LECTURE 8 (Human genetics 1) Flashcards
How are inherited human diseases recognized? how are they not?
- yes: looking at evolutionary history (family tree)
- no: DNA test
How many patterns are there of human disease?
hundreds but the most common ones are; autosomal recessive, autosomal dominant, x-linked recessive.
Describe and give example of autosomal dominant.
- transmuted through generations
- half offspring affected
- unaffected imdv don’t transmit disease
e. g achondroplasia
Describe and give example of autosomal recessive.
- only 1 generation affected
- non-affected individuals can transmit the disease
- if both parents carriers: 1/2 carriers 1/4 affected 1/4 unaffected
e. g CF
Give an example of X-linked recessive and describe.
- F are carriers if one of their X chr is affected, then give disease to half of their sons and carrier half of their daughters.
e. g hemophilia
Are males with CF fertile?
NO!!!
What does HGV stand for?
Human genome variation society to address discovery and characterization of genomic variations including population distribution and phenotypic association
HGV nomenclature: (11)
> : substitution
- : range of nt affected
dup: duplication
del: deletion
inv: inversion
ins: insertion
fs: frameshift
c: coding DNA seq
g: genomic DNA seq
r: coding RNA seq
n: non.coding RNA seq
m: mt RNA
Example of missense in HGV nomenclature
p.lys66Arg (which means the aa 66 changes from lysine to arginine
Example of stop codon in HGV nomenclature
tyr665x (which means the aa 665 which is a tyr generates a stop codon
example of insertion/deletion in HGV nomenclature
69_71del(p.Val115del) means there’s a deletion of 3 nt from 69 to 71
54insA (there’s an insertion of an A at position 54 –> p.val115fs fs is frameshift
example of splice site in HGV nomenclature
1408+2T>G (the 2nd nt after 1408 is a G instead of a T)
difference of mutation and polymorphism according to different disciplines
mutation: a change or a disease-causing change
polymorphism : a non-disease-causing change and found at a freq of 1% or more in the pop
does HGVS use the terms mutation and polymorphism? why?
no because they’re too confusing they prefer to use other terms such as seq variant, alteration, allelic variant
Does HGVS use the term pathogenic?
no because sth may or may not be pathogenic depending on the person plus some factors can affect to make it pathogenic or not
Which are the 5 categories used to classify variants?
5 affects funtion 4 probably affects function 3 unknown 2 probably does not affect function 1 does not affect function
different sequence variants in different diseases.
- more than 1500 in CF
- only 153 in achondroplasia
Why are there so many (1500) sequence variants for CF?
because for the development of CF CFTR has to be unfunctional and this can happen in many ways; misfolding, absent…
Why are there so few (153) sequence variants for achondroplasia?
because rather than a loss of function is a gain of function and there aren’t that many possibilities.
what are splice site mutations? give an example
interfering with the splice site(the intron) so normal splicing pattern changes
What are the 3 main splice site mutations?
intron retention, exon skip or in frame deletion
the two first occur when a base is excised right after an exon and the last two when a base is excised in the middle of an intron.
which percentage of our genes are alternatively spliced?
90%
Can you predict how a RNA is gonna look like(how many exons are kept) just by looking at splice site mutations?
no because there are many combinations of exons the cell can produce different isoforms as well.
How can stop codons be generated?
either nonsense mutation (point mutation) or a frameshift
What’s the effect of a premature stop codon?
they can produce a truncated protein or even no peptide at all.
Where do premature stop codons usually occur?
they usually occur in the middle of a transcript
What is NMD?
Nonsense mediated decay: it’s a quality control mechanism to destroy the mRNA transcript with a premature stop codon. it’s a surveillance mechanism.
What is EJC?
exon junction complex
Role of EJC in normal splicing.
EJC joins every exon-exon junction and in the first round of translation are displaced by the ribosome. when the unique stop codon is found the termination complex is formed
Role of EJC in premature stop codons.
when there’s a premature stop codon EJC remain bound to it and it’s not removed by the ribosome. when the termination complex appears and binds to EJC NMD appears and destroys the sequence
What’s PTC?
premature termination stop codon.
How’s muscular dystrophy caused? how can we reverse the process?
it’s caused by frmaeshift and nonsense generally by premature stop codons. by giving a drug that reverses the nonsense to a missense(although the disease isn’t totally eliminated)
How can a protein be formed with a premature stop codon? give an example of disease caused by this
muscular dystrophy, because PTC can override NMD sometimes
how is CF caused?
it’s caused by small in-frame deletions Phe508del (ant deletion) CFTR is misfiled degraded or poorly functional
Do mutations always cause disease?
no, just because nonsense and frameshift do doesn’t mean that missense or indels always do
