Via evolgen, a look at the question of whether cis (i.e. noncoding, regulatory sequence changes) or trans (i.e. coding sequence changes) play a greater role in the divergence of species. (Lucky that I stumbled across this blog post this morning because my P.I. brought it up when I went to talk with her this afternoon.) The weight seems to currently lie with people who argue that cis-regulatory variation is less likely to be deleterious, since trans mutations often have pleiotropic effects (i.e. affect multiple phenotypic traits).

Lemos et al., 2008: So the key point about the argument advanced in this paper seems to be that trans effects are more likely to be masked in a heterozygous background in Mendelian fashion, while cis effects tend to be additive. Hence, positive selection can act more effectively on cis-regulatory mutations when they are at very low allele frequencies.

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. This inference follows from two observations. First, the mutation variance for trans-variation is substantially larger than the mutation variance for cis-variation. [...]

Second, our findings that differences due to trans-regulation show higher degrees of dominance, whereas cis-variation arises from regulatory loci that are more additive (or with rare dominant alleles) may suggest a simple way by which too much trans within populations and too much cis between populations can be reconciled. Accordingly, despite selection against trans-regulatory variation within species being particularly strong because of a presumably larger pleiotropic effect of these mutations (13), substantial recessive variation with large trans-effects might still be maintained concealed in heterozygous in natural populations under mutation-selection balance. However, although cis-regulatory variation is produced at a slower rate than trans-variation, positive selection may act most efficiently on cis-regulatory variation, because allelic variation underlying cis differences might have greater additivity such that differences because of cis loci are less sensitive to genomic background.

The authors basically looked at chromosomal substitution lines (which are only genetically variant at one chromosome and hence are good for large-scale mapping, but that’s neither here nor there) and their F1 progeny, but it would be interesting to see if this model holds true in natural populations. E.g. in yeast, we have full genome sequences of several yeast species and many yeast strains within species. It’s not difficult to identify coding polymorphisms when you have well-annotated genomes; it’s slightly harder to identify potential cis-regulatory sequence variation. What’s most difficult though is the problem of whether those sequence differences are functionally relevant and have undergone selection. Naturally, you can use sequence analysis tools to estimate selection but once again, it boils down to the problem of connecting genotype to phenotype…

Other papers I read/skimmed today:

Kvitek et al., 2008: The authors phenotyped 52 S. cerevisiae strains (mostly natural isolates) under different environmental stresses. They also measured gene expression for some of their strains and found that the s288c lab strain has a markedly different transcription profile (not news: P.I.’s postdoctoral work was able to map most of these differences to major mutations, such as the Ty insertion in HAP1). However, they were also able to find major expression differences within the set of natural isolates as well, which drives home the only real point of the paper: there’s a wide range of phenotypic variation among the available S. cerevisiae strains. Although they were able to demonstrate that some of this variation can be caused by copy number (by comparing strains with duplicated or missing chromosomes), they didn’t succeed in actually doing an association mapping study, probably because not all the strains used were sequenced. I wonder why they didn’t try hybridizing to a SNP genotyping array though? They did do “an associative study to identify gene expression patterns correlated with environmental sensitivity across the 17 non-laboratory strains,” but that unfortunately doesn’t say anything about the sequence changes causing the phenotypic variation (whether it be at the level of transcription or at the level of growth under stress) in the first place. Still, it’s good to have confirmation that transcription does correspond to visible growth phenotypes.

Gasch, 2007: A review by the last author of the paper above looking at an identifiable “environmental stress response” that is shared among the major yeasts, i.e. S. cerevisiae, S. pombe and C. albicans.

Shalem et al., 2008: Paper looking at mRNA production and decay rates under a transient (as opposed to a chronic) stress response. I need to think more about this paper; I think I’m going to propose it for discussion in seminar. The methods section is also incredibly useful since I’m also interested in assaying dynamics for my own project.