W5L2 putting variation into context

Question 1

Mechanism of cis eQTL

Answer 1

-changes to the sequence of promoter
-changes to chromatin

Question 1

Mechanism of trans eQTL

Answer 1

-changes to transcription factor
- ligand and receptor
-cellular sensor
-transporter

Question 2

Disentangling and partitioning cis and trans effects

Answer 2

• sound simple on paper, hard on practice due to limited technology, cannot test everything
  -lack of statistical power to back it

Question 3

Mechanisms, and flavours of molQTLs

Answer 3

• QTL mapping links individual SNPs to a specific molecular phenotype
• molQTLs (molecular QTLs)
• Other types:
• pQTLs (protein abundance QTLs)
• sQTLs (splicing QTLs)
• caQTLs (chromatin accessibility QTLs)
• meQTLs (DNA methylation QTLs)
• etc

Question 4

Problem with QTL

Answer 4

-it show statistical data, not biological causal data
-the mechanism is unknown

Question 5

How predictive are eQTL

Answer 5

• mRNA expression is only the firsstep on the way to steady-state protein levels
• Variation at early stages can be buffered by downstream processes.
• Don’t have complete info to say how much, or how often
  Genetically-driven differences can also be separate from RNA expression!
  -there seems to be some predictive power

Question 6

How to know if a variation is important or not

Answer 6

• evolution constraint (conserved = important)
• Redundancy

Question 7

How predictive is eQTL at across situations

Answer 7

• across gene correlation seems to be 0.56
  -within gene correlation: fluctuate heavily, ranging from highly predictive or not at all

Question 8

What does constraint show

Answer 8

-constrain suggest evolutionary forces at work
* Constraint is simply a measure of sequence conservation across evolutionary time
* Things that don’t vary for a long time are interesting!
* Especially if they then start varying in a specific lineage

Question 9

The ultraconserved enhancer ZRS

Answer 9

• ZRS is an enhancer for the master developmental gene Shh for limb formation
• Located nearly 1,000,000 bp upstream from Shh
• Very localised expression pattern:
  -changed in snake 17bp

Question 10

Mouse ZRS vs Snake ZRS

Answer 10

• ZRS activity is disrupted in most snakes
• Mice with snake ZRS sequences have severe limb abnormalities

Question 11

Clues into importance (2): Redundancy

Answer 11

• measure gene expression in 18 different mammals and look at coefficientcy
• look at average number of gene promoter and enhancer (promoter does not affect expression level, a on and off switch but enhancer does)
• gene with more enhancer and promoter are more stable compare to gene with one copy.

Question 12

Variation vs evolution

Answer 12

Genes have eQTLs and/or variable expression levels because they can afford to have variable expression levels,
evolutionarily speaking.
* Constraint is a good indication of when this is not the case.
* Some of this variation is buffered by downstream forces, other bits are simply tolerated by the organism..