Cardiovascular Health Lecture 2.3 : Searching for Genetic Clues

Question 1

What is a first pass look?

Answer 1

Analysing the entire gene by mapping it, searching for points associated with disease.

Question 2

What is fine mapping?

Answer 2

Done after a first pass look, you focus on a particular area, using denser markers to pinpoint signals for diseases.

Question 3

Where are disease associated points of DNA found? What must be done with them?

Answer 3

In the non-coding region. They need to be tested to be sure they are the functional candidate.

Question 4

What is endothelin?

Answer 4

Potent vasoconstrictor.

Question 5

What happens with an endothelin knockout? What happens if a copy is added?

Answer 5

In a knockout, blood pressure is expected to decrease.
With an extra copy, blood pressure is expected to rise.
In practice, this doesn’t happen.

Question 6

How is endothelin associated with the lung? What does this say about abnormal levels?

Answer 6

Has lung development in utero. Abnormal levels therefore affect lung pathology more than cardiovascular health.

Question 7

What are the 5 types of linkage mapping?

Answer 7

Ld mapping
Transcriptomics
Proteomics
Computational biology
Systems biology

Question 8

What is Ld mapping?

Answer 8

Population-wide analysis

Question 9

What is transcriptomics?

Answer 9

mRNA analysis.

Question 10

What is proteomics?

Answer 10

Protein analysis

Question 11

What is computational biology?

Answer 11

Modelling biological data

Question 12

What is systems analysis?

Answer 12

Physiological analysis

Question 13

Do non-coding regions affect RNA expression?

Answer 13

Yes.

Question 14

Can genes themselves alter RNAs?

Answer 14

Yes, there are some genes specific to the expression of some RNAs.

Question 15

What is linkage disequilibrium?

Answer 15

There is a physical proximity between the marker used and a causative variant. LD means they are close enough that the distance doesn’t change following recombination.

Question 16

How does recombination play a role in linkage equilibrium?

Answer 16

Normally, they align and swap chromosomal regions, in doing so, chance that a non causative variant from one parent becomes associated with a marker to a causative variant from the other parent post recombination. Ie. Marker for diabetes found on dad chromosome. After recombination, this marker becomes associated with a non causative variant in the mother’s genome (wherever it may be). LD is that theyre close enough that this doesn’t happen.

Question 17

What are the most common variants?

Answer 17

SNPs.

Question 18

What kind of mutations can SNPs be?

Answer 18

Can be siltent mutations, and wont change the amino acid

Can also cause direct protein mutation, or mutate region controlling expression level.

Question 19

What is linkage analysis?

Answer 19

Use of pedigrees to track a marker and associate it with a disease.

Question 20

What effect does linkage disequilibrium have on a marker’s association to a disease?

Answer 20

Strengthens further down the generation.

Question 21

What is association analysis?

Answer 21

Create groups of interest that gives information on genetic markers being carried with the disease. Compares groups with the disease, to those without, and relatve percentages of SNP prevalence.

Question 22

How much of the blood pressure loci found to date account for the total heritability of blood pressure? Why is this so (name 3 reasons)?

Answer 22

Less than 5%. Not just in blood pressure, but most phenotypes assessed. Possibly due to synergy between the different systems affecting the phenotype.
ie with blood pressure, NO, renin and (para)symp might synergise, as well as epigenetics. SNPs also miss the rare variants.

Question 23

Human population was ~10k when it first left Africa. What is the effect of an ancient mutation in this population? Why is this useful?

Answer 23

The mutation will be present widely dispersed in the current population. It can be used as a marker or could be causing a disease.

Question 24

Assume a large population, what can be said of a mutation (marker or disease), being found only in a localised population of the overall?

Answer 24

A mutation implies an association between the two, but this is a trap.
The population could have a lifestyle that induces this disease.