Chapter 15 - Gene Mutation and Molecular Medicine

Define Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A change in the nucleotide sequence of DNA that can be passed on from one cell, or organism, to another.

In organisms that give rise to gametes, two types of mutations can occur, what are they?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Somatic mutations

2. Germ line mutations

Somatic mutations occur in what type of cells?

Concept 15.1 Mutations Are Heritable Changes in DNA

In non-gamete body/somatic cells. These cells don’t give rise to gametes.

Germ line mutations occur in what type of cells?

Concept 15.1 Mutations Are Heritable Changes in DNA

In sex/gametes/germ line cells. These cells give rise to gametes.

Which type of mutation, somatic or germ line, can be passed on to offspring?

Concept 15.1 Mutations Are Heritable Changes in DNA

Germ line mutations can be passed down to offspring. Somatic mutations only affect the individual.

Define Somatic Mutations

Vocab 15.1 Mutations Are Heritable Changes in DNA

Mutations that occur in somatic (non-gamete) cells that only affect the individual and are not passed on to sexually produced offspring.

Ex. A mutation in a single human skin cell could result in a patch of skin cells that all have the same mutation. But, this won’t be passed on to the person’s children. (From Text)

Define Germ Line Mutations

Vocab 15.1 Mutations Are Heritable Changes in DNA

Mutations that occur in germ line cells (specialized cells that produce gametes) that are passed on to new organisms at fertilization. (The offspring will have the mutation in every cell of its body and will pass it on to their offspring.)

Ex. The BRCA₁ mutation that Angelina Jolie, her aunt, and her mother inherited from Angelina’s grandmother is a germline mutation. (From Text)

Does every mutation have a phenotypic (observable) effect? Why?

Concept 15.1 Mutations Are Heritable Changes in DNA

Not necessarily since most mutations occur in a nonfunctional region of DNA resulting in no affected gene product.

On the other hand, a mutation can occur but cause no change in the gene product or function of the protein.

There are two types of mutations that do alter phenotypes, what are they called?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Loss-of-function mutation

2. Gain-of-function mutation

Define Loss-of-Function Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that codes for an unexpressed gene or a gene produces a dysfunctional RNA or protein. These mutations nearly always show recessive inheritance.

Define Gain-of-Function Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that codes for a protein with an altered function. These mutations usually show dominant inheritance.

For a protein-coding gene, which of the three types of mutations will be most common, and why?

a. Mutation w/ no phenotypic effect: codes for a functional protein.
b. Loss-of-function mutation: codes for a nonfunctional protein.
c. Gain-of-function mutation: codes for a protein w/ a new function.

Concept 15.1 Mutations Are Heritable Changes in DNA

Mutations with no phenotypic effect are most common since the genetic code is redundant.

Some mutations have effects on phenotypes only under certain conditions, true or false?

(If false, correct the statement.)

Concept 15.1 Mutations Are Heritable Changes in DNA

True

Define Conditional Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that alters phenotypes only under (restrictive) environmental conditions and is not detectable under free/unrestrictive/permissive conditions.

Ex. Point restriction phenotypes in Siamese cats and rabbits due to a temperature-sensitive (conditional, loss-of-function) mutation in a coat color gene.

Define Point Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that results from the insertion or deletion of a single base pair (nucleotide), or from the substitution of a base pair for another.

There are three types of substitutions, true or false? And what are they?

(If false, correct the statement.)

Concept 15.1 Mutations Are Heritable Changes in DNA

False. There are two types of substitutions in point mutations:

1. Transition

2. Transversion

What are the two types of point mutation base-pair substitutions?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Transition

2. Transversion

(Note: Transition and Transversion are the types of substitutions that can occur. Later you will see some flashcards about different types of mutations that include substitutions.)

Define Transition (regarding point mutation)

Vocab 15.1 Mutations Are Heritable Changes in DNA

A base pair substitution that converts a purine to the other purine (A ⇆ G) and a pyrimidine to the other pyrimidine (T ⇆ C).

Define Transversion (regarding point mutation)

Vocab 15.1 Mutations Are Heritable Changes in DNA

A base pair substitution that converts a purine to a pyrimidine (A/G ⇆ C/T).

Define Sense Codon

Vocab 15.1 Mutations Are Heritable Changes in DNA

A codon that encodes for an amino acid.

Define Nonsense Codon

Vocab 15.1 Mutations Are Heritable Changes in DNA

A codon that encodes for the stop codon.

