Lecture 4: Mutations and Disease Flashcards
Define mutation
a chnage or variation in the base sequence of DNA, can have a downstream influence on RNA and protein
What are the two origins of new mutations?
- endogenous mutations
- mutagens
What is the difference between an endogenous mutation and mutagens?
endogenous - spontaneous errors in DNA replication and repair, increased mutation load with aging in mitochondiral DNA
mutagens - the environment, somatic mutations, damage a particular nucleotide or become incorporated into the nucleic acid, increases frequency of mutant load
Name three types of mutations (class)
- chromosome disorders
- single gene (monogenic) disorders
- complex/ultifactorial disorders
What are chromosome disorders and how does this relate to phenotype?
- excess or deficiency of the genes contained in the whole chromosome or chromosome segments
- phenotype depends on how many genes are added or lost
- small - no severe phenotype chages
- large - can lead to miscarriage
rare 7/1000 liveborn infants
~50% spontaneous 1 trimerster miscarriages
Give an exaple of a chromosome disorder
- Trisomy 13- Patau syndrome
- 3 copies of chromosome 13
- increasing risk with maternal age
- 95% cases lead to miscarriage
- abnormally shaped heads, heart defects, seizures, intellectual disparity
explain what single gene disorders are and some examples
- caused by individual mutant genes
- may be recessive or dominant
- may be contained in the mitochondrial or nuclear genomes
how are single gene disorders visualised
pedigree patterns (inheritance through a family)
what are examples of gene mutations
substitutions
deletions
insertions
what are the two types of substitution mutations and explain the difference between them
transition - substitution of purines w/ purines (AG) or pyrimidines w/ pyrimidines (CT) - 2/3 of mutations
transversion - purine replaced by pyrimidine vice verca - 1/3 of mutations
what transition is most common and what triggers it
CT transition, triggered by UV damage in cancer
What are the different classes of substitutions
- synonymous (silent): no change in amino acid, usually in third base position
- nonsense (non-synonymous): replacement of amino acid with termination codon, drammatic reduction in gene function, premature protein truncation
- missense mutations (non-synonymous): replacement of amino acid with different amino acid. two types.
what are the two types of missense mutations?
a. conservative: replacement amino acid is similar = minimal effect on function
b. non-conservative: replacement amino acid is dissimilar = more serious effect on function
what is the molecular pathology of mutation to disease. what relationship does this show?
mutation - altered protein - abnormal functon - disease
shows close relationship between genotype and phenotype
how can the phenotype/genotype relationship be used in clinical diagnosis?
- look at genotype and succesfully predsct the phenotype of offspring
- can screen the genes that are the culprit of disease in other families and get those genes screened in patient
where do pathogenic mutations occur?
- protein coding regions (exons) - includes non synonymous mutations
- mutations disrupting RNA stability or RNA splicing - mutation in intron, 10% of m.
- Mutations affecting gene regulation or dosage - promoter/enhancer region mutation, ~1% of m
what effect does a framshift mutation have on phenotype and on the genotype
insertion or deletion results in different sequence of amino acid, usually ends in premature truncation of protein
associated with severe phenotypes
explain the difference between point mutations and frameshift mutations in terms of protein
point mutation - still get some product made that isnt affected
frameshift - product from instertion/deletion thereon down makes no sense, protein affected a lot more
the affect of the premature protein truncation will depend?
- the stability of the polypeptide product
- the extent of the truncation
- the functional importance of the missing amino acids
depends on what part of the protein is truncated
eg. if a key domain that is v important to protein function is affceted - bigger problem than if it is retained and other area is mutated
explain why a frameshift in a multiple of three is less severe?
they dont change the reading frame
insertion of new or removal of one aa - not as severe as complete shift in reading frame
Give an example of a 3base frameshift mutation
F508 mutation is cystic fibrosis 1:30 caucasians
one copy - carrier with mild symptoms
two copies - cystic fibrosis
high heterozgote incidence = evoliutionary survival advantage from cholera and typhoid fever
explain autosomal recessive inheritance pedigree patterns
- male and female equally affected
- appeards mainly in brother/sister proband
- Don’t tend to see it in the parents, both need to be carriers so you get two copies in proband
- Each mother and father is heterozygote, wont exhibit phenotype themselves - asymptomatic carriers of mutant alleles
- Each offspirn has a 1 in 4 chance in being affected
- 1 in 2 cahnce of being a carrier and pass on to offspring
- occurs more frequently when parents are relatives (consanguineous)
what is an example of an autosomal recessive disorder?
cystic fibrosis
1:30 caucasians
carriers are not clinically recognisable becuase remaining non-mutated copy of the gene creates enough good protein to compensate
explain autosomal dominant inheritance pedigree patterns
- Phenotype present in each generation
- each affected person has an unaffeced parent
- Heterozgous mutant and wildtype, you will exhibit the disease
- Every child has 50% risk of getting disorder themselves
- Male femlae equal affected
- Phenotypically normal family members do not transmit the phenotype to their children
what is an example of an autosomal dominant disease?
huntingtons, myotonic distrophy
- half of mendelian diseases are autosomal dominant
explain x-linked recessive inheritance pedigree patterns
- Much more prevalent in males than females
- Heterozygous females are mildly affected due to random x inactivation
- All affected males will pass gene onto their daughter who will be carriers
- Look out for father to son transmission – cant be x linked
- Dots represent carrier
- Transmission to males through carrier femlaes
give an example of an x-linked recessive inheritance disease
androgen insensitivity syndrome, muscular dystrophy
what is meant by random x-inactivation
- disease is milder in heterozygous women becuase of the random inactivation of one of the chromosomes (i.e inactivation of mutant copy or wildtype copy)
explain x-linked dominant inhetiance pedigree patterns
- affected males have no affected sons and no normal daughters, always pass onto female offspring
- daughter of affected male is affected themselves
- both male and female carriers have 50 % risk of inheriting phenotype
- affected females twice as common as affected males, but have milder diseas due to x inactivation
- similar to AD inheritance
what is an example of an x-linked dominant disease
retinitis pigmentosa
Explain the y-linked dominant inheritance pedigree pattern
- affects only laes
- affected males always have an affected father unless there is a sporadic ne dovo mutation
