure 12.4
Figure 12.5
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Figure 2.3
Tautomer Mispairing Animation
Please note that due to differingoperating systems, some animationswill not appear until the presentation is
viewed in Presentation Mode (SlideShow view). You may see blank slidesin the Normal or Slide Sorter views.
All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available at
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Figure 12.4
Spontaneous Mutation Rate
Rate differs between genes
- Larger genes usually have highermutation rates
Each human gene has about 1/100,000chance of mutating
Each individual has multiple new mutations
Mitochondrial genes mutate at a higher ratethan nuclear genes because they cannotrepair their DNA
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Mutation Rates
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Figure 12.4
Determining Mutation Rate
Estimates of spontaneous mutation ratecan be derived from observation of new,
dominant traits
For autosomal genes,
mutation rate = # of new cases/2Xwhere X = # of individuals examined
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Figure 12.4
Mutational Hot Spots
In some genes, mutations are more likelyto occur in regions called hot spots
Short repetitive sequences- Pairing of repeats may interfere withreplication or repair enzymes
Palindromes- Often associated with insertions ordeletions
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DNA symmetry
increases thelikelihood ofmutation
Figure 12.4
Figure 12.6
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Figure 12.4
Repeated genesare prone to
mutation bymispairingduring meiosis
Figure 12.7
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Figure 12.4
Induced Mutations
Caused by mutagens, many are alsocarcinogens and cause cancer
Examples:
- Alkylating agents: remove a base- Acridine dyes: add or remove base
- X rays: break chromosomes
- UV radiation: creates thymine dimers
Site-directed mutagenesis: Changes a gene in adesired way
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Figure 12.4
Ames Test
An in vitrotest of the mutagenicity of a substance
One version uses Salmonellabacteria with
mutation in gene for histidine- Bacteria are exposed to test substance
- Growth on media without histidine is recorded
- Bacteria only grow if mutations have occurred
- Substance can be mixed with mammalian livertissue prior to testing to mimic toxin processingin humans
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Figure 12.4
Exposure to Mutagens
Some mutagen exposure is unintentional
- Workplace
- Industrial accidents
- Chernobyl
- Medical treatments
- Weapons- Natural sources
- Cosmic rays, sunlight, earths crust
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Figure 12.4
Types of Mutations
Mutations can be classified in severalways
- By whether they remove, alter, or adda function
- By exactly how they structurally alterDNA
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Figure 12.4
Point Mutations
A change of a single nucleotide
Transition = Purine replaces purine orpyrimidine replaces pyrimidine
A to G or G to A or
C to T or T to C
Transversion = Purine replaces pyrimidineor pyrimidine replaces purine
A or G to T or C
T or C to A or G
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Figure 12.4
Consequences of Point Mutations
Missense mutation = Replaces one aminoacid with another
Nonsense mutation = Changes a codonfor an amino acid into a stop codon
- Creates truncated proteins that areoften non-functional
A stop codon that is changed to a codingcodon lengthens the protein
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Figure 12.4
Splice Site Mutations
Alters a site where an intron is normallyremoved from mRNA
Can affect the phenotype if:
1) Intron is translated or exon skipped
- Example: CF mutation
2) Exon is skipped
- Example: Familial dysautonomia (FD)
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Figure 12.4
Deletions and Insertions
The genetic code is read in triplets
Nucleotides changes not in multiples of 3lead to disruptions of the reading frame
Cause a frameshift mutation and alteramino acids after mutation
Nucleotide changes in multiples of 3 willNOT cause a frame-shift
- But they can still alter the phenotype
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Figure 12.4
Deletions and Insertions
A deletion removes genetic material
- Male infertility: Tiny deletions in the Y
An insertion adds genetic material- Gaucher disease: Insertion of one base
A tandem duplication is an insertion of
identical sequences side by side- Charcot-Marie-Tooth disease: Tandemduplication of 1.5 million bases
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Figure 2.3
Deletion/Insertion Animation
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the Normal or Slide Sorter views.
