design “The variable effects of variables” - What are we missing when we only profile the transcriptome? o Age, Diet, Sex How genetic variation affects the proteome o Liver, Kidney, Heart Getting into the “weeds” – Identifying regulators in subthreshold QTL peaks. Gary Churchill Ron Korstanje @stevemunger
design “The variable effects of variables” - What are we missing when we only profile the transcriptome? o Age, Diet, Sex o How genetic variation affects the transcriptome and proteome Liver study: Chick, Munger et al. 2016 Getting into the “weeds” – Identifying regulators in subthreshold QTL peaks. Takeaway: Many subthreshold peaks are real. Gary Churchill Ron Korstanje @stevemunger
discovery and validation • 40M+ SNPS • 2M+ indels • Balanced population structure • Each individual unique • 400+ recombinations in each animal • High heterozygosity @stevemunger
Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL F B C D E G E A Protein Complex Liver-specific Enhancer mutation in NOD = Less translated protein = Limiting Protein Partner
C D E G E A Protein Complex Liver-specific Enhancer mutation in NOD = Less translated protein = Limiting Protein Partner sets the maximum level of stable complex pQTL
tissue-specific effects. Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL Local eQTL F B C D E G E A Protein Complex Kidney-specific Enhancer mutation in PWK = Less translated protein = Limiting Protein Partner
tissue-specific effects. F B C D E G E A Protein Complex Kidney-specific Enhancer mutation in PWK = Less translated protein = Limiting Protein Partner pQTL
Don’t assume that changes to the transcriptome will confer to the proteome (and vice versa). Many of the most significant changes to the transcriptome – from genetic variation or experimental variables – do not get conferred to the proteome. o Many variants affect transcript abundance (eQTLs), but most are buffered at the protein level. Many of the most significant changes to the proteome – from genetic variation or experimental variables – are not mediated by transcription. o Stoichiometry of protein complex members underlies many pQTLs.
Chick Petr Simecek Narayanan Raghupathy Kwangbom Choi Dan Gatti Lisa Somes Steve Ciciotte Elissa Chesler Joel Graber Al Simons JAX Gene Expression Service Sanger Mouse Genomes Project Funding: NIGMS Center for Genome Dynamics GM076468 NIH F32HD074299