- Base analogs, - alkylating agents, - intercalating agents, - adduct-forming agents (acetaldehyde and heterocyclic amines) - UV LIGHT - IONIZING RADIATION

PRE LEC 3: GENE MUTATION Flashcards by Sunwoo's Berry

Alteration in DNA sequence that is rare in
the population
Typically affects phenotype
base - pair change in any part of the DNA molecule
are recessive and cause a loss-of-function

GENE MUTATION

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refers to theprocess of altering a DNA sequence.

MUTATE

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EFFECTS OF MUTATION
- genes’ product is reduced or absent

“loss-of-function”

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EFFECTS OF MUTATION
- gene’s activity changes
- tend to be dominant and are also called “TOXIC”

“gain-of-function”

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the differences between organisms caused by alternates form of DNA

GENETIC VARIATION

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SOURCES OF GENETIC VARIATION
- GENOTYPE
- alteration/change at the DNA or chromosome level.

MUTATION

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SOURCES OF GENETIC VARIATION
- “many forms”
- alteration in DNA sequence that is common in the population
- Do not severely affect the phenotype
- Short tandem repeats (microsatellites):

POLYMORPHISM

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: short repeating units (2-6 nucleotides), vary in number among individuals and is often used in DNA
profiling and paternity testing

Short tandem repeats (microsatellites)

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refers to phenotype; describes an allele.
depends upon how the mutation affects the gene’s product or activity, and usually connotes an abnormal or unusual characteristic.
may also be a rare variant that is nevertheless “normal,” such as red hair.

MUTANT

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___________ mutation treats HIV infection

CCR5

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o Occurs in the gametes during DNA
replication before meiosis
o All cells will have the mutation
- are transmitted to the next generation of individuals.

germline mutation

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occurs in ANY CELL IN THE BODY except germ cells
happens during DNA replication before mitosis
passed to the next generation of cells but NOT PASSED TO ALL CELLS
has “somatic mosaicism”

somatic mutation

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occur in cells that divide often, such as skin and
blood cells

Somatic mosaicism

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CAUSES OF MUTATION
- Changes in the nucleotide sequence of gene with no known cause
- Generally assumed to be accidental
- Originates as an error in DNA replication, may be due to the lack of DNA repair
- also manifests as “gonadal mosaicism”

Spontaneous mutation

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likelihood of a gene to undergo mutation in a single generation or in a single gamete

Spontaneous mutation rate

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where mutations are more likely to occur,
where sequences are repetitive
▪REPETITIVE SEQUENCES: symmetrical:
may confuse replication enzymes

Mutational hotspots

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CAUSES OF MUTATION
- Result from the influence of external factors (mutagens), such as exposure to CHEMICAL/RADIATION
- may be the result of either natural/artificial agents

Induced mutation

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agents of mutations

MUTAGENS

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MUTAGENS

Base analogs,
alkylating agents,
intercalating agents,
adduct-forming agents (acetaldehyde
and heterocyclic amines)
UV LIGHT
IONIZING RADIATION

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base pairing mutation
Base analogs,
alkylating agents,
intercalating agents,
adduct-forming agents (acetaldehyde
and heterocyclic amines)

CHEMICAL MUTAGENS

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point mutation, most common mutagen
➢ UV light, sunlight, and ionizing radiation

Radiation mutagens

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can be found inserted into our DNA
➢ Viruses and transposable elements

Biological mutagens

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caused by environmental pollutants and
lifestyle factors
➢ Tobacco smoke and alcohol

Environmental mutagens

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Common products containing mutagens

Hair dye
Smoked meats
Certain flame retardants in children’s sleepwear
Food additives

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* Developed by DR. BRUCE ARMES in 1970s * commonly used method that uses bacteria (Salmonella typhimurium) to test if the chemical can cause mutation in the DNA of the test organism * Indication: produces a measurable increase in the number of colonies

Ames Test

Accidental exposure to mutagens:

* Workplace contact before danger is known * Industrial accidents * Medical treatments (chemotherapy and radiation) * Exposure to weapons that emit radiation * Natural disasters that damage RADIATION EMITTING EQUIPMENT

Natural exposure to mutagens:

* Natural environment sources of radiation (cosmic rays, sunlight, & radioactive substances) * Medical X-rays and occupational radiation hazards (ionizing radiation) * Job sites with increased radiation exposure (weapon facilities, research lab, health care facilities, nuclear power plants, & certain manufacturing plants)

Types of Mutations * Change of one base pair to another in a DNA molecule a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

Point Mutations

Point Mutations : purine replaces PURINE (A-G) and pyrimidine replaces pyrimidine (T-C) a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

TRANSITION

POINT MUTATIONS - purine replaces a PYRIMIDINE (A-T; C-G) or vice versa a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

TRANSVERSION

POINT MUTATIONS - SUBSTITUTION in the codon that codes for a DIFFERENT amino acid a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

MISSENSE

POINT MUTATIONS - CHANGE in codon that codes for a stop codon, protein is shortened that leads to premature termination of the translation process a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

NONSENSE

POINT MUTATIONS - SUBSTITUTION in the codon that codes for the SAME amino acid a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

SILENT

POINT MUTATIONS - ALTERS A SITE in the junctions of exons and introns, happens after the mRNA processing a. Transition b. Transversion c. Missense d. Nonsense e. Silent f. Splice-site

SPLICE-SITE

Types of Mutations * Disrupts the reading frame during translation, causing a shift in the way codons are read * Results to nonfunctional proteins a. Deletion mutation b. Insertion mutation - Tandem duplication

Frameshift Mutation

Frameshift Mutation - REMOVAL of one or more nucleotides

Deletion mutation

Frameshift Mutation - ADDITION of one or more nucleotides

Insertion mutation

FRAMESHIFT MUTATION: INSERTION MUTATION - insertion of two complete copies of a gene next to each other Ex. Charcot-Marie-Tooth disease

Tandem duplication

TYPES OF MUTATIONS * DNA sequence very similar to the sequence of a protein-encoding gene * Not translated into protein, but is transcribed resulting to nonfunctional proteins

Pseudogenes

result from a CROSSOVER BETWEEN the WORKING GENE and its PSEUDOGENE, resulting to a fusion gene

Gaucher disease

Types of Mutations * Disrupts the site they jump into by SHUTTING OFF TRANSCRIPTION OF THE GENE they jump into, or alters the reading frame if not a multiple base of 3

Transposons “jumping genes”

Types of Mutation * Segment of DNA within a gene undergoes EXPANSION resulting in the amplification of a repetitive DNA sequence * Small part of the DNA sequence is copied and added to the gene * Anticipation: specific DNA sequence in the gene EXPANDS in size across generations, worsening symptoms

Expanding Repeats

Type of Mutation * Specific DNA sequence that VARIES IN NUMBER OF COPIES in individuals * Types: duplication, deletions, and triplet repeats * Common among people who have behavioral disorders (ADHD, autism, and schizophrenia)

Copy Number Variants

* Different mutations at the same site in a gene can have different effects * Can cause anemia without sickling, or cause CYANOSIS * Considered “clinically silent”

Globin gene mutations

Mutation in the b-globin Gene o First genetic illness understood at the molecular level o Cause: substitution of Valine from Glutamic Acid at the 6th codon of the b-globin chain o Effect: Valine increases the frequency of hemoglobin molecules in low-oxygen conditions

Sickle cell disease

Mutation in the b-globin Gene o Reduced production of either alpha or beta chains a. Thalassemia major (alpha thalassemia) b. Thalassemia minor (beta thalassemia)

Thalassemia

severe form, homozygous mutation in the gene

Thalassemia major (alpha thalassemia):

milder form, heterozygous mutation in the gene

Thalassemia minor (beta thalassemia)

* Major component of connective tissue

Collagen

MUTATION: Mutations in any of three genes (COL4A3, COL4A4, COL4A5) affect type IV collagen, which disrupts tissue boundaries. SIGNS AND SYMPTOMS: Deafness and inflamed kidneys A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Alport syndrome

