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Genes and Gene Mutations — Lecture III. Dr. Steven J. Pittler VH375B Office 4-6744 Cell 612-9720. Suggested Reading: Lewis 2 nd Edition Chapter on Gene Mutation. Mutation. Is a change in a genes nucleotide base sequence At the molecular level Substituting one DNA base for another

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genes and gene mutations lecture iii
Genes and Gene Mutations — Lecture III
  • Dr. Steven J. Pittler
  • VH375B
  • Office 4-6744
  • Cell 612-9720

Suggested Reading: Lewis 2ndEdition

Chapter on Gene Mutation

  • Is a change in a genes nucleotide base sequence
    • At the molecular level
      • Substituting one DNA base for another
      • Adding or deleting bases
      • Chromosome level
  • Chromosomes
    • Can exchange parts
    • Genetic material can jump from one chromosome to another
  • A mutation can stop or slow production of a protein, can over-produce it, or impair its function
  • Not all DNA changes are harmful: 1% of the general population is homozygous for a recessive allele that encodes the protein CCR5
    • This is a cell surface protein
    • HIV must bind to CCR5 and another protein to enter a T-cell
    • This mutation prevents CCR5 from traveling from the cytoplasm to the cell surface and therefore HIV cannot bind
  • The term mutation refers to genotype - a change at the DNA or chromosome level
  • Mutant refers to an unusual phenotype
    • How the alteration affects the genes product or activity
    • Or , an unusual variant such as a red-haired child in a class of brunettes and blondes
    • Mutations that do not alter the phenotype are called polymorphisms
  • The next slide gives examples of genetic tests that helps identify gene mutations
  • A point mutation is a change in the nucleotide sequence that composes a gene. This is a change or variation from the most common or wild type sequence.
  • A mutant allele is an allele that differs from the common allele in the population (also called the wild type allele).
  • A mutant phenotype refers to a phenotype that differs from the common or wild type phenotype.
  • Mutations are not good or bad, just different from the majority in the population.
  • In the evolutionary sense mutation has been essential to life
    • It produces individuals with variant phenotypes who are better able to survive in a specific environment
somatic mutations
Somatic mutations
  • Are mutations that occur in cells of the body excluding the germ line and happens during DNA replication before mitotic cell division
  • Affect subsequent somatic cell descendants
  • Are limited to impact on the individual and not transmitted to offspring
  • Are responsible for certain cancers (lecture IV)

Germline mutations

  • Are mutations that occur in the germ line cells and the change occurs during the DNA replication that precedes meiosis
  • Have the possibility of transmission to offspring
  • 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









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 (V->G).
  • 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 RBCs 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 RBCs and destroys heart, liver and endocrine glands.
  • heterozygous mutation -> milder thalassemia minor
  • homozygous mutation -> more severe thalassemia major
  • 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
12 03 jpg

Ehlers-Danlos Syndrome

alzheimer disease
Alzheimer disease
  • Mutations in presenilin1 cause early onset autosomal dominant Alzheimer disease
  • Presenilin protein is a receptor anchored in the Golgi membrane
  • The protein functions to monitor 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

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

Phenotype: Lung infections, pancreatic insufficiency

Phenotype: Loss of muscle function

Phenotype: High blood cholesterol, early heart disease

Phenotype: Slow or absent blood clotting


Genotype to disease phenotype

Huntington diseasehuntingtin protein

Mutation: Extra nucleotides in gene result in extra amino acids

Phenotype: Uncontrollable movements, personality changes

Marfan syndrome Fibrillin

Mutation: Too little elastic connective tissue protein

Phenotype: Long limbs, weakened aorta, spindly fingers, sunken chest, lens dislocation

