W5L2 putting variation into context Flashcards
Mechanism of cis eQTL
-changes to the sequence of promoter
-changes to chromatin
Mechanism of trans eQTL
-changes to transcription factor
- ligand and receptor
-cellular sensor
-transporter
Disentangling and partitioning cis and trans effects
- sound simple on paper, hard on practice due to limited technology, cannot test everything
-lack of statistical power to back it
Mechanisms, and flavours of molQTLs
- 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
Problem with QTL
-it show statistical data, not biological causal data
-the mechanism is unknown
How predictive are eQTL
- 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
How to know if a variation is important or not
- evolution constraint (conserved = important)
- Redundancy
How predictive is eQTL at across situations
- across gene correlation seems to be 0.56
-within gene correlation: fluctuate heavily, ranging from highly predictive or not at all
What does constraint show
-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
The ultraconserved enhancer ZRS
- 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
Mouse ZRS vs Snake ZRS
- ZRS activity is disrupted in most snakes
- Mice with snake ZRS sequences have severe limb abnormalities
Clues into importance (2): Redundancy
- 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.
Variation vs evolution
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..