MUTATION: Deletion, insertion, or missense mutation replaces Gly with bulky amino acids in COL2A1 type II collagen gene SIGNS AND SYMPTOMS: Stunted growth, deformed joints A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Chondrodysplasia

MUTATION: Mutation in "COL7A1 gene" that encodes type VII collagen breaks down fibrils that attach epidermis to dermis. SIGNS AND SYMPTOMS: Skin blisters upon any touch A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Dystrophic epidermolysis bullosa

MUTATION: DIVERSE mutations in at least a dozen genes affect collagens or the molecules to which they bind SIGNS AND SYMPTOMS: Stretchy, easily scarred skin, lax joints A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Ehlers-Danlos syndrome

MUTATION: MISSENSE mutation in "α1" collagen gene (COL1A1) substitutes Cys for Arg. SIGNS AND SYMPTOMS: Painful joints A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Osteoarthritis

MUTATION: INACTIVATION of "α1" COLLAGEN GENE (COL1A1 or COL1A2) reduces number of collagen triple helices by 50% SIGNS AND SYMPTOMS: Easily broken bones; blue eye whites; deafness A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Osteogenesis imperfecta type I

MUTATION: NONSENSE mutations in type II procollagen gene (COL2A1 or COL11A1) reduce number of collagen molecules SIGNS AND SYMPTOMS: Joint pain, degeneration of vitreous gel and retina A. Alport syndrome B. Chondrodysplasia C. Dystrophic epidermolysis bullosa D. Ehlers-Danlos syndrome E. Osteoarthritis F. Osteogenesis imperfecta type I G. Stickler syndrome

Stickler syndrome

* Caused by different mutations in the same gene resulting to different clinical phenotypes * May result from: - Mutations in different parts of the gene - Mutations that are localized (single base change) or catastrophic (missing gene) - Mutations that alter the protein in ways affecting its interaction with other proteins - Mutations that affect a protein used in different tissues

Allelic Diseases

Degree to which a mutation alters a phenotype depending where it occurs in the gene, and how it affects the folding, conformation, activity, or abundance of the protein

Importance of Positioning

Factors that Lessen the Effects of Mutation o Mutation in the 3rd position in a codon = SILENT mutation o Mutation in the 2nd position in a codon = REPLACE another amino acid that has a similar structure a. Genetic code b. Conditional mutation c. Stem cells

Genetic code

Factors that Lessen the Effects of Mutation o Only affects the phenotype under CERTAIN CONDITIONS: exposures that trigger the symptoms a. Genetic code b. Conditional mutation c. Stem cells

Conditional mutation

Factors that Lessen the Effects of Mutation - Therapeutic approaches a. Genetic code b. Conditional mutation c. Stem cells

Stem cells

* Change in the basic structure of DNA * Cell’s response: a. Apoptosis b. DNA Repair c. Cancer

DNA Damage

* Collection of cellular processes aimed to detect and correct DNA damage - DNA replication is very accurate = accomplishment because DNA replicates approx. 10 ^ 16 times during an average human lifetime - most mutation occur in somatic cells

DNA Repair

oversee the accuracy of replication

DNA polymerase & DNA damage response genes

proofreads the activity during DNA replication

DNA polymerase

complex network of cellular processes and signaling pathways activated in response to DNA DAMAGE RAD51: repairs double strand breaks

DNA damage response genes

Types of DNA Repair - Cut and paste mechanisms - Corrects damaged DNA base - Replaces 1-5 nucleotides at a time - DNA glycosylase: recognizes a specific base ▪ First to cut the glycosidic bond ▪ Creates an apyrimidinic or apurinic site - AP endonuclease: recognizes a sugar with the missing base ▪ Makes a cut in the phosphodiester backbone ▪ Removes the deoxyribose sugar ▪ Gap is filled by DNA polymerase and DNA ligase A. Photoreactivation Repair B. Excision repair: Base Excision Repair C. Excision repair: Nucleotide excision repair D. Mismatch repair E. Double-stranded break repair

