Mutation & Disease Flashcards
Define mutation
permanent, heritable change in DNA
Are mutations pathologic?
not necessarily
What is pathologic mutation
change in DNA taht has effect on the encoded protein or on gene expression that results in disease
What are examples of mutations
base substitution
insertions
deletions
mutations can be ____ or _____ line
somatic or germ line
will mutations be passed onto the next generation?
not unless they occur in the germline
What should you always keep in mind regarding mutations and how it affects protein
what affect the change in DNA sequence will have on gene function - look at protein folding, transcription, will function be completely lost, etc.
it’s not always loss of function, you can have what
gain of function of a protein
what is wild-type allele
most common allele for a gene within the population
what is a polymorphism
allele that is less common than the wt allele but occurs at frequency of less than 1%
they are still relatively “common”
What is a variant
change in DNA sequence that may or mayt notbe polymorphic and may or may not be pathogenic
what is a rare varient
found at frequency of less than 1%
How often do mutations occur per gene?
1.65 x 10^-7 per gene per cell division (1 in 10 billion)
There is one replication error per how many divisions?
1.66 diploid cell divisions
How many novel mutations are there per zygote?
138
How many novel mutationsin haploid sperm?
128
How many novel mutations in haploid egg?
10
What is mutagenesis
the process by which mutations occur
what are spontaneous mutations?
occur in affected person for the first time
not from parent
occur continuously
What are mutagens
they increase the rate of mutagenesis
describe dna repair
reduce mutation rate by 100 fold
What is a synonymous substitution?
silent mutation, same amino acid
What is a non-synonymous mutation?
aa will change - can have missense, nonsense, splice site, promoter
what is a conservative mutation
aa change to another aa of similar type (so like glutamic acid to aspartic acid)
what is non-conservative mutation?
aa changes to another type of aa so like glutamic acid to valine
synonymous and non-synonymous are both what class of mutations
substitution
what do promoter mutations do
alter gene expression
what do splice site mutations do?
aberrant splicing - exon skipping or intron retention
describe the three types of deletions
multiple of 3 - codon
not multiple of 3
large deltion
describe the affects of codon deletion
in-frame deletoin of one or more aa - may affect protein function or stability
what is a deletion, not a multiple of three clled?
frameshift
what are the results of a frameshift mutation?
likely to result in premature termination with loss of function or xpression
what are two types of large deletions
partial gene deletion
whole gene deltion
what is the result of partial gene deletion
may result in premature terminatino with loss of function or expression
what is the restulf of whole gene deletion
loss of expression
what are the four types of insertion mutations
codon
not multiple of 3
large insertion
expansion of trinucleotide repeat
what are the null mutations
nonsense frameshift deletion frameshift insertion partial gene or whole gene deletion sometimes splice site
what is the affect of codon insertion
in-frame insertion of one or more aa - may alter protein function or stability
what is the affect of not multiple of 3 insertion
premature termination with loss of function or expression
what is the affect of large insertion , partial gene duplication
may result in premature termination or loss of function,
what are the two type of large insertions
partial gene duplication
whole gene duplication
what is the affect of large insertion, whole gene duplication
may have affect due to increased gene dosage
what type of mutation is expansion of trinucleotide repeat
dynamic mutation
splicing always goes from splice donor to what
splice acceptor
whathappens if splice acceptor is mutated
the intron stays in messenger RNA
what is it called when the splice acceptor does not function
intron retention
what will intron retention do to protein
make it biger
what ahppens if splice donor looks for next splice acceptor when the one next to it doesn’t function
exon skipping
what does exon skipping do to protein
deletions, make it shorter
if exon skipping and intron retention are not multiples of 3 what happens
frameshift - a null mutation
if splie acceptor or splice donor is mutated which are the two possibilities that could happen for each
exon skipping or intron retention
what is activation of crytpic splice site
creating splice acceptor or splice donor
activation of cryptic splice acceptor site in intron what does what to the gene
extended exon 2
activation of cryptic splice donor in exon 2 does what to gene
shortened exon 2
GT acts as what
splice donor
AG acts as what
splice acceptor
splice site mutations almost always do what to protein function
completely destroy
what does Indels stand for
insertion/deletion mutations
what is at danger to ahve slippage
repetitive sequenes
what is at danger to have slippage
repetitive sequenes
what does backward slippage cause
insertions
forward slippage causes what
deletion
an indel that is not a multiple of 3 will result in what
frameshift
a dyanmic mutation due to expansion of trinucleotide repeat has what affect on protein?
altered gene expression or altered protein stability/function
If there’s a (-) or a (+) for designation what does it mean
it’s a splice mutation
What is incidence
the rate at which new cases (disease) occur
what is prevalence
the proportion of the population affected (usually less than incidence)
what is frequencey
usually synonymous with incidence
almost all enzyme and transporter defects lead to what mode of inheritance
recessive
almost all structural protein and transcription factor defects lead to what mode of inheritance
dominant
majority of mutations caused by transcription factors are what
AD
majority of modifier or protein function have what mode of inheritance?
1/2 AD 1/2 AR
majority of receptors have what mode of inheritance?
1/2 AD 1/2 AR
What is phenotypic heterogenity
variations in a trait, or in the cinical presentation of a disease
what is genetic heterogenity
may cause phenotypic heterogenity
what is allelic heterogeneity**
variety of mutations (alleles) occurring within the same gene (locus
Eg: some residual function alleles result in a mild phenotype, or partial phenotype
what is locus heterogeinity**
different genes are involved
mutations w/in a variety of genes (loci) may cause the same disease/trait
multiple inheritance patterns may occur
most diseases have what kind of heterogeneity
all 2 types: cliniical, allelic, locus
What is the most likely affect on gene of a large deletion or insertion?
most likely to abolish function completely
What is the most likely affect on a gene of duplication of whole gene?
increase product by 50% - normally no change phenotypically unless dosage-sensitive product
What is the most likely affect on a gene with mutation: change in promoter or regulatory sequence
reduces or increases level of transcription
product has normal structure and function
What is the most likely affect on a gene with mutation: change in intron
usually no affect. possibly change in splicing
What is the most likely affect on a gene with mutation: change in 5’ or 3’ untranslated region of mRNA
usually no affect. possibly affect stability or translation efficienty of mRNA
What is the most likely affect on a gene with mutation: splicing mutation
most likely complete loss of function
What is the most likely affect on a gene with mutation: frameshfit mutation
most likely complete loss of function
What is the most likely affect on gene with mutation: nonsense mutation
most likely complete loss of function
What is the most likely affect on gene with mutation: missense mutation
Variable
Loss or gain of function
No affect
What is the most likely affect on gene with mutation: synonymous substitution
most likely no affect
