Genome and Variation Flashcards
What are the cut offs for a common variant vs a rare variant in a population?
greater than 1% is common, less is rare.
What types of DNA variation are included in the term small variant?
- Single nucleotide variant (SNV) (most common, over 3,000,000 per person)
- Small nucleotide insertion or deletion
- Dynamic repeat
- Microsatellite
What is a CNV?
Copy number variation is a deletion or duplication of one or more exons.
What are the three stop codons and the one start codon?
Stop Codons:
- UGA
- UAA
- UAG
Start Codons:
- AUG
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?
- c.-2A
- c.1A
- c.6+2C
- c.7-2T
- c.10G>C
What is the type of mutation and nomenclature if the change occurs at the 25th amino acid in a protein?
CTA = Leu
CTG = Leu
It is a synonymous or silent mutation
p.Leu25=
What is the type of mutation and nomenclature if the change occurs at the 657th amino acid in a protein?
CTG = Leu
CCG = Pro
Non-synonymous or missense mutation
p.Leu657Pro
What is the type of mutation and nomenclature if the change occurs at the 49th amino acid in a protein?
TTA = Leu
TAA = Stop
Nonsense mutation
p.Leu49Ter or p.Leu49*
What is the type of mutation and nomenclature if the change occurs at the 1st amino acid in a protein?
ATG = Met
GTG = Val
Start codon variant
p.Met1?
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
Read-through or non-stop mutation
p.Ter807Gly causes Thanataphoric Dysplasia
Give an example of a syndrome caused by small duplications/ deletions.
Nager Syndrome is caused by a c.1147delC, p.His383MetfsTer75
Give an example of a mutation which occurs in somatic cells during early development.
Proteus syndrome AKT1 p.Glu17Lys
How is DNA damaged/ changed?
- errors in replication (10-10 errors per base per cell division)
- deamination
-depurination
-UV light
-mutagens
Give an example of a dynamic repeat/ expansion disorder.
- 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
What is premutation?
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.
What is anticipation in myotonic dystrophy Type I?
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.
What is the clinical impact of microsatellites?
How many are known to exist in the genome?
There is no clinical impact
over 10,000 microsatellites exist in the genome.
What are some uses of microsatellite analysis?
- DNA finger printing (forensics)
- twin studies/ paternity (relatedness)
- Disease-gene genomic localization
What can predispose a person to Non-Allelic Homologous Recombination (NAHR)?
direct repetitive sequences can easily lead to large duplications or deletions which lead to a change in copy number of a gene.
What kind of CNV causes CMT1a and HNPP? describe these diseases.
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.
What causes X-linked Duchenne muscular dystrophy?
Exon duplication or deletion in the DMD gene
