MT6315 GENETIC MUTATIONS Flashcards
GENETIC OR CHROMOSOMAL MUTATION: single gene is affected
GENETIC
GENETIC OR CHROMOSOMAL MUTATION: low influence
GENETIC
GENETIC OR CHROMOSOMAL MUTATION: sometimes lethal
CHROMOSOMAL
GENETIC OR CHROMOSOMAL MUTATION: errors in DNA replication and mutagens
GENETIC
GENETIC OR CHROMOSOMAL MUTATION: causes sickle cell anemia, hemophilia, CF
Genetic
GENETIC OR CHROMOSOMAL MUTATION: error in crossing over
chromosomal
GENETIC OR CHROMOSOMAL MUTATION: alteration in nucleotide sequence
GENETIC
GENETIC OR CHROMOSOMAL MUTATION: several genes are affected
CHROMOSOMAL
MUTATION OR POLYMORPHISM: <1% of the population
MUTATION
MUTATION OR POLYMORPHISM: Not affected
POLY
MUTATION OR POLYMORPHISM: Carrier; Diseased
MUTATION
Genetic polymorphism has at least how many alternate DNA sequences?
2
Genetic Polymorphism is generally not associated with disease but may cause the following?
result in phenotype
be a risk of disease
alter the function or
expression level of a protein
any heritable change in the amount or structure of genetic material.
Mutation
Classification of mutations can be based on?
Origin
Cell type
Expression
Effect on function
Molecular change and its effects on protein products
POLYMORPHISM OR MUTATION: Physical event
MUTATION
POLYMORPHISM OR MUTATION: presence of more than 1 allele at a particular locus in a particular population
POLYMORPHISM
POLYMORPHISM OR MUTATION: permanent alteration of a nucleotide
MUTATION
POLYMORPHISM OR MUTATION: Natural selection does not affect alleles
POLY
POLYMORPHISM OR MUTATION: Natural selection selects
MUTATION
POLYMORPHISM OR MUTATION: Human gender, ABO group
POLYMORPHISM
POLYMORPHISM OR MUTATION: Sickle cell anemia, CF, Klinefelter
MUTATION
Types of point mutation?
Silent
Missense
Nonsense
Types of frameshift mutation?
Addition
Deletion
Types of Gene Mutation?
Point
Frameshift
Genetic mutations based on origin?
Spontaneous
Induced
TYPE OF MUTATION BASED ON ORIGIN: Occurs in absence of known mutagen
Spontaneous
TYPE OF MUTATION BASED ON ORIGIN: Occurs in presence of known mutagen
Induced
TYPE OF MUTATION BASED ON ORIGIN: Statistically random, unpredictable events
Spontaneous
TYPE OF MUTATION BASED ON ORIGIN: happens in most mutations
Spontaneous
T or F: Each gene has its rate of mutation
T
The rate of mutation can (increase/decrease) with a mutagen or radiation
Increase
an agent that changes genetic material
Mutagen
Types of mutagens based on their effect?
Teratogens
Carcinogens
Clastogens
Non-specific
WHAT TYPE OF MUTAGEN: Congenital malformations
TERATOGEN
WHAT TYPE OF MUTAGEN: chromosomal abnormalities
CLASTO
WHAT TYPE OF MUTAGEN: DNA damage
NON-SPECIFIC
WHAT TYPE OF MUTAGEN: Tumor formation, cancer causing agents
CARCINO
CLASSIFICATION OF MUTAGENS?
PHYSICAL
CHEMICAL
BIOLOGICAL
EXOGENOUS OR ENDOGENOUS: UV-light
Exo
EXOGENOUS OR ENDOGENOUS: Smoking
EXO
EXOGENOUS OR ENDOGENOUS: Reactive oxygen species
Both
EXOGENOUS OR ENDOGENOUS: Spontaneous or enzymatic DNA base modifications
ENDO
EXOGENOUS OR ENDOGENOUS: DNA replication error
ENDO
WHAT DAMAGING AGENT: Dipyrimidine photoproducts
UV
WHAT DAMAGING AGENT: Bulky DNA adducts at guanines
Smoking (Benzopyrene)
WHAT DAMAGING AGENT: Oxidation of guanine
Reactive O2 species
WHAT DAMAGING AGENT: Deamination of 5-methylcytosine or cytosine
SPONTANEOUS OR ENZYMATIC DNA BASE MODIFICATIONS
WHAT DAMAGING AGENT: mismatch
DNA REPLICATION ERROR
Types of chemical mutagens?