What are the 5 types of point mutations?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Silent Mutation

2. Missense Mutation

3. Nonsense Mutation

4. Loss-of-Stop Mutation

5. Frame Shift Mutation

mRNA strand - AUG AUC UUA GGG UAA
Mutant strand - AUG AUC UUA GGA UAA

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What is the amino acid sequence of the original mRNA strand?
What is the amino acid sequence of the mutant mRNA strand?

What type of mutation is the mutant strand compared to the mRNA strand?

(Compare the two amino acid sequences and mRNA strands, what do you notice? Use the codon chart provided to help you out!)

Practice 15.1 Mutations Are Heritable Changes in DNA

The mRNA strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The mutant strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The mutation that is present is called a silent mutation.

(Despite the strands being different, there was no change in the amino acid sequence.)

Define Silent Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A DNA substitution that changes an mRNA sense codon into another that encodes for the same amino acid which has no effect on the amino acid sequence of a protein.

(Note: A change in codon does not always mean a change in the amino acid that gets translated since the genetic code is redundant.)

mRNA strand - AUG AUC UUA GGG UAA
Mutant strand - AUG AUC UUA GUA UAA

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What is the amino acid sequence of the original mRNA strand?
What is the amino acid sequence of the mutant mRNA strand?

What type of mutation is the mutant strand compared to the mRNA strand?

(Compare the two amino acid sequences and mRNA strands, what do you notice? Use the codon chart provided to help you out!)

Practice 15.1 Mutations Are Heritable Changes in DNA

The mRNA strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The mutant strand codes for Methionine, Isoleucine, Leucine, Valine, Stop

The mutation that is present is called a missense mutation.

(In the silent mutation example, the codons were GGG and GGA which coded for the same amino acid. However, a substitution occurred in this case which changed the amino acid that was coded for.)

Define Missense Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A DNA substitution that changes an mRNA sense codon into another that encodes for a different amino acid, such that one amino acid substitutes for another in the encoded polypeptide.

(Ex. The sickle cell anemia allele is a missense mutation that causes red blood cells to look like a sickle shape when an individual is homozygous recessive for that defective allele.)

mRNA strand - AUG AUC UUA GGG UAA
Mutant strand - AUG AUC UAA GUA UAA

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What is the amino acid sequence of the original mRNA strand?
What is the amino acid sequence of the mutant mRNA strand?

What type of mutation is the mutant strand compared to the mRNA strand?

(Compare the two amino acid sequences and mRNA strands, what do you notice? Use the codon chart provided to help you out!)

Practice 15.1 Mutations Are Heritable Changes in DNA

The mRNA strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The mutant strand codes for Methionine, Isoleucine, Stop, Valine, Stop

The mutation that is present is called a nonsense mutation.

(In this scenario, we notice a base-pair substitution that causes an mRNA codon to become a stop codon. This is a premature stop.)

Define Nonsense Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A base pair substitution that prematurely terminates translation by changing an mRNA sense codon into a nonsense codon, one that encodes for a stop codon.

(Note: A nonsense mutation results in a shortened protein.)

mRNA strand - AUG AUC UUA GGG UAA
Mutant strand - AUG AUC UUA GUA UAU

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What is the amino acid sequence of the original mRNA strand?
What is the amino acid sequence of the mutant mRNA strand?

What type of mutation is the mutant strand compared to the mRNA strand?

(Compare the two amino acid sequences and mRNA strands, what do you notice? Use the codon chart provided to help you out!)

Practice 15.1 Mutations Are Heritable Changes in DNA

The mRNA strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The mutant strand codes for Methionine, Isoleucine, Leucine, Glycine, Tyrosine

The mutation that is present is called a loss-of-stop mutation.

(In this scenario, we notice a base-pair substitution that causes the mRNA stop codon to code for a different amino acid that’s not the stop codon. So there is no stop.)

Define Loss-of-Stop Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A base pair substitution that changes an mRNA stop (nonsense) codon to a sense codon causing additional amino acids to be added to the end of the protein/polypeptide.

(Note: A nonsense codon is a stop codon and a sense codon is one that codes for an amino acid.)

mRNA strand - AUG AUC UUA GGG UAA
Mutant strand - AUG AU_ UUA GGG UAA (Deletion Occurs)
New Mutant Strand - AUG AUU UAG GGU AA …

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What is the amino acid sequence of the original mRNA strand?
What is the amino acid sequence of the new mutant mRNA strand?

