Slightly Deleterious in Trans

One of the hot topics in evolutionary biology concerns the relative contributions of protein coding sequence changes and non-coding changes that lead to differences in the expression of protein coding genes. A subset of this debate can be summarized as cis versus trans. Non-coding sequences that regulate gene expression are known as cis regulatory elements (CREs). The protein coding genes that bind to CREs and control the expression of genes act in trans.


That's the background,and here are some more details. The poster boy for the importance of CREs is Sean Carroll, who argues that the pleiotropic effects of trans changes makes them unlikely to play a large role in the evolution of form (doi:10.1371/journal.pbio.0030245). On the other side of the debate is Jerry Coyne, who penned a strongly worded opinion piece with Hopi Hoekstra arguing that the evidence does not favor Carroll's hypothesis (doi:10.1111/j.1558-5646.2007.00105.x). The past few years have seen a multiple studies examining the relative contributions of cis and trans changes using analyses of gene expression in hybrids (e.g., doi:10.1038/nature02698). In the end, the data reveal that both cis and trans changes play important roles.

Along similar lines as the experiments testing for cis and trans contributions to gene expression differences, Bernardo Lemos and colleagues in Dan Hartl's lab have examined the dominance of cis and trans mutations by measuring gene expression in the parents and progeny of crosses between Drosophila melanogaster from various populations (doi:10.1073/pnas.0805160105). It's a nifty study, and I'm interested in a conclusion they draw regarding the temporal dynamics of cis and trans changes.

Here is the relevant passage from the discussion of their paper:

We argue that cis- and trans-regulation undergo distinct population genetic dynamics across short and long timescales, which lead to a relative overabundance of trans-regulation within population and a relative overabundance of cis-regulation between populations.

They support this conclusion with two observations. First, there is an excess of trans variation within populations. And, second, cis changes tend to be additive, while trans changes are dominant/recessive. That means recessive trans mutations can segregate in populations without phenotypic effects, while cis changes are exposed to selection from the get go (either purged by purifying selection or fixed by positive selection).

What's interesting is how this model explains the maintenance of slightly deleterious mutations (namely, trans variation) by describing their dominance. While there may be a lot of trans variation in a population, it is unlikely to contribute to the divergence between species because, once a slightly deleterious trans mutation reaches an appreciable frequency, it will be purged by purifying selection in homozygotes. It's an interesting angle, and it supports Carroll's hypothesis -- although without directly invoking the pleiotropic effects of trans mutations.

Carroll 2005. Evolution at Two Levels: On Genes and Form. PLoS Biol. 3: e245 doi:10.1371/journal.pbio.0030245

Hoekstra and Coyne 2007. The locus of evolution: evo devo and the genetics of adaptation. Evolution 61: 995-1016 doi:10.1111/j.1558-5646.2007.00105.x

Lemos et al. 2008. Dominance and the evolutionary accumulation of cis- and trans-effects on gene expression. PNAS 105: 14471-14476 doi:10.1073/pnas.0805160105

Wittkopp et al. 2004. Evolutionary changes in cis and trans gene regulation. Nature 430: 85-88 doi:10.1038/nature02698

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