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Post-translational mechanisms buffer protein abundance against transcriptional variation

Steve Munger
October 10, 2015

Post-translational mechanisms buffer protein abundance against transcriptional variation

This is a copy of the platform presentation I first gave at ASHG 2015 in Baltimore. I gave the same talk with minor changes to the summary slides at IMGC 2015 in Yokohama Japan. If you have any questions or comments, feel free to email me at [email protected]

Steve Munger

October 10, 2015
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  1. Post-translational Mechanisms Buffer Protein
    Abundance Against Transcriptional Variation.
    OR
    The Coolest Thing I’ve Ever Worked On.
    Steve Munger
    The Jackson Laboratory
    @stevemunger
    Slides can be downloaded at https://speakerdeck.com/stevemunger
    Please tweet my talk J

    View full-size slide

  2. Disclosure: I love mouse genetics

    View full-size slide

  3. Our starting point is the Central Dogma
    DNA RNA Protein
    DNA RNA Protein
    Transcrip)on   Transla)on  
    DNA RNA Protein
    Francis  Crick  1956  

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  4. Nature July 2013
    “We estimate that approximately one-half
    of pQTLs are probably also eQTLs. However,
    many pQTLs do not correspond to eQTLs,
    even at a relaxed stringency.”
    Emerging evidence of post-transcriptional
    buffering of protein abundance.
    September 2014
    February 2015
    “QTLs affecting mRNA levels are, on
    average, attenuated or buffered at
    the protein level…

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  5. Diversity Outbred (DO) mice:
    A designed discovery population.
    -­‐  45M+  SNPS  
    -­‐  2M+  indels  
    -­‐  Balanced  popula)on  
               structure  
    -­‐  Each  individual  unique  
    -­‐  400+  recombina)ons  
               in  each  animal  
    -­‐          High  heterozygosity  

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  6. 192 DO Livers
    Transcripts
    Short Reads
    RNA-Seq
    eQTL pQTL
    eQTL Mapping pQTL Mapping
    Proteins
    Peptides
    MS/MS
    Compare
    ?
    Munger  et  al.  2014   Chick*,  Munger*  et  al.  In  review  
    “Next Gen” Genetics, Transcriptomics, and Proteomics

    View full-size slide

  7. An unprecedented view of protein regulation.
    3692 pQTL detected for 2901 proteins.
    Protein Location
    pQTL Location
    1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1819 X
    1
    2
    3
    4
    5
    6
    7
    8
    9
    10
    11
    12
    13
    14
    15
    16
    17
    18
    19
    X

























































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































    Total
    eQTL
    pQTL
    3477  
    2289   1403  
    N=8050  
    p  <  2.2e-­‐16  
    Chick*,  Munger*  et  al.  In  review  
    FDR  <  0.05  

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  8. 80% of proteins with local pQTL have
    concordant local eQTL
    Protein Location
    pQTL Location
    1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1819 X
    1
    2
    3
    4
    5
    6
    7
    8
    9
    10
    11
    12
    13
    14
    15
    16
    17
    18
    19
    X














































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































    Local
    eQTL
    pQTL
    2322  
    338   1390  
    −2 −1 0 1 2
    −3
    −2
    −1
    0
    1
    2
    Protein Observed
    Transcript Observed
    r = 0.75
    −2 −1 0
    −2
    −1
    0
    1
    2
    Founder Protein
    Predicted Protein
    QTL RNA Protein
    cis cis

    View full-size slide

  9. Protein Location
    pQTL Location
    1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1819 X
    1
    2
    3
    4
    5
    6
    7
    8
    9
    10
    11
    12
    13
    14
    15
    16
    17
    18
    19
    X
    20% of proteins with local pQTL
    lack concordant local eQTL
    Local
    eQTL
    pQTL
    2322  
    338   1390  
    −2 −1 0 1 2
    −3
    −2
    −1
    0
    1
    2
    Protein Observed
    Transcript Observed
    r = 0.26
    QTL RNA Protein
    cis
    −1 0 1
    −2
    −1
    0
    1
    2
    Founder Protein
    Predicted Protein

    View full-size slide