What type of mutation is the new mutant strand compared to the mRNA strand and mutant strand?

(Compare the two mutant strands, what do you notice? Use the codon chart provided to help you out!)

Practice 15.1 Mutations Are Heritable Changes in DNA

The mRNA strand codes for Methionine, Isoleucine, Leucine, Glycine, Stop

The new mutant strand codes for Methionine, Isoleucine, Stop, Glycine

The mutation that is present is called a Frame-Shift mutation.

(In this scenario, we notice a base-pair deletion that causes the rest of the base-pairs to shift.)

Define Frame-Shift Mutation

Vocab 15.1 Mutations Are Heritable Changes in DNA

The insertion or deletion of a single or two adjacent base pairs in a gene’s sequence results in mRNA misreading during translation and almost always, the production of a nonfunctional protein.

Mutations never occur outside coding regions, true or false?

(If false, correct the statement.)

Concept 15.1 Mutations Are Heritable Changes in DNA

False. Mutations can occur outside the coding region and either have no effect or significant effects.

What are some regions outside the coding region where mutations can occur?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Introns

2. Intergenic regions (regions between genes that have no function)

3. Promoters or regulatory sequences

4. RNA splicing sites

From the regions outside the coding region that can have mutations, which have no effect or significant effects on phenotype?

1. Introns

2. Intergenic regions (regions between genes that have no function)

3. Promoters or regulatory sequences

4. RNA splicing sites
   
   Concept 15.1 Mutations Are Heritable Changes in DNA

1. Mutations in introns and intergenic regions have no effect on phenotype.
   

2. Mutations in promoters or regulatory sequences can alter the rate of transcription.
   

3. Mutations in RNA splicing sites can lead to incorrectly spliced mRNA and the synthesis of an abnormal protein.

Define Chromosomal Rearrangement

Vocab 15.1 Mutations Are Heritable Changes in DNA

Large changes in DNA that disrupt the genetic sequence caused by the breakage and rejoining of DNA molecules.

What leads to chromosomal rearrangements?

Concept 15.1 Mutations Are Heritable Changes in DNA

Damage to chromosomes by:

1. Mutagens

2. Errors in chromosome replication

What are the 4 types of chromosomal rearrangement?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Deletion

2. Duplication

3. Inversion

4. Reciprocal Translocation

Define Deletion

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that results from the loss of a chromosome segment when a chromosome breaks at two points and then rejoins, leaving out the DNA between the breaks.

Define Duplication

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that results when homologous chromosomes break at different positions and swap segments.

Define Inversion

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that results from the rejoining of a segment that broke and flipped, so that it runs in the opposite direction (180° turn).

Define Reciprocal Translocation

Vocab 15.1 Mutations Are Heritable Changes in DNA

A mutation that results when nonhomologous chromosomes break at different positions and swap segments.

Mutations can be spontaneous or induced, true or false?

(If false, correct the statement.)

Concept 15.1 Mutations Are Heritable Changes in DNA

True

Define Spontaneous Mutations

Vocab 15.1 Mutations Are Heritable Changes in DNA

A permanent mutation in the genetic material caused by internal cellular mechanisms and not outside influences.

(Ex. An error in DNA replication.)

Define Induced Mutation

Concept 15.1 Mutations Are Heritable Changes in DNA

A mutation in the genetic material caused by an agent outside the cell, a mutagen.

Define Mutagen

Concept 15.1 Mutations Are Heritable Changes in DNA

Any agent that increases the mutation rate.

(Ex. chemicals, radiation, etc.)

What are some mutagens mentioned in class that can lead to an induced mutation?

Concept 15.1 Mutations Are Heritable Changes in DNA

1. Chemical mutagen (can alter bases)

2. Radiation (can damage bases and is unrecognizable by DNA polymerase)

All mutations are bad, true or false?

(If false, correct the statement and provide 3 benefits.)

False.

1. They provide genetic diversity for natural selection.
2. Somatic cell mutations can benefit an organism immediately.
3. Germ-line mutations may cause an advantageous change in the offspring’s phenotype.

Mutations in what cells would prove beneficial for evolution?

Question 15.1 Mutations Are Heritable Changes in DNA

A mutation in germ-line cells.

Which type of mutations are under our control?

