W11 Flashcards
(42 cards)
what does a somatic mutation refer to
- not inheritable
- only affect somatic cell patches arising from the original cell
- the earlier in development the mutation occurs, the bigger the patch
- cancers are often somatic
HOWEVER, risk factors can be inherited
what does a genetic mutation refer to
- occurs in egg and sperm
- is heritable
- all cells in the offspring carry the mutation (genotype), but the phenotype is only in cells/tissues usually expressing the gene
what are the inheritance consequences of somatic and genetic mutation
somatic mutations are not inherited whilst genetic mutations are
what are examples of somatic and genetic mutation
eg. germline mutation: bithorax on Drosophila melanogaster where there is two sets of wings
or antenapaedia: hair of function turns antenna into ectopic legs
or HMA
eg. somatic mutations
patches of colour ie. on hair or a petal of a flower
what are the types of a chromosomal mutation
mutations can be chromosomal (large) or affect small number of DNA bases (small)
- chromosomal mutations can involve many genes and be visible at the light microscope level if it affects >4mb, which contain ~200-300 genes
- smaller mutations affecting individual genes can occur in coding(affect gene product) or non-coding regions (affect gene expression)
HOW SEVERE THE RESULTING PHENOTYPE IS, DEPENDS ON MANY FACTORS
what are examples of DNA mutation
change amount of genetic material:
- deletion: may loose important genes
- duplication: gene dosage effect
not change amount of genetic material
- inversion: disrupt or fuse genes (rearrangement)
- translocation: disrupt or fuse gemes (rearrangement)
HOW SEVERE THE RESULTING PHENOTYPE IS, DEPENDS ON MANY FACTORS
can occur anywhere, but the effects described here are assuming these changes occur within the coding sequence
use examples of two different DNA mutations to describe how one might have only little consequence, whilst another may lead to a dramatic phenotype/disease?
SINGLE BASE PAIR MUTATIONS:
- can have different effects on the amino acid polypeptide
1. silent: (no change in gene product) degeneracy and wobble
2. missense: (amino acid substitution in gene product) can be first, second or third base - could have very little effect on protein function, unless a very important amino acid is lost or the added amino acid changes the 3D protein or binding location
3. nonsense: (premature termination of translation
DELETION OR INSERTION MUTATION CAN HAVE SUBTLE OR LARGE EFFECTS
- amino acid deletion/insertion if divisible by three
- frameshift if not divisible by three
how does that CF mutation affect protein functioning
- there is a defect due tot eh cystic fibrosis transmembrane conductance regulator (CFTR) protein important fir cl- ion transport
- mutations cause cl- ion to build up which in turns leads to accumulation of sticky mucus in ducts of exocrine, lungs, vas deferens
what are the two key components of haemoglobin
- alpha like genes in chr16
- beta like genes on chr11
these have age dependent expression that gives rise to a difference between adult haemoglobin and metal haemoglobin - adult 2alpha2beta
- fetal 2alpha2gamma
how are sickle cell anaemia and thalassemia different
sickle cell anaemia cause: 1. one single base pair change in beta haemoglobin leads to a misuse mutation 2. the sixth AA changes from glutamic acid to valine, which alters the charge at this site
thalessemia cause: mutations in alpha or beta thaeleseemia lead to decreased synthesis or stability of either alpha or beta globing respectively. abnormal Hb may lead to excessive RBC loss and cause anaemia.
- autosomal recessive
whilst sickle cell anaemia only has one phenotype of a change in AA, alpha and beta thalessemia have a range of phenotypes respectively
Alpha thalessemia:
1. silent carriers,
2. alpha thalessemia trait (not have ideas yet, one or two alpha genes),
3. Haemoglobin disease- three alpha genes deleted
4. Barts Hydrops fettles syndrome- all foru alpha genes deleted
Beta thalessemia:
1. trait/minor- one gene
2. intermedia reduced - two genes
3. major- 2 genes
what is one type of mutation associated with thalessemia
BETA THALASSAEMIA
- missense mutants- changes amino acid
- nonsense mutants premature stop codon
- frameshift mutants
- splice mutation: single nucleotide changes may create new splice sites or single nucleotide changes may destroy splice sites and activate cryptic ones
what is a triple repeat mutation
changes in phenotype due to expansion of a triplet repeat (3 base sequence)
- the location and type of the expanded repeat varies and results in different outcomes
cases: Huntington’s disease, Fragile X syndrome
use one disease example, how do triple repeat mutations result in a phenotype
Fragile X syndrome:
- Fragile X mental retardation protein is a regulatory protein which binds mRNA in neurons and dendrites
- synaptic development requires functional FMRP
- CGG expansion in 5;YTR triggers methylation of promoter and BLOCKS TRANSCRIPTION ie. loss of FMRP
Huntington’s disease:
- autosomal dominant gain of function
- CAG repeats in exon 1 of 67 makes protein toxic
- this leads to clinical symptoms (extra: such as movement disorders, dementia and psychiatric disturbances)
what type of mutation is CF and what is its frequency fact
- autosomal recessive mutation in 7q 31 (chromosome 7 at location 31)
- there is a high carrier frequency, 1:25. incidence is 1:2500 caucasians
- the most common mutation is ΔF508: in frame deletion of phenylalanine at position 508
most common mutation in caucasians:
DNA change: c.1521_1523delCTT
amino acid change: Phe508del
how is genetic diagnosis of CF done?
- PCR region of exon 10 with ΔF508 mutation
- detect deletion on gel: 95 bp versus 98 bp
Homozygous for ΔF508: only 95 bp
Heterozygous for ΔF508: both 95bp and 98bp
homozygous wild type: only 98bp
list CF facts
- CFTR gene cloned in 1989
- currently 2073 mutations identified in this gene
how is CF tested through a Guthrie spot test
partial blockage of pancreatic duct leads to increased immunoreactive trpsinogen (IRT)
describe beta globin in terms of its gene, mRNA and polypeptide
- gene size of 1.5kb
- mRNA ~500bp
- polypeptide contains 146 amino acids
what are the effects of the sickle cell mutation
- Glu to Val causes a defective beta globin which affects haemoglobin structure particularly in hypoxia where the sickle Hb aggregates as rod/rope shaped fibres
- this aggregation in turn changes the shape of the RBC to sickle shape, which can block capillaries
- the lifespan of RBCs in HbS is reduced from 120-20 days resulting in anaemia
which Haemoglobinopathy has varying prevalence across the what and in what way does it vary
beta thalassaemia mutations include predictable missense, nonsence, frameshift and less predictable splice mutants: destroy/create site/ activate cryptic site
what is Huntington’s disease?
- progressive late onset neurological diseases on chromosome 4
- homozygosity affects phenotype and disease progression rate
<35 normal 27-35 rare but unstable when transmitted via male 36-39 intermediate (reduced penetrance) 40-50 most adult cases >50 juvenile onset
what is a direct test for Huntington’s disease
PCR amplify CAG repeat region of exon 1
<35 normal 27-35 rare but unstable when transmitted via male 36-39 intermediate (reduced penetrance) 40-50 most adult cases >50 juvenile onset
what is Fragile X syndrome
when there are fragile sites in human chromosomes
- there are many people without phenotype
- though not causative, fragile site on X chromosome correlates with mutation
6-54 normal
55-200 premutation
>200 full mutation
how can Fragile X syndrome be detected
- visible when cells cultured in folate deficient thymidine deficient medium
