Lecture 21: Searching for Genetic Clues

Question 1

What genetics offers:

Answer 1

Risk prediction

Better prevention

Novel treatment

Personalised treatment

Question 2

How is the effect of variation on blood pressure in the non-coding region tested?

Answer 2

1) genome-wide mapping
2) fine-mapping
3) Identifying functional candidate alleles
4) Testing alleles in living systems
5) Contribution by candidate alleles to phenotype variation is understood better.

Question 3

What is endothelin?

Answer 3

endothelin is secreted by endothelian cells and is a potent vasoconstrictor

Question 4

What happens if endothelin is knocked out?

Answer 4

Increasing or decreasing endothelin does not affect BP.

Endothelin is also functional in the lungs and had a more exacerbated effect in the lungs rather than taking a massive effect on BP.

Question 5

What are the genome tools used?

Answer 5

Linkage mapping (families)

Linkage Disequilibrium (LD) mapping (broad population)

Transcriptomics (looking at RNA sequence both mRNA and other RNAs involved in gene expression)

Proteomics (Concentration and distribution of proteins mapped)

Computational biology (looking for correlations between information provided from previous methods and modelling it)

Systems biology (looking at the effect of everything on the overall phenotype)

Question 6

How many nucleotides in the human genome?

Answer 6

2.84 billion

Question 7

How many genes in the human genome?

Answer 7

20 - 25000 (2% of genome)

Question 8

What does the human genome consist of?

Answer 8

2.85 billion nucleotides

20 - 25000 genes

non-coding RNAs

Segmental duplications/deletions

Question 9

What are the kinds of variation being looked for?

Answer 9

Protein function changes

Changes in RNA expression:
genes, non-coding RNA, and epigenetic marks

Question 10

What is linkage disequilibrium?

Answer 10

physical proximity between marker and causative variant on the same chromosome. Crossing over of chromosomes causes variants involved to come together.

Question 11

What are the characteristics of SNPs?

Answer 11

15 million per genome (11% of genome)

Mostly transitiions from G A and CT

Question 12

How common are SNPs?

Answer 12

15 million per genome

Average frequency of 11%

12 per gene

6 in coding regions (cSNPs)

3 alter protein sequenc

6 in the perigenetic regions

Question 13

What are linkage analyses?

Answer 13

Linkage analysis uses pedigree diagrams to link conditions with certain alleles.

Question 14

How are association analyses performed?

Answer 14

cases vs control are compared and correlation is made.

Question 15

What are the problems that arise with using association analyses?

Answer 15

Can cause scientists to abandon projects due to lack of correlation.

Association studies use markers (not actual variants).

Prone to bias

Marker used could potentially be completely unrelated by arised in a population separately.

Question 16

How much do we know about the heritability of BP? How is this known?

Answer 16

All of the BP loci discovered to date only account for less than 5% of the heritability of BP.

Known from GWAS.

Question 17

What are potential causes of the unknown BP loci?

Answer 17

gene-gene interactions (epistasis)

Gene-environment interaction (epigenetics)

Rare coding variants (GWAS tend to miss these variants)

Inflated heritability (heritability could be much more or less than what is predicted)

Question 18

What is the important factors to consider when looking at RNA expression?

Answer 18

Where the RNA was expressed

When the RNA was expressed