Pgx Basic Concepts II Flashcards
Allele
DNA sequence at a locus of one of the two homologous chromosomes
Genotype
combination of alleles at the same locus of the homologous chromosomes in a genome/cell
Homozygote
individual that has a pair of identical alleles at the locus
Heterozygote
individual that has two different alleles at the locus
Hemizygote
one allele is present, another allele is missing/deleted
also a heterzygous
Mendel’s Law
each of the parents passes a randomly selected allele (1 of the 2 homologous chromosomes) to the offspring –> Law of Segregation
Types of Polymorphisms
- SNP
- CNV
- Indel
Single Nucleotide Polymorphism
- a single nucleotide is changed to another
- most common sequence variation that accounts for 90% of variations
- 1 SNP for every 300-750 base pairs
- many of us contains SNP but they are located in the intron or a non-important location cause little to no functional affects
Reference Sequence that is compared to patients
- database that takes into account SNP where they survey lots of individuals and find the most popular/common SNP
Types of SNP in the coding region (cSNP)
Non-synonymous: changing amino acid in protein
- Missense SNP
- Nonsense SNP
Synonymous: does not change amino acids
- Silent SNP
Missense SNP
amino acid substitution (changes 1 AA to another AA)
Effects: gain or loss of function
Nonsense SNP
amino acid is changed to a stop codon (UGA, UAA, UAG)
Effect: loss of function
Silent SNP
does not change amino acids and therefore does not change gene/protein function
Noncoding Region SNP
- intronic SNP
- SNP in gene flanking region
- SNP in UTR region
Copy Number Variation (CNV)
- a DNA region has 0 to n copies in a population
- structural variation
- makes each chromosome longer or shorter
- 1 kb to several Mb
Effect: gain of function
Example of CNV
CYP2D6 –> 0-13 copies
if 0/0: cannot metabolize certain drugs
1/6: metabolizes certain drugs at much faster rate –> increase the dose
Insertion/Deletion (Indel)
- nucleotide present or absent from locus
- can be 1 to N nucleotides
- single Indel are is a specific form of SNP
- large Indel are CNV’s
INSERTION AND DELETION OF < 3 NUCLEOTIDES CAUSES A FRAMESHIFT OF THE OPEN READING FRAME LEADING TO A TRUNICATED PROTEIN
Trunicated Protein
loss of function
Ex)
- Indel
- nonsense SNP
Website for Nomenclature
pharmgkb.org
rs number
reference SNP
ID used for SNP’s
MDR1 G2677T
MDR1 2677G>T
a G to a T polymorphism at the nucleotide position 2677 of mRNA
CYP4AF2 V433M
CYP4AF2 433V>M
CYP4AF2 Val433Met
Val to Met amino acid polymorphism at the position 433 on the protein sequence
c. 1297G>A
count from the first nucleotide of the CODING DNA sequence (start codon: AUG)
p. Val433Met
protein position
Human CYP2C19*17
Species: Human
Superfamily: CYP
Family: CYP2
Subfamily: CYP2C
Allele/Haplotype: *17
ITALICIZED: gene/allele
REGULAR + PERIOD: protein
CYP2C19 Allele Nomenclature
CYP2C19*1A
- no change
- no SNP
- normal function
CYP2C19*2D
- splicing defect
- c. 99C>T
- loss of function
CYP2C19*3A
- nonsense
- p. W212X
- loss of function
CYP2C19*17
- missense
- p. I331V
- gain of function
