Chapter 11
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Chapter 11. Gene Mutation. Mutation. A mutation is a change in the nucleotide sequence that composes a gene. This is a change or variation from the most common or wildtype sequence.

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Chapter 11

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Chapter 11

Chapter 11

Gene Mutation


Mutation

Mutation

  • A mutation is a change in the nucleotide sequence that composes a gene. This is a change or variation from the most common or wildtype sequence.

  • A mutant allele is an allele that differs from the common allele in the population (also called the wildtype allele).

  • A mutant phenotype refers to a phenotype that differs from the common or wildtype phenotype.

  • Mutations are not good or bad, just different from the majority in the population.


Somatic mutations

Somatic mutations

  • are mutations that occur in cells of the body excluding the germline.

  • Affects subsequent somatic cell descendants

  • Limited to impact on the individual and not transmitted to offspring

Germline mutations

  • are mutations that occur in the germline cells.

  • Possibility of transmission to offspring


Hemoglobin

Hemoglobin

  • Linus Pauling, 1949

  • Four globular proteins surrounding heme group with iron atom: two beta chains and two alpha chains

  • Function is to carry oxygen in red blood cells from lungs to body and carbon dioxide from cells to lungs


Single base change in hemoglobin gene causes sickle cell anemia

mutant

allele

wildtype

allele

wildtype

phenotype

mutant

phenotype

Single base change in hemoglobin gene causes sickle cell anemia


Hemoglobin genotype causes sickle cell anemia phenotype

Hemoglobin genotype causes sickle cell anemia phenotype

  • Sickle cell anemia was the first illness understood at the molecular level:

  • mutation encodes valine in place of glutamic acid.

  • Phenotype associated with homozygotes:

  • Altered surface of hemoglobin allows molecules to link in low oxygen conditions and creates sickle shape of red blood cells.

  • Sickling of red blood cells causes anemia, joint pain, and organ damage when RBC become lodged in small blood vessels.


Different sites in a gene can mutate and cause distinct phenotypes

Different sites in a gene can mutate and cause distinct phenotypes

  • Some beta hemoglobin mutations resulting in too few protein molecules cause thalessemia.

  • Excess of alpha hemoglobin compared to beta hemoglobin leads to iron release which kills RBC and destroys heart, liver and endocrine glands.

  • heterozygous mutation => milder thalassemia minor

  • homozygous mutation => more severe thalassemia major


Collagen

Collagen

  • Comprises:

  • 60% of protein in bone and cartilage

  • a significant proportion of skin, ligament, tendon, tooth dentin and connective tissue.

  • Has a precise structure:

  • triple helix of two alpha1 and one alpha2 proteins

  • the longer precursor called procollagen is trimmed to form collagen


Different collagen mutations distinct disorders

Different collagen mutations => Distinct disorders


Alzheimer disease

Alzheimer disease

  • Mutations in presenilin1 cause early onset autosomal dominant Alzheimer disease

  • Presenilin protein is a receptor anchored in the Golgi membrane

  • Monitors beta amyloid usage

  • 30+ missense mutations in presenilin result in beta amyloid accumulation.


Genotype to disease phenotype

Genotype to disease phenotype

  • Cystic fibrosis diseaseCFTR protein

  • Duchenne muscular dystrophy dystrophin protein

  • Familial hypercholesterolemia LDL receptor protein

  • Hemophilia A Factor VIII protein

  • Huntington disease huntingtin protein

Mutation: Many different mutations, common missing amino acid

Mutation: Deletion of gene

Mutation: Deficient LDL receptors lead to cholesterol buildup

Mutation: Absent or deficient factor

Mutation: Extra nucleotides in gene result in extra amino acids

Phenotype: Lung infections, pancreatic insufficiency

Phenotype: Loss of muscle function

Phenotype: High blood cholesterol, early heart disease

Phenotype: Slow or absent blood clotting

Phenotype: Uncontrollable movements, personality changes


Spontaneous mutation

Spontaneous mutation

  • De novo or new mutations

  • Not caused by exposure to known mutagen

  • Errors in DNA replication

  • DNA bases have slight chemical instability

  • (exists in alternating forms called tautomers)


Spontaneous mutation rate

Spontaneous mutation rate

  • Rate differs for different genes

    • Size dependence

    • Sequence dependence

    • Hot spots

  • On average 1 in 100,000 chance of acquiring a mutation in a gene each round of replication.

  • Each individual has multiple new mutations. Most by chance are not in coding regions of genes.


Determining mutation rate

Determining mutation rate

  • Estimates of spontaneous mutation rate can be derived from observation of dominant traits.

