I recently attended a workshop at my institution covering a broad range of evolutionary topics (including many exciting hominin fossil finds in the offing it seems). The last talk of the day was Adam Siepel of Cornell University who gave a talk about positively selected genes reflecting this recent paper in PLoS Genetics. His group used well-sequenced genomes of human, chimp, macaque, mouse, rat and dog to infer positive selection in protein-coding genes using likelihood ratio tests. Bayesian methods were used to establish likely selection histories (which suggested frequent state changes along the phylogeny implying that positive selection occurs and re-occurs over short intervals).
Interestingly positively selected genes tended to be expressed at lower levels and with more tissue-specific expression patterns. This mirrors inverse/positive correlations found elsewhere between substitution rate and expression level/tissue-specificity. More subtly, though, the inverse correlation between substitution rate and expression level was more pronounced in genes not subject to positive selection indicating that responses to purifying selection might be responsible for most of the trend. Thus: “It appears that genes may be more likely to come under positive selection if they are in a state of evolutionary flexibility brought on by reduced or tissue-specific expression, but once positive selection has taken hold their subsequent evolutionary course is not strongly dependent on their expression patterns.”
The inverse correlation with expression may relate to selection against protein-misfolding but the picture with tissue-specificity is about the costs imposed by pleiotropy and is interesting to me because I recently ran an argument about escaping pleiotropy in a recent paper with Samir Wadhawan and my advisor Anton Nekrutenko about the mammalian Gnas locus. The Gnas locus is formidably complex. Crudely it consists of multiple alternative transcripts which share downstream exons but which differ in first exons. These transcripts are subject to complex patterns of tissue-specific and imprinted gene expression with the non-canonical transcripts showing tissue-specificity. We observed an increased rate of evolution (by likelihood ratio testing of dN/dS) among exons unique to these alternative tissue-restricted and imprinted transcripts. I argued that the selection pressures commonly invoked to explain the evolution of imprinting were not sufficient to explain sustained elevated rates and that an escape from pleiotropy was also required in the explanation.
My point was that pleiotropic genes disproportionately attract imprinting (because are more likely to have phenotypes relevant to asymmetric kin interactions: see manuscript), while imprinting of widely expressed transcripts imposes heavier phenotypic costs, which may be avoided by imprinting of alternative tissue-specific forms or acquisition of tissue-specific imprinted expression (demonstrated by the canonical, near-ubiquitously expressed Gnas locus transcript). I used this to motivate an argument for the complexity of imprinted loci separate from Wilkins’ competitive signal discrimination argument for regulative complexity. From Siepel’s data it may be that the tissue-specificity alone is then sufficient to explain elevated rates (contra my thought that patrilineal/matrilineal arms races were involved at this stage). I wonder if this dynamic is generalisable – perhaps pleiotropic genes attract various forms of intragenomic conflict, which then favour the development of baroque modifications?
Siepel’s study had other interesting things to say about the functions of genes subject to positive selection (with some unsurprising targets such as immune system genes), but all-in-all the dynamical aspects seem very interesting to me.