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Principles of Drug Discovery > Pharmacogenomics 2 > Flashcards

Pharmacogenomics 2 Flashcards

1
Q

What are the different types of variations in the genome ?

A

Single nucleotide polymorphisms - most common
Deletion/insertion
Tand em repeat
Copy variation number

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2
Q

What is a single nucleotide polymorphism ?

A

It is a single nucleotide alteration
- sometimes they don’t make any difference
The frequency at whihc they occur is 12000000a this is good because they can be used to determine why someone has a disease or if they have a genetic predisposition to a disease

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3
Q

What is a deletion/insertion variation ?

A

Deletion or insertion of 1-1000 nucleotides

The frequency at which they occur is >1000000

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4
Q

What is tandem repeat variation ?

A

Repeat of 2-1000 nucleotides
Eg like the CAG repeat in huntingtons
Occurs at a frequency of >500000

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5
Q

What is a copy number variation ?

A

Deletion/multiplication of regions >1kb - occurs in large regions
- this often occurs in cancer and this causes the cell to stop growing

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6
Q

What are synonymous SNP ?

A

Is a nucleotide difference in mRNA coding sequence that doesn’t alter the amino acid encoded

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7
Q

What is a non-synonymous SNP?

A

Is a nucleotide difference in mRNA coding sequence that does alter the amino acid sequence

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8
Q

What are the methods to study polymorphisms ?

A

Candidate gene approach
Candidate pathway gene approach
Genome wide association studies
Next generation sequencing

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9
Q

What are the advantages of candidate gene approach ?

A

Focuses on genes with known or proposed biological functions if resources are limited
Capable of identifying polymorphisms with low allele frequency
Allows deep ressequencing on interesting candidate genes in the post GWAS phase

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10
Q

What are the disadvantages of candidate gene approach ?

A

May potentially miss important genes

A priori knowledge of candidate gene is required

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11
Q

What are the advantages of candidate pathway gene approach ?

A

Only genes of biological functions are tested
Only requires a small number of samples
Association information obtained on genes known to be relevant to drug

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12
Q

What are the disadvantages of candidate pathway gene approach ?

A

Not comprehensive

A priori knowledge of candidate genes and/or pathways required

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13
Q

What are Gs advantages of genome wide association studies ?

A

A complete unbiased picture of the genome

No prior hypotheses required

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14
Q

What are the disadvantages of genome wide association studies ?

A

Large numbers of samples required
Lack of info about gene function
Insensitive to both structural and rare variants

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15
Q

What are the advantages of next generation sequencing ?

A

Least expensive for genome wide coverage per variant
Individual needs only to be sequenced once
Can identify causative snp

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16
Q

What are the disadvantages of next generation sequencing ?

A 
Missing variations within large stretches of highly duplicate DNa 
High levels of noise 
Large numbers of samples are required
Lack info about gene function 
Cost
17
Q

What is a major issue with candidate gene approach and candidate pathway gene approach ?

A

They are biased

18
Q

What exactly is next generation sequencing ?

A

Enables HTS to sequence genomes

- enables you to look at the whole genome to find changes

19
Q

What is transformational technology -iPSC?

A

Induced pluripotent stem cells
Can take human cells from adults and convert the, to stem cells - these can then be differentiated into other cells
They vm be used to model diseases
It will help to develop better treatments and test them safely

20
Q

What does full sequencing of a patients genome and then computer analysis of all the SNPs allow ?

A

It can help determine the causes of diseases
Help to determine whether a patient has an increased susceptibility to disease
Help to determine whether a patient will have aversive or therapeutic response to a treat,net

It would enable tailor made prescriptions

21
Q

Why are SNPs so important ?

A

Account for 90% of all human genetic variation
Occur every 100 to 300 bases along the 3 billion base human genome
May have no effect but could be used as a marker
May have different effects
- coding region- may affect proton function or stability
- non coding region of RNA can affect processing or stability of mRNA
- promoter region - can affect where expressed when expressed or the level of expression

22
Q

What is microarray analysis currently been used in ?

A

Used as part of cancer research

  • easy to get tumour samples
  • therefore normal cell samples and tumour samples can be compared, deomonstrating changes in genes expressiion levels
23
Q

What could the research using microarray anayaldis in cancer be helpful for ?

A

Because all cancers are different, different drugs should be better to treat different ones
- therefore it could be used to determine the best drugs to treat a patient based upon the genome sequence of their tumour

24
Q

What is the example where specific treatment for a tumour has been carried out ?

A

Identified adenocarcinoma proliferation was driven activity of the protooncogen RET
Stabilised the disease using protein kinase pathway inhibitors for 7 months
New lesions then appeared
Nine new mutations discovered and therapeutic resistance seen because of activation of the MAPK and AKt pathway

  • there was upregulation of he genes involved in producing ERK1 whihc is involved in cell proliferation - therefore they inhibited the overactive pathway which initially worked but then another tumour was produced
25
Q

What was the RET inhibited used ?

A

Sunitnib

26
Q

After the formation of the new tumour what treatmemt was then used ?

A

Once new lesions formed then hey changed treatment to sorafenib and sulindac
Stabilised for a few months and then another tumour developed - further upregulation of of the RET pathway and increases on the AKT pathway

27
Q

What did the expression of genes in tumours tell us?

A

Showed us it is feasible to sequence patient and tumour DNA and to look at gene expression levels
- analyse the changes in gene expression
We can interrogate the vast amount of data we get back
And make sensible conclusions

28
Q

What are the variabilities between individuals and our bodies repsonses to a drug ?

A

Metabolism/removal- we can have variations in enzymes that metabolise drugs which can affect half life of drugs - therefore this affects the dosing in different individuals

Effect- individuals will have variations in receptors and enzymes - the targets for drugs to interact with - this will affect the response

29
Q

What are cytochrome p450s important for ?

A

Important for phase 1 drug metabolism

- oxidations, hydroxylation, carboxylation and reduction - genes can affect the rates of these reactions

30
Q

What is included in phase 2 metabolism !

A 
Acetylation 
Methylation 
Sulphation 
Glucuronidation 
These are different types of modification
31
Q

What are cytochrome p450s involved in ?

A

Involved in metabolism of over 100 drugs

32
Q

What does the cytochrome CYPD26 enzyme cause ?

A 
It is highly polymorphics - over 75 different alleles and frequency varies with ethnicity 
Therefore individuals can be 
- poor metabolisers 
- intermediates metabolisers - normal 
- extensive metabolised - normal
- ultra rapid metabolisers
33
Q

In humans what are the variations in drug metabolism caused by CYP2D6 ?

A

Pm - the concentration rises to very high levels that’s are toxic and can remain in the body for a long time
Im- drug reaches relatively high levels for quite a long time and can cause some toxic effects
Em- they reach the therapeutic window and then it drops quite quickly
Um- metabolisers it too quickly so it doesn’t reach therapeutic window

34
Q

How could we provide a personalised drug regime ?

A

If we knew each point at which an individual’s genome sequence varied from the norm and if we knew the affect of each variation on the drug response
- individuals will be required to take more or less of a drug dependent upon the genome to enable them e gain the most beneficial effects

Principles of Drug Discovery (20 decks)

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