ch12 gene mutation

8/3/2019 Ch12 Gene Mutation

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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 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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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

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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

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

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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

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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

ch12 gene mutation

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