Question 15.1 Mutations Are Heritable Changes in DNA

Induced mutations. For example, we can stop smoking or use sunscreen to prevent radiation.

Which of the following is generally true of somatic mutations?

a. They do not affect the protein function.
b. They lead to a loss of function.
c. They are not passed on to the organism’s offspring.
d. They are beneficial to the organism.
e. They occur at a specific rate in humans; there is nothing we can do to alter their frequency.

Question 15.1 Mutations Are Heritable Changes in DNA

c. They are not passed on to the organism’s offspring.

Which mutation is least likely to be a frame-shift mutation?

a. An insertion of six nucleotides.
b. A deletion of four nucleotides.
c. an insertion of two nucleotides.
d. A deletion of eight nucleotides.

Question 15.1 Mutations Are Heritable Changes in DNA

a. An insertion of six nucleotides.

(Note: Frame-shifts can’t be multiples of 3 base pairs that are inserted/deleted. They must be 1 or multiples of 2 base-pairs that are inserted/deleted hence why 3, 6, 9 insertions/deletions are unlikely a frame-shift.)

Suppose that in one cell in your skin, chromosome 14 and chromosome 18 exchange genetic materials. This change is inherited by subsequent cells. This is an example of a ______ mutation that is also a(n) ______.

a. germ line; inversion
b. germ line; point mutation
c. germ line; translocation
d. somatic; inversion
e. somatic; translocation

Question 15.1 Mutations Are Heritable Changes in DNA

e. somatic; translocation

Mutations result in what type of proteins?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Mutant proteins

Are mutations expressed phenotypically?

Question 15.2 Mutations in Humans Can Lead to Diseases

Yes, they are expressed as mutant proteins that differ from the normal/wild-type proteins.

Abnormalities in enzymes, receptor proteins, transport proteins, structural proteins, and others result in what?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Genetic diseases

What type of genetic diseases can arise from mutant proteins?

Concept 15.2 Mutations in Humans Can Lead to Diseases

1. Loss of Enzyme Function (Ex. phenylketonuria, PKU)

2. Abnormal Hemoglobin (Ex. Sickle-cell Disease)

3. Large Deletions in Chromosomes (Ex. Duchenne Muscular Dystrophy)

4. Mutations in Somatic Cells (Ex. Cancer)

(Note: All examples were mentioned in the slides.)

Loss of Enzyme Function

What causes the disease Phenylketonuria (PKU)?

Concept 15.2 Mutations in Humans Can Lead to Diseases

An abnormality in a single enzyme called phenylalanine hydroxylase (PAH).

Loss of Enzyme Function

What does the enzyme phenylalanine hydroxylase (PAH) do?

Concept 15.2 Mutations in Humans Can Lead to Diseases

The enzyme PAH catalyzes the conversion of phenylalanine to tyrosine.

Loss of Enzyme Function

What happens when an abnormal/inactive PAH is present? (This causes the disease Phenylketonuria (PKU))

Concept 15.2 Mutations in Humans Can Lead to Diseases

When phenylalanine hydroxylase is inactive, there is an excess amount of phenylalanine and phenylpyruvic acid in the blood.

How many possible mutations in the enzyme PAH can cause PKU disease?

(I don’t think this is rlly important but I’m just adding this since it was mentioned in the slides. Just to be safe!!)

Concept 15.2 Mutations in Humans Can Lead to Diseases

More than 400 disease-causing mutations.

Loss of Enzyme Function

When it comes to loss-of-function mutations, the mutant alleles are what type?

a. Homozygous recessive or recessive
b. Homozygous dominant or dominant
c. Heterozygous

Concept 15.2 Mutations in Humans Can Lead to Diseases

a. Recessive

(Note: All it takes is one functional allele to produce enough function PAH enzyme to prevent the disease.)

Abnormal Hemoglobin

What causes Sickle-cell disease?

Concept 15.2 Mutations in Humans Can Lead to Diseases

A recessive, missense mutation.

Abnormal Hemoglobin

For sickle-cell disease to occur, there has to be a mutation in a(n):

a. α-chain
b. β-chain

(Note: Human hemoglobin is composed of four globin subunits- two α-chains and two β-chains and the pigment heme.)

Concept 15.2 Mutations in Humans Can Lead to Diseases

For sickle-cell disease to occur, there has to be a mutation in a b. β-chain.

