Pharmacogenomics

Question 1

pharmacogenomics

Answer 1

‘the study of a combination of genes that affects response to a drug’

Question 2

The following regions of a gene are also non‐coding :

Answer 2

promoter, 5’‐UTR, introns, 3’‐UTR

Question 3

single nucleotide polymorphism (SNP)

Answer 3

change in a single base within the DNA sequence

Question 4

An allele

Answer 4

the variable form of a specific gene

Question 5

wildtype

Answer 5

if it has the sequence that is considered ‘normal’ for a population, i.e. occurs with the highest frequency

Question 6

allelic variant

Answer 6

can be used to describe differences in DNA sequence that exist between the alleles on the maternal and paternal chromosomes

Question 7

haplotype

Answer 7

combination of alleles that are located within a chromosome, or more typically for pharmacogenomics, is defined as the combination of SNPs (allelic variants) that are located within a particular gene

Question 8

Tag SNPs

Answer 8

• Some SNPs are inherited together, i.e. they ‘travel’ together – if we know the inheritance of certain SNPs is linked, we only need to assess the presence of 1 of the SNPs within the group to know that the others are present.
• Tag SNPs can be used to establish haplotypes for patients/determine what haplotype a patient belongs to.

Question 9

PM

Answer 9

• Poor metabolizers
• two non‐functional (null) alleles

Question 10

IM

Answer 10

• Intermediate Metabolizer
• Two reduced function alleles OR one null allele and the other with reduced function

Question 11

EM

Answer 11

• Extensive metabolizer
• At least one or two functional alleles (i.e. normal)

Question 12

UM

Answer 12

• Ultra Rapid metabolizer
• More than 2 functional alleles

Question 13

The most common reasons for mismatch between genotype and phenotype are :

Answer 13

1. Dominant negative behavior of the mutant/non‐functional protein (it can inhibit the function of the wildtype protein)
2. Haploinsufficiency (only half the amount of protein that is needed is synthesized because the mutant mRNA isn’t translated).

Question 14

Translocations can result in :

Answer 14

1. A gene moving from a region of euchromatin to a region of heterochromatin (or vice versa),
2. A gene moving to a region next to a ‘strong’ promoter (or ‘weak’ promoter).

Both result in an alteration in gene expression levels

Question 15

What could result in an alteration in protein expression levels ?

Answer 15

1. Promoter methylation : decrease transcription —> decrease mRNA –> decrease protein expression

E.g. methylation of cytosines in the promoter region inhibits transcription through preventing formation of transcription initiation complex = no/reduced transcription = no/reduced translation of the protein that gene codes for. Methylation of the promoter of a gene that codes for a protein involved indrug metabolism can therefore affect drug metabolism/patient response to a drug

2. Gene deletion : will decrease expression of proteins
3. Mutation in an intron : will affect the expression if they occur in an enhancer or silencer element

Question 16

Truncated (nonsense) or abnormal (frameshift) proteins

Answer 16

often recognized as defective by cell and degraded in the lysosome

Question 17

Amplification

Answer 17

increased expression

Question 18

Deletion

Answer 18

decreased expression

Question 19

Genotype

Answer 19

A set of alleles that determines the expression of a particular characteristic (can also be used to predict phenotype/disease)