Base analogs
Base altering agents
Intercalating agents
Types of Base altering agents?
Deaminating agents
Hydroxylating agents
Alkylating agents
Mutations based on cell type?
Somatic
Germ Line
SOMATIC OR GERM LINE: Occurs in nonreproductive cells
SOMATIC
SOMATIC OR GERM LINE: Can yield a genotypic mixture (mosaic) of normal and mutant tissue
SOMATIC
SOMATIC OR GERM LINE: Most common cancers
SOMATIC
SOMATIC OR GERM LINE: Autosomal
SOMATIC
SOMATIC OR GERM LINE: non-inheritable
SOMATIC
SOMATIC OR GERM LINE: Occurs in reproductive cells
GERM
SOMATIC OR GERM LINE: common in sperm cells
GERM
SOMATIC OR GERM LINE: Inherited
GERM
What kind of mutations are common in sperm cells?
de novo
T or F: In germ line mutations, not all inherit or have the mutation
F, all have the mutations
In somatic mutations do all offspring have the mutation?
No, it is not inheritable
Mutations based on expression?
Conditional
Unconditional
TYPE OF MUTATION BASED ON EXPRESSION: Expressed only under restrictive conditions
CONDITIONAL
TYPE OF MUTATION BASED ON EXPRESSION: Effect of mutation can be turned on or off by experimenter
CONDITIONAL
Effect of mutation can be turned on or off by experimenter through the use of?
Transcription factors that turn off/on the gene
TYPE OF MUTATION BASED ON EXPRESSION: Expressed under permissive conditions as well as restrictive conditions
UNCONDITIONAL
“Normal conditions”
Permissive conditions
What precipitates conditional expressions?
Restrictive conditions
Types of mutations based on effect on function?
Loss of/amorphic (Knockout or null)
Hypermorphic (Leaky) – loss of
WHAT TYPE OF MUTATION BASED ON EFFECT ON FUNCTION: Eliminates normal function
LOSS OF
WHAT TYPE OF MUTATION BASED ON EFFECT ON FUNCTION: Results in complete gene inactivation or in a completely nonfunctional gene product
LOSS OF
Loss of function results in complete gene inactivation or in a completely nonfunctional gene product through?
Deletion of all or part of a gene or deletion of the part of the gene that helps in its expression
Amino acid replacement that inactivates the protein
Example of amoprhic gene?
Bombay phenotype
WHAT TYPE OF MUTATION BASED ON EFFECT ON FUNCTION: still has level of expression but it is severely reduced
LOSS OF
WHAT TYPE OF MUTATION BASED ON EFFECT ON FUNCTION: Reduces normal function, but does not eliminate, the level of expression of a gene or the activity of the gene product
LOSS OF
Individuals with loss of function may have enough enzyme activity to ____ to produce a quasi- normal phenotype
“leak through”
LOSS OF OR GAIN OF: Hypermorphic
GAIN
LOSS OF OR GAIN OF: Increases normal function; produces a greater than normal level of gene expression
GAIN
LOSS OF OR GAIN OF: ectopic expression
GAIN OF
WHAT MUTATION BASED ON EFFECT OF FUNCTION: Expressed at incorrect time or in inappropriate cell types
NEOMORPHIC
WHAT MUTATION BASED ON EFFECT OF FUNCTION: Qualitatively alters the action of a gene
NEMORPHIC
LOSS OF OR GAIN OF: Neomorphic
GAIN OF
WHAT MUTATION BASED ON EFFECT OF FUNCTION: Mutant gene product interferes with normal gene product
ANTIMORPHIC
LOSS OF OR GAIN OF: Antimorphic
LOSS OF
WHAT MUTATION BASED ON EFFECT OF FUNCTION: creating abnormal proteins that replaces the normal one
ANTIMORPHIC
Recessive mutations are usually (gain of/loss of) function.
