Genome and Variation

Question 1

What are the cut offs for a common variant vs a rare variant in a population?

Answer 1

greater than 1% is common, less is rare.

Question 2

What types of DNA variation are included in the term small variant?

Answer 2

• Single nucleotide variant (SNV) (most common, over 3,000,000 per person)
• Small nucleotide insertion or deletion
• Dynamic repeat
• Microsatellite

Question 3

What is a CNV?

Answer 3

Copy number variation is a deletion or duplication of one or more exons.

Question 4

What are the three stop codons and the one start codon?

Answer 4

Stop Codons:

• UGA
• UAA
• UAG

Start Codons:

• AUG

Question 5

In the RNA-like strand sequence: A A A A T G C G G G C G T T G T G A G/C C U U A G
where the bold bps are introns and the letter after the slash represents a nucleotide substitution what is the cDNA nomenclature of the underlined bps?

Answer 5

• c.-2A
• c.1A
• c.6+2C
• c.7-2T
• c.10G>C

Question 6

What is the type of mutation and nomenclature if the change occurs at the 25th amino acid in a protein?

CTA = Leu
CTG = Leu

Answer 6

It is a synonymous or silent mutation

p.Leu25=

Question 7

What is the type of mutation and nomenclature if the change occurs at the 657th amino acid in a protein?

CTG = Leu
CCG = Pro

Answer 7

Non-synonymous or missense mutation
p.Leu657Pro

Question 8

What is the type of mutation and nomenclature if the change occurs at the 49th amino acid in a protein?

TTA = Leu
TAA = Stop

Answer 8

Nonsense mutation
p.Leu49Ter or p.Leu49*

Question 9

What is the type of mutation and nomenclature if the change occurs at the 1st amino acid in a protein?

ATG = Met
GTG = Val

Answer 9

Start codon variant
p.Met1?

Question 10

What is the type of mutation and nomenclature if the change occurs at the 807th amino acid in the FGFR3 protein? What disease does this variant cause?

TGA = Stop
GAA = Gly

Answer 10

Read-through or non-stop mutation
p.Ter807Gly causes Thanataphoric Dysplasia

Question 11

Give an example of a syndrome caused by small duplications/ deletions.

Answer 11

Nager Syndrome is caused by a c.1147delC, p.His383MetfsTer75

Question 12

Give an example of a mutation which occurs in somatic cells during early development.

Answer 12

Proteus syndrome AKT1 p.Glu17Lys

Question 13

How is DNA damaged/ changed?

Answer 13

• errors in replication (10^-10 errors per base per cell division)
• deamination

-depurination

-UV light

-mutagens

Question 14

Give an example of a dynamic repeat/ expansion disorder.

Answer 14

• Fragile X syndrome, which effects 1/4,000 boys and is caused by a repeated (CGG)_n element near the FMR1 promoter
• Friedreich ataxia
• Huntington
• Myotonic Dystrophy

Question 15

What is premutation?

Answer 15

It is an excessive number of repeats which are at high risk of increasing in length during reproduction but do not affect the actual carrier.

Question 16

What is anticipation in myotonic dystrophy Type I?

Answer 16

an earlier age of onset and increased severity of symptoms through successive generations. This can occur through just one parent.

50-150 repeats = Mild DM1 cataract, mild myotonia
100-1000 repeats = classic DM1 muscle wasting, myotonia, cataract, cardiac conduction
>1000 repeats = Congenital DM1 sever hypotonia at birth, respiratory insufficiency, early death.

Question 17

What is the clinical impact of microsatellites?
How many are known to exist in the genome?

Answer 17

There is no clinical impact
over 10,000 microsatellites exist in the genome.

Question 18

What are some uses of microsatellite analysis?

Answer 18

• DNA finger printing (forensics)
• twin studies/ paternity (relatedness)
• Disease-gene genomic localization

Question 19

What can predispose a person to Non-Allelic Homologous Recombination (NAHR)?

Answer 19

direct repetitive sequences can easily lead to large duplications or deletions which lead to a change in copy number of a gene.

Question 20

What kind of CNV causes CMT1a and HNPP? describe these diseases.

Answer 20

CMT1a

• Charcot-Marie-Tooth Disease Type 1A
• duplication
• progressive peripheral motor and sensory neuropathy. (numbness/ weakness). enlarged nerves, slow conduction velocity

HNPP

• Hereditary Neuropathy with liability to Pressure Palsies
• deletion
• Peripheral nerves are unusually sensitive to pressure and result in numbness, tingling and loss of muscle function.

Question 21

What causes X-linked Duchenne muscular dystrophy?

Answer 21

Exon duplication or deletion in the DMD gene