  • For autosomal genes,

  • mutation rate= number of cases

  • 2 ( # of individuals)


Mutation rates of genes causing disease

Mutation rates of genes causing disease


Mutations in pathogens

Mutations in pathogens

  • Bacteria and viruses undergo mutation

  • Mutation in bacteria can lead to antibiotic resistance.

  • Overuse and incomplete course of treatment increases chances of antibiotic resistance arising.

  • Viruses mutate rapidly.

  • Influenza vaccines are reassessed each season to accommodate viral changes.

  • Rapid mutation of HIV virus makes treatment difficult.


Mutational hot spots exist

Mutational hot spots exist

  • Short repetitive sequences

  • pairing of repeats may interfere with replication or repair enzymes

  • Palindromes

  • often associated with insertions or deletions

  • Duplications of larger regions

  • mispairing during meiosis


Small or large insertion or deletions

Small or large insertion or deletions

Palindromes can cause

small insertion or deletions

Duplications can cause

large insertion or deletions


Induced mutations

Induced mutations

  • Chemicals and radiation can cause mutations.

  • Chemicals causing mutations are called mutagens.

  • Chemicals causing cancer are called carcinogens.

  • Alkylating agents remove a base

  • Acridine dyes add or remove base

  • Xrays break chromosomes

  • delete few nucleotides

  • UV radiation creates thymidine dimers


Ames test

Ames test

  • is an in vitro test of the mutagenicity of a substance using Salmonella bacteria with mutation in gene for histidine.

  • Bacteria are exposed to test substance.

  • Growth of bacteria on media without histidine is recorded.

  • Bacteria only grow if mutations have occurred.

  • Rate of mutation is determined.

  • Substance can be mixed with mammalian liver tissue prior to testing to mimic toxin processing in humans.


Chapter 11

Normal

THE ONE BIG FLY HAD ONE RED EYE

Missense

THQ ONE BIG FLY HAD ONE RED EYE

Nonsense

THE ONE BIG

Frameshift

THE ONE QBI GFL YHA DON ERE DEY

Deletion

THE ONE BIG HAD ONE RED EYE

Insertion

THE ONE BIG WET FLY HAD ONE RED EYE

Duplication

THE ONE BIG FLY FLY HAD ONE RED EYE

generation 1

THE ONE BIG FLY HAD ONE RED EYE

generation 2

THE ONE BIG FLY FLY HAD ONE RED EYE

generation 3

THE ONE BIG FLY FLY FLY HAD ONE RED EYE

Type of mutation

Example

Expanding


Point mutation

Point mutation

  • A point mutation is a change of a single nucleotide to one of the other three possible nucleotides

  • Transition

  • purine replaces purine

  • A -> G or G -> A

  • pyrimidine replaces pyrimidine

  • C -> T or T -> C

  • Transversion

  • purine replaces pyrimidine or

  • pyrimidine replaces purine

  • A or G -> T or C

  • T or C -> A or G


Missense mutation

Missense mutation

  • A point mutation that exchanges one codon for another causing substitution of an amino acid

  • Missense mutations may affect protein function severely, mildly or not at all.

  • Hemoglobin mutation

  • glutamic acid -> valine causes sickle cell anemia


Nonsense mutation

Nonsense mutation

  • A point mutation changing a codon for an amino acid into a stop codon (UAA, UAG or UGA).

  • Premature stop codons create truncated proteins.

  • Truncated proteins are often nonfunctional.

  • Some truncations have dominant effects due to interference with normal functions.

  • Most common cause of factor XI deficiency is a nonsense mutation change glutamic acid to a stop. Short protein cannot function in clotting.


Insertion or deletion mutations

Insertion or deletion mutations

  • The genetic code is read in triplet nucleotides during translation.

  • Addition or subtraction of nucleotides not in multiples of three lead to a change in the reading frame used for translation. Amino acids after that point are different, a phenomenon called a frameshift.

  • Addition or subtraction of nucleotides in multiples of three leads to addition or subtraction of entire amino acids but not a change in the reading frame.


Insertion or deletion mutations1

Insertion or deletion mutations

  • Deletion is the removal of sequences.

  • Two-thirds of Duchenne musular dystrophy cases are large deletions.

  • Insertion is the addition of sequences.

  • Gaucher disease is caused by a single base insertion creating a frameshift.

  • A tandem duplication is a particular form of insertion in which identical sequences are found side by side.

  • Charcot-Marie-Tooth disease is caused by a tandem duplication of 1.5 million bases


Expanding repeats

Expanding repeats

  • Insertion of triplet repeats leads to extra amino acids.

  • Some genes are particularly prone to expansion of repeats.

  • Number of repeats correlates with earlier onset and more severe phenotype.