Abnormal Hemoglobin

The hemoglobin’s polypeptide β-chain consists of 146 amino acids. How many of these amino acids must be affected to cause sickle-cell disease?

a. 2
b. 73
c. 1
d. 4

Concept 15.2 Mutations in Humans Can Lead to Diseases

Only c. 1 amino acid must be affected to cause sickle-cell disease.

(Just in case this is a question on the exam, the exact amino acid is the one in position 6, glutamic acid, if changed will cause the disease. “S” in the picture is the sickle-cell allele.)

Abnormal Hemoglobin

With regards to the β-globin chain, can other mutations occur?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Yes, more than a hundred of amino acid substitutions have been reported but they don’t alter the function of blood. Some cause different disease. (Refer to picture)

Abnormal Hemoglobin

What happens as a result of the abnormal protein in the β-globin chain (specifically position 6)?

Concept 15.2 Mutations in Humans Can Lead to Diseases

The blood’s shape becomes sickle-shaped which blocks capillaries and impairs the ability to carry oxygen.

Large Deletions

What causes Large Deletions?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Large mutations that involve many base pairs of DNA.

Large Deletions

Deletion in which chromosome leads to the disease Duchenne’s Muscular Dystrophy?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Deletions in the X Chromosome.

Large Deletions

The X Chromosome has which protein, where if deleted will result in the disease Duchenne Muscular Dystrophy?

Concept 15.2 Mutations in Humans Can Lead to Diseases

The X Chromosome has the protein Dystrophin. If this protein is deleted, then the individual will have serve muscle weakness.

Large Deletions

What happens if the entire dystrophin gene is deleted?

Concept 15.2 Mutations in Humans Can Lead to Diseases

The individual will have a severe form of muscular dystrophy.

Large Deletions

Is it possible for only part of the dystrophin gene to be deleted??

(If yes, then what happens as a result of that?)

Concept 15.2 Mutations in Humans Can Lead to Diseases

Yes, as a result, the dystrophin protein will partially function and the individual will have a mild form of the disease.

Large Deletions

How large can deletions be and what happens as a result?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Deletions can be as large as entire sequences, or even millions of base pairs causing adjacent genes to be affected.

Because of this, an individual can have multiple diseases.

Somatic Cell Mutations

Mutations in somatic cells can lead to what disease?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Cancer

Somatic Cell Mutations

How many mutations are required for cancer to occur?

Concept 15.2 Mutations in Humans Can Lead to Diseases

More than two mutations are typically needed.

Somatic Cell Mutations - Colon Cancer

How many genes must be mutated in a single cell to produce colon cancer? And which genes?

Concept 15.2 Mutations in Humans Can Lead to Diseases

4 genes in total must be mutated in a single cell which include:

• 3 tumor suppressor genes

• 1 oncogene

Somatic Cell Mutations - Colon Cancer

What is the function of a proto-oncogene?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Proto-oncogenes help in cell growth and division.

Somatic Cell Mutations - Colon Cancer

What do proto-oncogenes become when mutated?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Proto-oncogenes turn into oncogenes which cause a large uncontrollable amount of growth.

Somatic Cell Mutations - Colon Cancer

What do tumor suppressor genes do?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Tumor suppressor genes control cell division and stop growth.

Somatic Cell Mutations - Colon Cancer

What happens if tumor suppressor genes are mutated?

Concept 15.2 Mutations in Humans Can Lead to Diseases

Uncontrollable cell division can occur.

The phenotypic effects of Duchenne muscular dystrophy vary considerably. This variation is explained largely by:

a. how much of the dystrophin gene is deleted.
b. how much of the dystrophin gene is duplicated.
c. which chromosome the dystrophin gene is translocated to.
d. which point mutation is involved.

Question 15.2 Mutations in Humans Can Lead to Diseases

The phenotypic effects of Duchenne muscular dystrophy vary considerably. This variation is explained largely by a. how much of the dystrophin gene is deleted.

Sometimes identical twins are genetic carriers of a disease but only one is affected. This is likely to be due to the disease being caused by:

a. a point mutation and a chromosomal deletion.
b. genes and proteins interacting with environmental factors.
c. only environmental factors.
d. only point mutation.

Question 15.2 Mutations in Humans Can Lead to Diseases

Sometimes identical twins are genetic carriers of a disease but only one is affected. This is likely to be due to the disease being caused by b. genes and proteins interacting with environmental factors.