Expression profiling in primates reveals a rapid evolution of human transcription factors

Abstract

Although it has been hypothesized for thirty years that many human adaptations are likely to be due to changes in gene regulation 1 , almost nothing is known about the modes of natural selection acting on regulation in primates. Here we identify a set of genes for which expression is evolving under natural selection. We use a new multi-species complementary DNA array to compare steady-state messenger RNA levels in liver tissues within and between humans, chimpanzees, orangutans and rhesus macaques. Using estimates from a linear mixed model, we identify a set of genes for which expression levels have remained constant across the entire phylogeny (,70 million years), and are therefore likely to be under stabilizing selection. Among the top candidates are five genes with expression levels that have previously been shown to be altered in liver carcinoma. We also find a number of genes with similar expression levels among non-human primates but significantly elevated or reduced expression in the human lineage, features that point to the action of directional selection. Among the gene set with a human-specific increase in expression, there is an excess of transcription factors; the same is not true for genes with increased expression in chimpanzee.A number of recent studies have used DNA microarrays to compare patterns of gene expression between closely related species 2-9 . Within primates, the focus has been primarily on human-chimpanzee comparisons, estimating gene expression profiles for a number of tissues, including liver, brain and heart 2,6,7,10 . The aim has been to characterize general trends in the evolution of gene expression rather than to identify specific genes of interest. To date, conclusions about the selection pressures acting on gene expression have been conflicting 2,3,6,[11][12][13] .These studies have all relied on data collected from arrays using gene probes that were designed on the basis of human sequences only. However, sequence mismatches affect hybridization intensity and can therefore bias estimates of gene expression differences between species 14 . This limitation of single-species arrays is especially problematic when the goal is to study how expression changes over evolutionary time. To make comparisons between more distantly related primate species, we generated a multi-species cDNA array that allows comparison of gene expression between species without the confounding effects of sequence divergence 14 . This cDNA array contains probes for 1,056 orthologous genes from four species (see Supplementary Methods) 14 .We used this array to compare gene expression profiles in the livers of humans, chimpanzees (Pan troglodytes), orangutans (Pongo pygmaeus) and rhesus macaques (Macaca mulatta), the phylogeny of which represents approximately 70 million years (Myr) of evolution. By assigning expression changes in the liver to particular lineages, we were able to identify the first set of genes for which regulation seems to be under lineage-specific selection pressures. In order to measure gene...

Optimization of gene expression by natural selection

“…Phylogenetically distant comparisons had a smaller sample size than close comparisons and so were biased toward large estimates of expression divergence (7). Another study of primate-expression divergence using species-specific probes found that, in the majority of cases, a constant level gene expression across the phylogeny could not be rejected (24). Although this result is consistent with stabilizing selection, a low rate of neutral divergence will have the same effect.…”

A Comparison of Two Nicotiana attenuata Accessions Reveals Large Differences in Signaling Induced by Oral Secretions of the Specialist Herbivore Manduca sexta

“…It is generally accepted that genetic changes in both cis-and trans-regulatory elements contribute remarkably more than changes in functional genes to phenotypic variation (Doebley and Lukens, 1998;Carroll, 2000;Gilad et al, 2006). Among the regulatory elements that account for herbivore resistance in plants, those involved in early responses are particularly interesting because many play key roles in transducing responses to various environmental stresses into changes in downstream gene expression and eventually into changes in phenotypic traits.…”

Tissue-driven Hypothesis with Gene Ontology (GO) Analysis

“…4,10,23 Briefly, large number of quantitative changes in gene expression is found among primates in the initial study, 2 but follow-up studies had somewhat conflicting results. Some studies support a neutral model of expression divergence, 11,12,14,25 while other studies 5,9,17 showed the general existence of stabilizing constraints. Some studies have also found positive selection in primate or mammal expression divergence.…”

“…Some studies have also found positive selection in primate or mammal expression divergence. 5,13 There are also many studies on expression divergence in non-mammal species, 3,16,[18][19][20]24 most support a stabilizing selection model but do not exclude the existence of neutral or positive factors.…”