  • Expansion of the triplet repeat and coincident increase in severity of phenotype occur with subsequent generations, a phenomena termed anticipation.


Myotonic dystrophy a triplet repeat disease

Myotonic dystrophy: a triplet repeat disease

  • 5 -37 copies of CTG repeat normal phenotype

  • 50-1000 repeats myotonic dystrophy

  • Genes with 40+ copies are unstable and can gain (or less commonly lose) repeat copies in successive generations.


Triplet repeat disorders

Triplet repeat disorders


Noncoding repeats can cause phenotypes

Noncoding repeats can cause phenotypes

In myotonic dystrophy the expanded repeat is not in the exon.

The expansion may affect the exportation of the mRNA from

the nucleus.


Pseudogenes

Pseudogenes

  • A pseudogene is a DNA sequence reminiscent of a gene but which is not translated (may or may not be transcribed).

  • Pseudogenes may have evolved from original functional gene by duplication and acquired mutation.

  • Crossing over between a pseudogene and a bona fide gene can disrupt gene expression.


Different mutations may cause the same disorder

Different mutations may cause the same disorder

Mutations in the LDL receptor disrupt function leading to

increased blood cholesterol and early heart disease.


Mutations in different parts of a gene may have distinct impacts

Mutations in different parts of a gene may have distinct impacts


Prion disorders

Prion disorders

  • Prion disorders are caused by mutation in the prion gene which leads to an abnormally shaped prion protein.

  • The mutant form of the protein can convert normal prion proteins to mutant protein shapes.

  • Mutant protein occurs in two ways:

  • A mutation in the gene can be inherited.

  • The mutant protein can be transmitted like an infection from tissue with the mutant protein.

    • In cows a mutant prion protein causes mad cow disease.

    • Humans can obtain the protein by eating beef with mutant prions and develop Creutzfeldt-Jakob disease.


Chapter 11

Prions change shape

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Abnormal PrP

Neuron

Normal PrP

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Converted

molecule

Normal

PrP

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

Nucleus

Cytoplasm


Chapter 11

Prions change shape

Intracellular

membrane

Neuron

All abnormal PrP

Nucleus

Cytoplasm


Not all mutations impact protein function

Not all mutations impact protein function

  • Silent mutations are mutations that do not alter the

  • amino acid encoded.

AAA and AAG both encode the amino acid lysine.

A mutation from AAA to AAG in a gene alters the DNA sequence but protein sequence remains unchanged.

These codons are called synonymous codons.


Not all mutations impact protein function1

Not all mutations impact protein function

  • Missense mutations are those that alter the encoded amino acid to another amino acid.

  • The alteration creates a nonsynonymous codon.

Some nonsynonymous mutations are conservative;

chemically similar amino acid may not alter function

The impact of a missense mutation is not predictable from protein sequence alone.


Not all mutations impact protein function2

Not all mutations impact protein function

  • Conditional mutations are those that only produce a phenotype under particular conditions or environments.

G6PD enzyme is used to respond to oxidants, chemicals that strip electrons from other molecules.

High levels of oxidants occur when eating fava beans or taking antimalarial drugs.

Conditions Individuals with mutations in G6PD

Low oxidants no phenotype

High oxidants red blood cells burst, anemia


Dna repair

DNA Repair

  • Errors in DNA replication or damage to DNA create mutations.

  • Most errors and damage are repaired by the cell.

  • The manner in which DNA repair occurs depends upon the type of damage or error.

  • Different organisms vary in their ability to repair DNA.

  • In humans, mutations in DNA replication occur in 1 in 100 million bases.


Mismatch repair

Mismatch repair

  • Mismatch repair occurs when enzymes detect nucleotides that do not base pair in newly replicated DNA.

  • The incorrect base is excised and replaced.

  • The detection of mismatches is termed proofreading.


Excision repair

Excision repair

  • Damaged DNA is removed by excision of the bases and replacement by a DNA polymerase.

  • Nucleotide excision repair

  • Replaces up to 30 bases

  • used in repair of UVB and some carcinogens

  • Base excision repair

  • Replaces 1-5 bases

  • Repairs oxidative damage


Failure of dna repair

Failure of DNA repair

  • When DNA repair fails, fewer mutations are corrected leading to an increase in the number of mutations in the genome.

  • The protein p53 monitors repair of damaged DNA.

  • If damage is too severe, the p53 protein promotes programmed cell death or apoptosis.

  • Mutations in genes encoding DNA repair proteins can be inherited and lead to overall increase in mutations when DNA errors or damage are no longer fixed efficiently.


Dna replication and repair disorders

DNA replication and repair disorders


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