Neurofibromatosis Neurofibromin

Mutation: Defect in protein

Phenotype: Benign tumors of nervous tissue beneath skin

genetic disease of the teeth
Genetic Disease of the Teeth
  • AmelogenesisImperfectais a genetic condition that causes teeth to be abnormally small or discolored. Teeth are also likely to be pitted or grooved and more susceptible to being worn down and breaking. There are at least 14 forms of the condition, each with its own characteristic display of tooth abnormalities and form of genetic inheritance. Amelogenesisimperfecta is caused by mutations to the AMELX, ENAM and MMP20 genes and affects an estimated one in 14,000 people in the United States.
  • DentinogenesisImperfectais a genetic disorder that interferes with normal tooth development. It affects approximately one in 6,000 to 8,000 people, according to the National Institute of Health. There are three types of dentinogenesisimperfecta. Type I occurs in individuals who have another inherited disorder called osteogenesis imperfect (causes brittle bones), whereas type II and type III occur in those without other genetic disorders. Some researchers believe types II and III are part of a single disorder along with another condition called dentin dysplasia type II, which primarily affects baby teeth more than adult teeth. General symptoms of dentinogenesisimperfecta include tooth discoloration (blue-gray or yellowish-brown), tooth translucency and weaker than normal teeth which make them prone to erosion, breakage and loss.
  • 48,XXYY Syndrome is arare chromosomal condition that affects one in 18,000 to 50,000 males, 48,XXYY syndrome interferes with sexual development, causing reduced height, facial and body hair, increased risk of breast enlargement, infertility, progressive tremor and other serious medical problems that develop increasingly later in life. Dental problems are also common. According to the NIH, the delayed appearance of primary and secondary teeth, crowded and/or misaligned teeth, numerous cavities and thin tooth enamel often accompany the disorder.
  • Hypohidrotic Ectodermal Dysplasia is an inherited condition affecting approximately one in 17,000 people worldwide that causes abnormalities of the skin, nails, hair, sweat glands and teeth. Those with the condition usually have absent teeth (hypodontia) or malformed teeth. It is common for malformed teeth to appear small and pointed. According to the NIH, approximately 70 percent of carriers of the gene that causes the condition (those with only one, but not both, recessive mutated genes) display symptoms, including some missing or abnormal teeth, sparse hair and some sweat gland dysfunction.
  • OculodentodigitalDysplasia is an extremely rare genetic disease (with fewer than 1,000 people diagnosed worldwide) that affects the eyes, fingers and teeth. Common tooth abnormalities include small or missing teeth, numerous cavities, weak enamel and early tooth loss. The condition can also lead to small eyes, vision loss, webbed skin and neurological problems. An autosomal dominant disorder, it develops when only one mutated gene is inherited from a parent.
  • Recombinant 8 Syndrome is a rare disease of unknown incidence primarily affecting an Hispanic population descending from the San Luis Valley of Colorado and Northern New Mexico. Inherited in an autosomal dominant pattern, recombinant 8 syndrome causes distinctive facial abnormalities, moderate to severe intellectual disability and heart and urinary tract problems. Abnormal teeth, an overgrowth of gums, small chin, thin upper lip and downturned mouth are all associated with the condition.
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.
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
  • More than 1/3 of the many mutations that cause alkaptonuria occur at or near one or more CCC repeats, even though these repeats account for only 9% of the gene (hot spot)
  • Mutations in the gene for clotting factor IX, which causes hemophilia B occur 10 to 100 times at any 11 sites in the gene that have direct repeats of CG (CGCGCG…..)
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