LOSS OF
Dominant mutations are usually (gain of/loss of) function.
BOTH
MUTATIONS BASED ON MOLECULAR CHANGE?
Substitutions
* Deletions
* Insertions
* Duplications
Inversions
* Translocations
In molecular genetics,
base pair substitutions are also termed?
point mutations
In classical genetics, point mutations denote?
any mutation small enough to be unobservable under a microscope
MUTATIONS Based on Molecular Change: Most common type of mutation
SUBSTITUTIONS
MUTATIONS Based on Molecular Change: Replacement of a single nucleotide by another
SUBSTITUTIONS
TYPES OF SUBSTITUTIONS?
TRANSITION
TRANSVERSION
TYPE OF SUBSTITUTION: Replacement by the same type of nucleotide
TRANSITION
TYPE OF SUBSTITUTION: pyrimidine for a pyrimidine (C for T or vice versa)
TRANSITION
TYPE OF SUBSTITUTION: Most frequent due to CpG dinucleotides
TRANSITION
TYPE OF SUBSTITUTION: purine for a purine (A for G or vice versa)
TRANSITION
TYPE OF SUBSTITUTION: Substitution of a pyrimidine by a purine or vice versa
TRANSVERSION
TYPE OF SUBSTITUTION: More silent
TRANSITION
TRANSITION VS TRANSVERSION: Most common type of point mutation
TRANSITION
TRANSITION VS TRANSVERSION: 2 possible
TRANSVERSION
TRANSITION VS TRANSVERSION: One possible only
TRANSITION
TRANSITION VS TRANSVERSION: more likely to cause amino acid sequence changes, more pronounced effect on the resulting protein
TRANSVERSION
TRANSITION VS TRANSVERSION: Less likely to cause AA sequences, silent mutation
TRANSITION
TRANSITION VS TRANSVERSION: Interchanges between bases within single ring structures
TRANSITION
MUTATIONS Based on Molecular Change: Involves the loss of one or more nucleotides
DELETIONS
TYPES OF DELETION PATTERNS?
MULTIPLES OF 3 NUCLEOTIDES (CODON)
NOT MULTIPLE OF 3
LARGE DELETION
WHAT DEL PATTERN: Deletion of amino acids that may affect protein function or stability
Multiple of 3 nucleotides (codon)
WHAT DEL PATTERN: Likely results to frameshift mutation
Not multiple of 3
WHAT DEL PATTERN: May arise through unequal crossover between repeat sequences
Large deletion
WHAT DEL PATTERN: Either: Partial gene deletion or Whole gene deletion
Large deletion
Three-base deletion in the common cystic fibrosis (CF) allele results in synthesis of a protein that lacks amino acid ______
508 (phenylalanine).
MUTATION Based on Molecular Change: Involves the addition of one or more nucleotides into a gene
INSERTION
TYPES OF INSERTION PATTERNS?
Multiple of 3 nucleotides (codon)
Not multiple of 3
Large insertion
Expansion of trinucleotide repeat (most contain C and/or G)
WHAT TYPES OF INSERTION PATTERNS: Insertion of amino acids that may affect protein function or stability
Multiple of 3 nucleotides (codon)
WHAT TYPES OF INSERTION PATTERNS: Likely results to frameshift mutation
Not multiple of 3
WHAT TYPES OF INSERTION PATTERNS: Results from unequal crossover (e.g., hereditary sensory and motor neuropathy type 1a) or the insertion of transposable elements
Either: Partial gene duplication or Whole gene duplication
Large insertion
WHAT TYPES OF INSERTION PATTERNS: Amplification of a sequence of three nucleotides, which prevents normal expression of the gene
Expansion of trinucleotide repeat (most contain C and/or G)
WHAT TYPES OF INSERTION PATTERNS: Involves dynamic mutations wherein the repeat sequence becomes more unstable as it expands in size
Expansion of trinucleotide repeat (most contain C and/or G)
Possible causes of Expansion of trinucleotide repeat (most contain C and/or G)?