Base excision repair

Types of DNA Repair * Targets DNA lesions caused by exposure to UV light * Found in fungi, bacteria, archaea, plants, and some vertebrates * Photolyases: enzymes that absorb energy from the visible light and use it to detect and bind pyrimidine dimers to break the extra bonds A. Photoreactivation Repair B. Base excision repair C. Excision repair: Nucleotide excision repair D. Mismatch repair E. Double-stranded break repair

Photoreactivation Repair (light-dependent)

Types of DNA Repair - Repair bulky DNA lesions that alter the double helix - Replaces up to 30 nucleotides A. Photoreactivation Repair B. Base excision repair C. Excision repair: Nucleotide excision repair D. Mismatch repair E. Double-stranded break repair

Nucleotide excision repair

Types of DNA Repair * Excise mismatched base and replace it with the correct base * Often occur in microsatellites A. Photoreactivation Repair B. Base excision repair C. Excision repair: Nucleotide excision repair D. Mismatch repair E. Double-stranded break repair

Mismatch repair

Types of DNA Repair * Heal a broken sugar-phosphate backbone in both DNA strands as two types of multiprotein complexes reseal the backbone structure * Result from exposure to ionizing radiation or oxidative damage A. Photoreactivation Repair B. Base excision repair C. Excision repair: Nucleotide excision repair D. Mismatch repair E. Double-stranded break repair

Double-stranded break repair

* INCORRECT DNA base is placed, but replication and transcription proceed * DNA polymerase read past the error

Damage tolerance

- Heterozygotes who have one mutant repair gene may be more sensitive to damage from environmental factors, such as TOXINS and RADIATION - CHROMOSOME BREAKAGE PERSISTS - Cancer develop as errors in the DNA sequence accumulate & are perpetuated to a much greater extent

DNA Repair Disorders

DNA Repair Disorders - Caused by at least 5 genes - Genes affected: ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A - Faulty repair: NER, BER, or both - Symptoms: dwarfism, intellectual disability, failure to develop, brittle hair, scaly skin Hearing & vision may fail a. Trichothiodystrophy b. Hereditary nonpolyposis colon cancer (Lynch syndrome) c. Xeroderma pigmentosum d. Ataxia telangiectasia

Trichothiodystrophy

DNA Repair Disorders - DNA repair defect in MICROSATELLITES (all the same length) o Faulty repair: MMR o Effects: increased risk of developing colorectal cancer and other cancer a. Trichothiodystrophy b. Hereditary nonpolyposis colon cancer (Lynch syndrome) c. Xeroderma pigmentosum d. Ataxia telangiectasia

Hereditary nonpolyposis colon cancer (HNPCC) (Lynch syndrome)

DNA Repair Disorders o Rare recessive genetic disorder that results to EXTREME SENSITIVITY TO UV - deficient "sloppy" DNA polymerase o Faulty repair: NER or damage tolerance ▪ Allows thymine dimers to stay and block replication o Symptoms: skin cancers, severe skin abnormalities, developmental and neurological defects a. Trichothiodystrophy b. Hereditary nonpolyposis colon cancer (Lynch syndrome) c. Xeroderma pigmentosum d. Ataxia telangiectasia

Xeroderma pigmentosum

DNA Repair Disorders o Genes affected: ATM, defect in KINASE ▪ Kinase: cell cycle checkpoint ▪ Cells proceed through cell cycle without pausing after replication for inspection and repair o Faulty repair: DSBR o Characterization: have 50 times increased risk of developing leukemia o Symptoms: Poor balance and coordination (ataxia), telangiectasia (red marks on the face), delayed sexual maturation, high risk of infection and diabetes mellitus a. Trichothiodystrophy b. Hereditary nonpolyposis colon cancer (Lynch syndrome) c. Xeroderma pigmentosum d. Ataxia telangiectasia

Ataxia telangiectasia

PRE LEC 3: GENE MUTATION Flashcards

(77 cards)