This presentation describes published pQTL data from the liver and compares it to *new* pQTL data from the kidney. Note: Conclusions about the tissue comparison are preliminary.
The effects of natural genetic variation on transcript and protein abundance. Steve Munger The Jackson Laboratory Free your slides! https://speakerdeck.com/stevemunger Twitter: @stevemunger
How does genetic variation impact transcript and protein abundance? DNA RNA Protein DNA RNA Protein Transcrip)on Transla)on DNA RNA Protein Francis Crick 1956
192 DO Mice Transcripts Short Reads RNA-Seq eQTL pQTL eQTL Mapping pQTL Mapping Proteins Peptides MS/MS Compare ? Munger et al. 2014 Chick*, Munger* et al. Nature, 2016 How does genetic variation influence transcript and protein abundance in the liver and kidney? Compare kidney to liver
Searching for protein and transcript mediators of distant pQTL –> Mediation Analysis RNA Protein QTL trans cis RNA Protein Target Causal Intermediates RNA Protein trans QTL cis Target Target Protein ~ pQTLdistant Target Protein ~ pQTLdistant + MediatorProtein x 8000 proteins Target Protein ~ pQTLdistant + MediatorRNA x 21000 Transcripts X
Mediation analysis to identify subtle genetic interactions Step 2: Mediate all subthreshold peaks LOD > 5. Aka “Pull the weeds”. Step 3: Repeat process for all 8k proteins. Step 4: Find proteins that share same subthreshold peak and mediator
Conclusions • Transcriptional mechanisms are responsible for most local pQTL, but… – Most local variants that affect transcript levels do not affect protein levels. • Post-transcriptional mechanisms underlie all but a few of distant pQTL. – Very few distant pQTL shared by liver and kidney. • Mediation analysis can identify protein intermediates that confer significant or subtle effects on protein abundance. • Tissue-specific local e/pQTL drive tissue-specific distant pQTL.