Unequal sister chromatid exchange on nonreplicating DNA
Slipped-strand mispairing and polymerase slippage in replicating DNA
Examples of disorders on the Expansion of trinucleotide repeat (most contain C and/or G)?
Fragile X syndrome (FMR1 gene) – CGG
Mutation
repeats
Huntington disease (HTT gene) – CAG repeats
Myotonic dystrophy (DMPK gene) – CTG repeats
Friedreich ataxia (FXN1 gene) – GAA repeats
MUTATIONS Based on Effect on Protein Products?
Synonymous
Nonsynonymous
SYNO OR NONSYNO: Silent
SYNO
Types of non synonymous mutations?
Missense mutations
Nonsense mutations Frameshift mutations
SYNO OR NONSYNO: Mutation does not alter the polypeptide product of the gene
SYNO
WHAT IS REFERRED TO AS “Base substitution occurs but does not change the amino acid sequence”
Silent mutations
SYNO OR NONSYNO: Mutation leads to an alteration in the encoded polypeptide
NONSYNO
SYNO OR NONSYNO: Likely to result in abnormal function, which is usually associated with disease,
or lethality
NONSYNO
WHAT TYPE OF NONSYNO: Base-pair substitutions that produce a change in a single amino acid
MISSENSE
WHAT TYPE OF NONSYNO: Change in amino acid may affect the protein structure
MISSENSE
WHAT TYPE OF NONSYNO: Sickle cell anemia
MISSENSE
Sickle cell anemia affects?
β-globin chain of hemoglobin at the position G
What happens with the AA sequence changes in hemoglobin?
Hb crystallizes when O2 levels are low, causing RBCs to sickle and get stuck in small blood vessels
WHAT TYPE OF NONSYNO: Base-pair substitutions that produce a stop codon in the mRNA
Nonsense mutations
WHAT TYPE OF NONSYNO: Result in a premature termination of the polypeptide chain
Nonsense
Base-pair substitutions that produce a stop codon in the mRNA results in?
premature termination of the polypeptide chain
WHAT TYPE OF NONSYNO: Unlikely to retain normal biological activity, especially when there is a loss of an important functional domain(s) of the protein
Nonsense
What is an example of nonsense mutation?
β0-thalassemia
β0-thalassemia affects what in hemoglobin?
β-globin chain wherein codon for glutamine (CAG) creates a stop codon (UAG) as U is substituted for C
WHAT TYPE OF NONSYNO: When a mutation involves the insertion or deletion of nucleotides that are not a multiple of three, it will disrupt the reading frame
Frameshift mutations
WHAT TYPE OF NONSYNO: Resulting amino acid sequence bears no resemblance to the normal sequence and may have an adverse effect on its function
Frameshift mutations
Example of frameshift mutation?
Single-base deletion at the ABO (glycosyltransferase) locus, leading to a frameshift mutation responsible for the O allele.
Tay-Sachs disease
How is there frameshift in Tay-Sachs disease?
Four-base insertion in the hexosaminidase A gene
What is caused by greater than or equal to 40-121 CAG repeats?
HD
What level of penetrance of HD is 36-39 CAG repeats?
Reduced penetrance
What level of penetrance of HD is 27-35 CAG repeats?
Mutable Normal Allele
What level of penetrance of HD is less than or equal to 26 CAG repeats?
Normal alleles
Types of splice site mutations?
Exon Skipping
Intron inclusion
Cryptic splice site use
T OR F: All polymorphisms are equally detrimental for all populations
F, can be harmless to another and harmful to one
When do somatic mutations usually occur?
Before mitosis
When do germ line mutations usually occur?
DNA replication preceding meiosis
Most mutations are spontaneous or induced?
Spontaneous
“Surprise” mutation
Spontaneous
Spontaneous mutation usually originates as an error in?
DNA replication
What triggers spontaneous mutations?
DNA bases existing in tautomers which can be inserted into the newly formed DNA causing errors
T or F: Different genes have different spontaneous mutation rates
T
Spontaneous mutation lies behind many instances of? Give an example disease
Somatic mutation
Proteus syndrome
Spontaneous mutation also manifests as?
