Transcript Gen660_Lecture10B_eQTL_2014

What evolutionary forces act on gene expression regulation?
Before considering selection, it’s important to characterize
how gene expression varies within and between species.
What facilitates regulatory evolution?
* Gene dispensibility
Genes with variable expression within species are heavily enriched
for non-essential genes
* Genes with upstream TATA elements
TATA regulation in yeast (and other organisms?) is associated
with variable expression
* Redundancy
Either gene or regulatory redundancy
* Modularity in regulation
Genes with more upstream elements or greater environmental responsiveness
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What contributes to the evolution of gene expression?
How many loci underlie expression variation?
Few major effectors or many minor contributors?
What are the mechanisms of expression evolution?
Relative prominence of cis vs. trans effects?
How much of expression variation has been selected for?
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eQTL mapping: understanding the genetic basis of expression variation
first done in strains of yeast
First done by Rachel Brem et al.
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From Rockman & Kruglyak 2006
eQTL mapping in yeast spore clones
First done by Rachel Brem et al.
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From Rockman & Kruglyak 2006
LOD threshold in standard QTL mapping (* 1 trait)
•1000 permutations
10% LOD score threshold: 3.19
5% LOD score threshold: 3.52
Challenge with eQTL mapping is that there are thousands of traits.
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Lessons for eQTL studies
• Only ~25% of heritable expression traits can even be mapped
- on average they explain only 30% of heritable variation
• Most traits explained by many loci
- only 3% explained by 1 locus
- Alan Orr exponential QTL model: few big effectors with lots of modifiers
• Majority of traits explained by transgressive segregation
- distribution of F2 phenotypes extends
beyond parental phenotypes
- indicates many small effectors
- suggests stabilizing selection
- also consistent with epistasis
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Lessons for eQTL studies
• Fewer traits show
directional segregation
- Phenotypic distribution of F2’s
between the parents
- Also implies many minor
effectors
- Suggests directional selection
by ‘tweaking’
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Local vs. Distant and cis vs. trans
Local eQTL: “near” the affected gene
Distant eQTL: “far” from the affected gene
cis effect: often taken to mean on the DNA molecule affected
trans effect: often taken to mean takes effect through the protein/RNA
Local QTL that work in cis:
ORF
TF binding site
affects transcription
3’ UTR
affects RNA stability
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Local vs. Distant and cis vs. trans
Local eQTL: “near” the affected gene
Distant eQTL: “far” from the affected gene
cis effect: often taken to mean on the DNA molecule affected
trans effect: often taken to mean takes effect through the protein/RNA
Local QTL that work in trans:
ORF
Coding polymorphism
that affects TF activity
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Local vs. Distant and cis vs. trans
Local eQTL: “near” the affected gene
Distant eQTL: “far” from the affected gene
cis effect: often taken to mean on the DNA molecule affected
trans effect: often taken to mean takes effect through the protein/RNA
Distant QTL that work in trans:
ORF
ORF
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Local vs. Distant and cis vs. trans
Local eQTL: “near” the affected gene
Distant eQTL: “far” from the affected gene
cis effect: often taken to mean on the DNA molecule affected
trans effect: often taken to mean takes effect through the protein/RNA
PHYSIOLOGY
Distant QTL that work in trans:
ORF
ORF
Most trans acting effects are likely secondary responses
(distantly-acting loci are NOT enriched for TFs)
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Also see ‘hot
spot’ loci
Proportion of local versus distant
linkages
Transcript
to where many transcripts map abundance maps
to the gene
that encodes it
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8 9 10 11
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5 6
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1 2 3
Transcript Location
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Ethanol Response eQTLs
1 2 3
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5 6
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8 9 10
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eQTL Location
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4.0
4
LOD
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4.3
4.33
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4.9
4.92
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6.5
6.54 14.8
14.77
Chromosome of Peak Score
Local vs. Distant and cis vs. trans
Which is more prevalent?
Estimates vary:
- Brem et al papers: ~25% traits explained by local polymorphs
- other studies say close to 100%
- Many MORE individual genes explained by distant polymorphs
* but because many link to same loci, there are
fewer distantly acting loci
But … statistical challenges likely enrich for local polymorphisms:
- FDR hurdle is higher for trans acting loci
- cis (local) polymorphisms may have larger effect size
- also depends on how “local” is defined
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Local vs. Distant and cis vs. trans
Which is more prevalent?
Using hybrid diploids and allele-specific expression
ORF-1
ORF-2
A cis acting polymorphism will affect only the allele it’s physically linked to
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Local vs. Distant and cis vs. trans
Which is more prevalent?
Using hybrid diploids and allele-specific expression
ORF-1
ORF-2
A trans acting polymorphism will affect BOTH alleles
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Local vs. Distant and cis vs. trans
Which is more prevalent?
Tricia Wittkopp et al. 2004. Nature.
- 29 differentially expressed genes between D. melanogaster & D. simulans:
- Measured allele-specific expression in D. mel/D. sim hybrid with pyrosequencing
28 out of 29 show cis variation in expression
16 out of 29 affected by trans and cis variation
Conclusion: cis-acting variation is more common to explain
interspecific variation
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Local vs. Distant and cis vs. trans
Which is more prevalent?
Tricia Wittkopp et al. 2008. Nature Genetics.
- 78 genes examined (48 within, 49 between species … 16 genes overlapping)
4 D. melanogaster strains and 4 D. simulans strains
-cis regulatory effects explained more variation
between (64%) species rather than within (35%)
… argues against neutrality, since effects should occur
at same ‘rate’ over time
- compensatory cis + trans effects also more common between species
Conclusion: trans-acting variation is more common within species (over shorter
time frames) but is more likely to have more pleiotropic and deleterious effects
… trans-acting variation more likely to be removed over time
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