All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available at
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Figure 12.4
Note: Different types of mutations can cause thesame single-gene disorder
- Example: Familial hypercholesterolemia
Figure 12.9
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Figure 12.4
Pseudogenes
A DNA sequence similar to a gene butwhich is not translated
May not even be transcribed into RNA
May have evolved from original gene byduplication and acquired mutation
Crossing over between a pseudogeneand functional gene can disrupt geneexpression
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Figure 12.4
Expanding Repeats
Insertion of triplet repeats leads to extra aminoacids
- The longer proteins shut down the cells
Some genes are particularly prone to expansionof repeats
Number of repeats correlates with earlier onsetand more severe phenotype
Anticipation is the expansion of the triplet repeatwith an increase in severity of phenotype withsubsequent generations
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Myotonic Dystrophy:
A Triplet Repeat Disease
Figure 12.10Figure 12.10
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Triplet Repeat Disorders
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Figure 12.4
Copy Number Variants (CNV)
Are sequences that vary in number fromperson to person
Range in size from a few bases to millionsAccount for about 25% of our genome
CNVs may have no effect on the
phenotype or they can disrupt a genesfunction and harm health
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Figure 12.4
Copy Number Variants (CNV)
Indeed, CNVs correlated to cholesterol levelmight be used to give medical advice
Figure 12.11
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Figure 12.4
Importance of Position
The degree that a mutation alters phenotypedepends on:
- Where in the gene the change occurs- How it affects conformation or expressionof encoded protein
Examples Hemoglobin and prions- Certain mutations exert effects whileother do not
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Globin Mutations
Table 12.8
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Figure 12.4
Prion Disorders
A prion disease can be inherited or acquired
The prion protein exists in both normal andinfectious conformations
- The normal form has a central core made
up of helices- In a disease-causing form, the helicesopen into a sheet
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Figure 12.4
Prion Disorders
The amino acid in 129th position is key todeveloping prion disease
Individuals homozygous with valine (VV) ormethionine (MM) develop disease
Heterozygotes have normal function
Position 178 is also important due to thefolding of the protein
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Figure 12.4
Not All Mutations
Impact Protein FunctionSilent mutations are mutations that do not
alter the encoded amino acid
Example:- A mutation from CAA to CAG alters theDNA, but the protein sequence remains
unchanged- CAA and CAG both code for glutamine
- These are called synonymous codons
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Figure 12.4
Not All Mutations
Impact Protein FunctionA missense mutation alters the encoded
amino acid to another amino acid
- Creates a nonsynonymous codonSome nonsynonymous mutations are
conservative; Encode a chemically similar
amino acid and may not alter functionThe impact of a missense mutation is not
predictable from protein sequence alone
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Figure 12.4
A conditional mutation produces a phenotypeunder particular conditions or environments
Glucose 6-phosphate dehydrogenase enzymeresponds to oxidants, chemicals that stripelectrons from other molecules
High levels of oxidants occur when eating favabeans or taking certain antimalarial drugs
Conditions Individuals with G6PD mutationsLow oxidants No phenotype
High oxidants RBCs burst; Hemolytic anemia
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G6PD Deficiency Hemolytic
Anemia
Figure 12.12
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Figure 12.4
DNA Repair
Errors in DNA replication or damage to DNAcreate mutations
- May result in cancer
Fortunately, most errors and damage arerepaired
Type of repair depends upon the type ofdamage or error
Organisms vary in their ability to repair DNA
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Figure 12.4
Types of DNA Repair
In many modern species, three types ofDNA repair peruse the genetic material
1) Photoreactivation repair
2) Excision repair
3) Mismatch repair
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Figure 12.4
Photoreactivation Repair
Enzymes called photolyases use lightenergy to break the extra bonds in apyrimidine dimer
Enables UV-damaged fungi to recoverfrom exposure to sunlight
Humans do not have this type of repair
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Figure 12.4
Excision Repair
Pyrimidine dimers and surrounding basesare removed and replaced
Humans have two types of excision repair
Nucleotide excision repair
- Replaces up to 30 bases
- Corrects mutations caused by different insults
Base excision repair
- Replaces 1-5 bases
- Specific to oxidative damage
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ExcisionRepair
Figure 12.13
Figure 12.13
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Figure 2.3
DNA Repair Animation
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (Slide
Show view). You may see blank slidesin the Normal or Slide Sorter views.
All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available at
http://get.adobe.com/flashplayer.
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Figure 12.4
Mismatch Repair
Enzymes detectnucleotides that donot base pair in
newly replicated DNAThe incorrect base is
excised and replaced
Proofreading is thedetection ofmismatches
Figure 12.14
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Figure 12.15
Figure 12.15
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Figure 12.4
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 proteinpromotes programmed cell death orapoptosis
Mutations may occur in genes encodingDNA repair proteins
Lead to overall increase in mutations
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Figure 12.4
Repair Disorders:
TrichothiodystrophyAt least five genes are involved
Symptoms reflect accumulating oxidativedamage
Faulty nucleotide excision repair or baseexcision repair or both
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Figure 12.4
Repair Disorders:
Inherited Colon CancerHereditary nonpolyposis colon cancer
Affects 1/200 individuals
Defect in mismatch repair
HNPCC gene is on chromosome 2
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Figure 12.4
Repair Disorders:
Xeroderma PigmentosumAutosomal recessive;
Seven genes involved
Malfunction of excisionrepair
Thymine dimers remain
and block replicationMust avoid sunlight
Only 250 cases worldwide
Figure 12.16
R i Di d
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Figure 12.4
Repair Disorders:
Ataxia TelangiectasisAutosomal recessive disorder
Defect in cell cycle checkpoint kinase
Cells continue through cell cycle withoutpausing to inspect DNA
Individuals with AT have 50X the risk of
developing over general population
Heterozygotes have a two- to sixfoldincrease in cancer risk