Editorial: Pinpointing expression differences

Nature Genetics 39, 1175 (2007)
doi:10.1038/ng1007-1175


Pinpointing expression differences

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Common gene variants influencing transcript levels can now be reproducibly
identified by genome-wide screens. Some of the same variants contribute to
clinical traits.


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IntroductionGenetic variants can affect the quantity and timing of
transcription and transcript stability, as well as splice efficiency and the
ratio of alternative splices, all of which can be detected as differential
transcript levels by array methods. Three papers in this issue use linkage
and association to identify variant loci that are correlated with RNA
transcript abundance of human genes expressed in peripheral blood
lymphocytes and immortalized lymphoblastoid cells.

Harald Göring and colleagues (p 1208) studied the loci influencing
transcript levels in native peripheral blood lymphocytes by carrying out
linkage analysis with 432 polymorphic microsatellites. One of these
quantitative trait loci for expression (eQTLs) corresponds to a locus
influencing HDL cholesterol levels. They found 42 eQTLs with 70% or greater
heritability that they considered 'essentially monogenic' in their
contribution to expression level of the closely linked transcription unit.
However, the overall picture is polygenic. The mean effect size for eQTLs
mapping to the same locus as the transcription unit at which RNA level was
measured (cis eQTLs) was about 5% of the variance in transcript levels.
There was a long tail, with over half of cis eQTLs accounting for more than
2% of the variance in transcript levels.

An earlier study by Morley et al. (Nature 430, 743-747; 2004) identified cis
regulators, which they defined as variants within 5 Mb of the measured
transcription unit, and trans regulators that mapped outside this window.
Göring et al., using a stricter definition in which a trans eQTL had to map
to a different chromosome from the target gene, were able to replicate 11
cis-acting loci of the Morley study but did not find 4 trans-acting loci
reported by Morley et al. Trans effects are intrinsically harder to study:
because there is no a priori hypothesis as to the location of a
trans-regulatory element, detecting trans effects requires a very much
larger number of tests of association or linkage. This means that small
effects of trans variants are harder to detect than corresponding effects of
cis variants.

Anna Dixon and colleagues (p 1202) report an eQTL associated with the same
SNPs found in an association to childhood asthma recently reported by the
group (Moffattet al. Nature 448, 470-474; 2007). This study also confirms
that 'master regulators' of strong effect (at a distance >100 kb from the
target transcript) are not widespread. Only 13 SNPs were associated with
more than 10 heritable expression traits among some 6,660 genes with
heritable expression differences (heritability, H2, of >0.3). Interactions
between SNPs regulating gene expression were demonstrated, providing an
interesting area for future research.

Barbara Stranger and colleagues (p 1217) found 1,348 cis eQTLs and 180 trans
eQTLs by association of 2.2 million SNPs in 270 individuals comprising the
families used in the HapMap study. This study is notable for the number of
associations that were replicated in multiple populations; indeed, 57 of the
cis eQTLs and 5 of the trans eQTLs were found in all four populations
examined. In 95-97% of the shared associations, the direction of the allelic
effect was the same across populations. Interestingly, most of the
cis-regulatory effects found map very close to the transcriptional start
site of the target gene and were enriched in regions of high sequence
conservation. In this study, trans regulation was defined as variants
mapping >1 Mb from the center of the measured transcription unit. Because of
the statistical implications of the large number of possible tests for trans
eQTLs, Stranger and colleagues limited their examination to some 25,000
candidates-nonsynonymous SNPs and those predicted to affect splicing or
miRNAs.

Despite the confidence engendered by the high degree of concordance among
these studies, the differences reported are likely to be biologically
interesting. Immortalized lymphoblasts that are clonal or of restricted
lineage might be more suitable for the study of trans regulation and might
be more readily studied without the environmental influences and
transcriptome diversity found in a mixed lymphocyte population in vivo.
However, as Stranger et al. discuss, trans regulation also involves
intercellular communication in a multicellular organism and is consequently
intrinsically harder to study.

Source: Nature
http://www.nature.com/ng/journal/v39/n10/full/ng1007-1175.html

Posted by
Robert Karl Stonjek


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