Gonadal mosaicism
Why can mitochondrial genes mutate at a higher rate than the nucleus?
Mitochondria cannot repair their DNA
Spontaneous mutation rate can be computed by?
de novo cases / 2X (X = individuals examined)
*2 is for non mutated homologous chromosome
T or F: Spontaneous mutations are hard to assess
T
Where are mutations more likely to occur?
Hotspots
What dyes remove or add a single DNA base for induced mutations?
Acridine
Best known test for mutagenicity of substance?
Ames test - uses a strain of Salmonella that cannot grow when histidine is absent
T or F: Chemical mutagens are only artificial
F, can be seen in the environment
What mutation is seen only in certain conditions?
Conditional mutation
How to avoid conditional mutation?
Avoid exposure to certain triggers
T or F: Point mutations are visible under the microscope
F, unobservable
Until how many base pair inversions are NOT seen in karyotypes?
~500 pairs
Who are resistant to malaria?
Homozygous HbS and HbC individuals
Who is (+) for sickle cell anemia? HbS or HbC?
HbS
HbS and HbC result from?
Mutation in the 6th amino acid in the beta-globin polypeptide
If the beta-globing chain is dysfunctional, what happens?
RBC will crystallize and become sickle cell
Detects numerical and gross structural aberrations
Karyotypes
Detects trisomies, monogamies, and microdeletions
FISH
Detects copy number variations of genetic material
CGH
Depends on the melting point of DNA to detect its ability to stick
PCR testing
Detects missense mutations
PTT
A specific DNA sequence that varies in number of copies from person to person
Copy Number Variant
What causes exon skipping?
A missense mutation that includes intron splicing sites in places where it should not be
Point mutation that alters the site where introns are normally removes from the mRNA
Splice-site mutation
Why is retaining an intron unusual?
Because it has stop codons
What are predictable because we are able to identify which codons can mutate to become a stop codon?
Nonsense mutations
What kind of mutagen: Halouracil and nitrogen mustard
Chemical
What kind of mutagen: Virus and bacteria
Biological
What kind of mutagen: X-rays and gamma rays
Physical
A point mutation can greatly affect a gene’s product if it alters a site where introns are normally removed from the DNA. This is called a ____ mutation
Splice site
Thymine and cytosine dimerization are seen in ____ exposure in direct sunlight
UV-C
What is the most energetic ionizing radiations?
Gamma rays
A missense mutation that created an intron splicing site where there should not be one can cause ____, which removes a few contiguous AAs from the protein product
Exon skipping/ Frameshift
Major source of exposure to human-made radiation
X rays
Biological agent implicated in t8;14
Virus (EBV)
Mutagen used to label cells are like thymine but can pair up with either adenine or guanine which causes DNA replication
Bromouridine
The BS allele combined with a ____ HBB allele results in HbSB thalassemia disorder which is generally milder than sickle cell anemia
Leaky
Cytosines in ____ dinucleotides can be methylated to form 5-methylcytosines
CpG
Mutation of p53 gene is common in tobacco cancers, with a variation in the amount of G to T _____ in lung cancer from smokers and non-smokers
Transversions
T or F: Germ line mutation is the most common cause of cancers
F, somatic
T or F: Germ line mutation happens in egg and sperm cells
T
T or F: Genetic mutation have no effect on the individual at all
T
T or F: Silent mutations are not associated with any diseases
T
The methylation of __________ results in stable silencing of gene expression
CpG islands
The _____________ of CpG islands results in __________________ of gene expression
methylation
stable silencing
When do somatic mutations occur?
Before mitosis
When do germ line mutations occur?
During DNA replication before meiosis
How many CGG repeats in Fragile X syndrome is still viable for wild type phenotype?
30
How many CGG repeats in fragile X syndrome cause pre-mutation?
50-200
How many CGG repeats in fragile X syndrome cause the mutant allele?
> 230, heavy methylation prevents normal transcription
What amino acid is affected in the missense mutation of sickle cell anemia?
Glutamic acid
