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eQTLs
microarray
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Complementary DNA
probes are prepared and
added to a chip
mRNA is extracted,
fluorecently labeled, and
hybridized to the probes
The intensity of
fluorescence is a measure
of the mRNA quantity
http://www.mun.ca/biology/scarr/VDA_schematic_Carr_et_al_2007c.jpg
Supplementary fig. 2. Expression levels of predictive genes in independent dataset. The expression levels of the 50
genes most highly correlated with the ALL-AML distinction in the initial dataset were determined in the independent
dataset. Each row corresponds to a gene, with the columns corresponding to expression levels in different samples.
The expression level of each gene in the independent dataset is shown relative to the mean of expression levels for
that gene in the initial dataset. Expression levels greater than the mean are shaded in red, and those below the mean
are shaded in blue. The scale indicates standard deviations above or below the mean. The top panel shows genes
highly expressed in ALL, the bottom panel shows genes more highly expressed in AML.
eQTLs in Yeast
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Brem and Krugluak, Science 2002
Two yeast strains were chosen (BY/RM)
6 independent microarray measurements of each
1528 genes were differentially expressed at
P<0.005
• These differences can be shown to be genetic
eQTLs in Yeast
• 40 haploid segregant crosses were isolated and
genotyped.
• 3312 genetics markers were identified
QuickTime™ and a
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QuickTime™ and a
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are needed to see this picture.
Linkage of markers and gene expression
• Expression levels of
parents and
segregants for gene
YL007C, and
YIL101C
QuickTime™ and a
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Linkage of markers
• Brem and Kruglyak treated each of the expression
values of 6215 genes as a ‘phenotype’
• Each phenotype was tested against each of 3312
markers
• 570 messages showed linkage to at least one marker
P<10-5
• Is this significant?
• 53 is expected by chance (?)
• The loci might act in cis, or in trans.
Causal mechanisms for eQTL
• The transcription of a gene is
governed by DNA binding
transcription factors (TFs)
that switch the gene on or off
• Mutations might have a
clear effect on the
expression of a nearby gene
(a ‘cis’ effect)
• The expression of the gene
can affect the expression of
more distant genes (a ‘trans’
effect)
A connection to biological networks
• Cellular proteins function as a complex network.
• Extra-cellular and other signals are propagated, and result in
switching on/off of other pathways (by regulation of gene
expression)
• eQTLs can help identify some of these regulatory dependencies
Cis trans eQTLs
• 185 of the 570 messages were linked to cis-eQTLs
• The linked loci clustered into distinct bins, with 10 dense bins
– Each bin contains the number of transcripts linking to the markers in
the bin
– In many case, the genes are members of the same pathway.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
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The trans e-QTLs seem to be associated with groups of genes that
have a ‘common purpose’
Critique this assertion! Is there a mangling of cause and effect here?
eQTLs in other species
FIGURE 1. Genomic architecture of eQTL across five Arabidopsis chromosomes
• Other studies in
Arabidopsis,mouse
seem to reinforce these
findings
• Regulatory genetic
variation is
characterized by a high
rate of cis-acting alleles,
and a small number of
trans-acting alleles with
widespread
transcriptional effects.
West, M. A. L. et al. Genetics 2007;175:1441-1450
Copyright © 2007 by the Genetics Society of America
Computational problem
eQTL
Regulatory edge
• An eQTL identifies a regulatory relationship between 2 genes.
• Given eQTL, and other data, can we reconstruct regulatory
networks?
• Some of the questions on inferring networks will be addressed
in Bix 3