cis versus trans effects - senecio7の日記

McManus CJ, Coolon JD, Duff MO, Eipper-Mains J, Graveley BR & Wittkopp PJ 2010 Regulatory divergence in Drosophila revealed by mRNA-seq. Genome Res 20:816-825.

the regulation of gene expression is critical for organismal function and is an important source of phenotypic diversity between species
understanding the genetic and molecular mechanisms responsible for regulatory divergence is therefore expected to provide insight into evolutionary change
we quantified total and allele-specific mRNA expression levels genome-wide in two closely related Drosophila species (D. melanogaster and D. sechellia) and their F₁ hybrids
78% of expressed genes have divergent expression between species
cis- and trans-regulatory divergence affects 51% and 66% of expressed genes, respectively, with 35% of genes showing evidence of both
this is a relatively larger contribution of trans-regulatory divergence than was expected based on prior studies, and may result from the unique demographic history of D. sechellia
cis-regulatory differences contributed more to divergent expression of genes that showed additive rather than nonadditive inheritance
a correlation between sequence similarity and the conservation of cis-regulatory activity was also observed that appears to be a general feature of regulatory evolution

phenotypic differences between species can arise from genetic changes affecting the function of gene products as well as their expression
there has been extensive debate over the relative importance of these two different types of changes

functional divergence of a gene product has historically been much easier to detect than expression divergence
however, advances in methods for measuring gene expression during the last decade have made differences in gene expression much easier to identify
identifying the genetic changes underlying expression divergence, however, remains challenging
because gene expression is controlled by biochemical interactions between cis-regulatory DNA sequences and trans-acting RNAs and proteins that form a complex network
most expression differences between species appear to be polygenic
multiple genetic changes have occurred that affect expression of even a single gene

distinguishing between cis- and trans-acting sources of expression differences is important because these molecular mechanisms can influence the way in which gene expression levels are inherited and evolve
gene expression levels can be inherited additively or nonadditively
cis-regulatory changes appear to have additive effects on gene expression more often than trans-regulatory changes

the net effects of cis- and trans-regulatory changes on total expression divergence can be estimated by comparing the magnitude of the expression difference between two genotypes of interest to the relative allelic expression in F₁ hybrids produced by crossing these two genotypes
because allele-specific measures of gene expression in heterozygotes reflect the relative activity of two cis-regulatory alleles in the same trans-regulatory cellular environment (Cowles et al. 2002)
the fraction of the total expression difference between the two genotypes of interest that is not explained by cis-regulatory divergence is attributed to trans-regulatory divergence (Wittkopp et al. 2004)
until recently, applications of this method for studying regulatory evolution have been limited by the paucity of techniques that could distinguish between mRNA molecules derived from different alleles of the same gene in a high-throughput manner
advances in sequencing technology, however, are beginning to change this

expression differences between species can arise from changes in either cis- or trans-regulation
cis-regulatory sequences have allele-specific effects on gene expression, whereas trans-regulatory factors impact expression of both alleles in a diploid cell
comparing relative allelic expression in hybrids to relative expression between the parental strains allows these two types of changes to be distinguished (Fig. 3A; Wittkopp et al. 2004)
in hybrids, the maternal and paternal cis-regulatory alleles are exposed to the same set of trans-acting factors
thus, the relative allelic expression in hybrids provides a direct readout of relative cis-regulatory activity (Cowles et al. 2002)
note that this assumes that expression of each allele is independent of the other allele
that is, there is no transvection
expression differences observed between species that were not attributable to cis-regulatory divergence were assumed to be caused by trans-regulatory divergence (Wittkopp et al. 2004)

the 3473 genes with significant evidence of both cis- and trans-regulatory differences were subdivided into three groups
"cis + trans," differentially expressed genes for which both cis- and trans-regulatory divergence favored expression of the same allele
"cis × trans," differentially expressed genes for which cis- and trans-regulatory divergence favored expression of opposite alleles
"compensatory," genes with no significant expression differences between species, despite evidence for both cis- and trans-regulatory divergence.
genes classified as cis + trans are more likely to have divergent expression resulting from directional selection than genes classified as cis × trans or compensatory
genes that fall into the latter classes may contribute to hybrid incompatibilities

a larger relative contribution of trans-regulatory changes to expression divergence than was reported for D. melanogaster and D. simulans (Wittkopp et al. 2004; Wittkopp et al. 2008; Graze et al. 2009)
this pattern may reflect differences in the sensitivity of methods used in different studies
it may also reflect the unique evolutionary history of D. sechellia

we observed an excess of regulatory changes that decrease expression in D. sechellia, as well as many more dominant regulatory alleles in D. sechellia than D. melanogaster
these findings appear to contradict a simple null model in which regulatory mutations with different types of effects are fixed at similar rates in the two lineages
we also observed fewer genes affected by cis-regulatory divergence than were reported for D. melanogaster and D. simulans (Wittkopp et al. 2008)
this difference may reflect the fixation of many (presumably trans-acting) deleterious alleles in D. sechellia facilitated by a dramatic reduction in population size
divergent expression of genes responding to the environment may be preferentially caused by trans-regulatory changes (Tirosh et al. 2009)