LECTURE 8 (Human genetics 1)

Question 1

How are inherited human diseases recognized? how are they not?

Answer 1

• yes: looking at evolutionary history (family tree)

- no: DNA test

Question 2

How many patterns are there of human disease?

Answer 2

hundreds but the most common ones are; autosomal recessive, autosomal dominant, x-linked recessive.

Question 3

Describe and give example of autosomal dominant.

Answer 3

• transmuted through generations
• half offspring affected
• unaffected imdv don’t transmit disease
  e. g achondroplasia

Question 4

Describe and give example of autosomal recessive.

Answer 4

• 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

Question 5

Give an example of X-linked recessive and describe.

Answer 5

• 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

Question 6

Are males with CF fertile?

Answer 6

NO!!!

Question 7

What does HGV stand for?

Answer 7

Human genome variation society to address discovery and characterization of genomic variations including population distribution and phenotypic association

Question 8

HGV nomenclature: (11)

Answer 8

> : 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

Question 9

Example of missense in HGV nomenclature

Answer 9

p.lys66Arg (which means the aa 66 changes from lysine to arginine

Question 10

Example of stop codon in HGV nomenclature

Answer 10

tyr665x (which means the aa 665 which is a tyr generates a stop codon

Question 11

example of insertion/deletion in HGV nomenclature

Answer 11

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

Question 12

example of splice site in HGV nomenclature

Answer 12

1408+2T>G (the 2nd nt after 1408 is a G instead of a T)

Question 13

difference of mutation and polymorphism according to different disciplines

Answer 13

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

Question 14

does HGVS use the terms mutation and polymorphism? why?

Answer 14

no because they’re too confusing they prefer to use other terms such as seq variant, alteration, allelic variant

Question 15

Does HGVS use the term pathogenic?

Answer 15

no because sth may or may not be pathogenic depending on the person plus some factors can affect to make it pathogenic or not

Question 16

Which are the 5 categories used to classify variants?

Answer 16

5 affects funtion
4 probably affects function 
3 unknown
2 probably does not affect function
1 does not affect function

Question 17

different sequence variants in different diseases.

Answer 17

• more than 1500 in CF

- only 153 in achondroplasia

Question 18

Why are there so many (1500) sequence variants for CF?

Answer 18

because for the development of CF CFTR has to be unfunctional and this can happen in many ways; misfolding, absent…

Question 19

Why are there so few (153) sequence variants for achondroplasia?

Answer 19

because rather than a loss of function is a gain of function and there aren’t that many possibilities.

Question 20

what are splice site mutations? give an example

Answer 20

interfering with the splice site(the intron) so normal splicing pattern changes

Question 21

What are the 3 main splice site mutations?

Answer 21

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.

Question 22

which percentage of our genes are alternatively spliced?

Answer 22

90%

Question 23

Can you predict how a RNA is gonna look like(how many exons are kept) just by looking at splice site mutations?

Answer 23

no because there are many combinations of exons the cell can produce different isoforms as well.

Question 24

How can stop codons be generated?

Answer 24

either nonsense mutation (point mutation) or a frameshift

Question 25

What’s the effect of a premature stop codon?

Answer 25

they can produce a truncated protein or even no peptide at all.

Question 26

Where do premature stop codons usually occur?

Answer 26

they usually occur in the middle of a transcript

Question 27

What is NMD?

Answer 27

Nonsense mediated decay: it’s a quality control mechanism to destroy the mRNA transcript with a premature stop codon. it’s a surveillance mechanism.

Question 28

What is EJC?

Answer 28

exon junction complex

Question 29

Role of EJC in normal splicing.

Answer 29

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

Question 30

Role of EJC in premature stop codons.

Answer 30

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

Question 31

What’s PTC?

Answer 31

premature termination stop codon.

Question 32

How’s muscular dystrophy caused? how can we reverse the process?

Answer 32

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)

Question 33

How can a protein be formed with a premature stop codon? give an example of disease caused by this

Answer 33

muscular dystrophy, because PTC can override NMD sometimes

Question 34

how is CF caused?

Answer 34

it’s caused by small in-frame deletions Phe508del (ant deletion) CFTR is misfiled degraded or poorly functional

Question 35

Do mutations always cause disease?

Answer 35

no, just because nonsense and frameshift do doesn’t mean that missense or indels always do