  • The blood disorder alpha thalassemia illustrates the effect of direct repeats of an entire gene
    • Wild-type has four genes that specify alpha globin chains, two next to each other on chromosome 16
    • Homologs with repeated genes can misalign during meiosis when the first sequence on one chromosome lies opposite the second sequence on the homolog
    • If crossing over occurs, a sperm or oocyte can form that has one or three of the alpha globin genes instead of the normal two
    • A person with three alpha globin genes produces enough hemoglobin and is considered healthy
    • Individuals with only two copies of the gene are mildly anemic
    • Single alpha globin individuals are severely anemic, and a fetus lacking alpha globin does not survive
    • Alpha thalassemia is common because carriers have an advantage, they are protected against malaria
induced mutations
Induced mutations
  • Chemicals and radiation can cause mutations.
  • Chemicals causing mutations are called mutagens.
  • Chemicals causing cancer are called carcinogens.
induced mutations1
Induced mutations
  • Alkylating agents remove a DNA base, which is replaced with any of the four bases-three of which creates a mismatch with the complimentary strand
  • Acridine dyes add or remove a single DNA base. Adding or deleting a single base destroys a gene’s information, altering the amino acid sequence of the encoded protein
  • Mutagenic chemicals alter base pairs, so that an A-T replaces G-C, or vice versa, thereby changing a genes DNA sequence
  • X-rays and other forms of radiation delete a few bases or break chromosomes
ames test
Ames test
  • is an in vitro test of the mutagenicity of a substance using Salmonella bacteria with a mutation in the 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.
natural exposure to mutagens
Natural Exposure to Mutagens
  • Natural environment sources of radiation include:
    • Cosmic rays, sunlight, and radioactive minerals in the earth’s crust
  • Medical x-rays and radiation hazards
    • Weapons facilities, research laboratories, health care facilities, nuclear power plants, and certain manufacturing plants
  • Radiation exposure is measured in millirems and the annual exposure in the northern hemisphere: 360 millirems
  • Most of the radiation that we are exposed to are ionizing type which removes electrons from atoms
  • Ionizing radiation breaks the sugar-phosphate backbone DNA
natural exposure to mutagens1
Natural Exposure to Mutagens
  • There are three major types of ionizing radiation
    • Alpha is the least energetic and most short-lived
    • Absorbed by the skin
    • Uranium and radium
    • Beta can penetrate deeper
    • Trtium (isotope of hydrogen), Carbon-14, and strontium-70
    • Both alpha and beta tend not to harm us
    • However if eaten or inhaled they will do damage
    • Gamma can penetrate all the way through the body therefore it damages our tissues
    • Plutonium and cesium isotopes used in weapons
    • This form of radiation is intentionally used to kill cancer cells
natural exposure to mutagens2
Natural Exposure to Mutagens
  • X-rays are non-ionizing radiation
    • Have less energy and do not penetrate the body to the extent that gamma rays do
  • The effects of radiation damage to DNA depends on the functions of the mutated genes
    • Mutations in oncogenes or tumor suppressor genes can cause cancer
  • Chemical mutagens
    • The risk that a chemical will cause a mutation is often less than the natural variability in susceptibility within a population
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
  • The DNA sequence CTC encodes for mRNA GAG which specifies glutamic acid
  • There is a point mutation in sickle cell disease that changes (transversion) the DNA sequence to CAC, that encodes for mRNA GUG that specifies valine, and this causes an alteration in function
nonsense mutation
Nonsense mutation
  • In 15% of people who have Becker muscular dystrophy (milder adult form of the condition) the muscle protein dystrophin is normal, but, its levels are reduced
    • The mutation causing the protein shortage is in the promoter for the dystrophin gene and thus slows the transcription process
  • The other 85% who have Becker muscular dystrophy have shortened proteins, not a deficiency of normal-length proteins
  • Point mutations can disrupt the trimming of long precursor molecules
    • A type of Ehlers-Danlos syndrome
splice site mutations
Splice Site Mutations
  • Point mutations can affect a gene’s product when it alters a site where introns would normally be removed from mRNA
  • It can affect the phenotype if an intron gets translated into amino acids, or an exon is skipped instead of being translated
  • When we retain an intron the bases are added to the protein coding portion of mRNA
    • Cystic fibrosis: missense mutation alters an intron site so that it is not removed
splice site mutations1
Splice Site Mutations
  • A missense mutation can cause harm if it disrupts intron/exon splicing
    • A missense mutation in the BRCA 1 gene that causes breast cancer is due to the missing of several amino acids resulting from an intron splicing site that skipped an entire exon when mRNA is translated into a protein
    • Familial dysautonomia (FD) results from a splice site mutation that causes exon skipping. An exon in the gene encoding an enzyme called I-kappa beta kinase-associated protein is not translated because a point mutation in one of its splice site signals the spliceosome not to translate the segment.
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 leads 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 muscular 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
  • 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.
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.















generation 1


generation 2


generation 3



Type of mutation

Expanding mutation

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.

myotonic dystrophy an expanding triplet repeat disease
Myotonic dystrophy: an expanding 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.
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 (bovine spongiform encephalitis).
      • Humans can obtain the protein by eating beef with mutant prions and develop Creutzfeldt-Jakob disease.
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.
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
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.
xeroderma pigmentosa
Xeroderma Pigmentosa

Deficient excision repair

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.