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Most phenotypic differences between human and chimpanzee are likely to result from differences in gene regulation, rather than changes to protein-coding regions. To date, however, only a handful of human–chimpanzee nucleotide differences leading to changes in gene regulation have been identified. To hone in on differences in regulatory elements between human and chimpanzee, we focused on 10 genes that were previously found to be differentially expressed between the two species. We then designed reporter gene assays for the putative human and chimpanzee promoters of the 10 genes. Of seven promoters that we found to be active in human liver cell lines, human and chimpanzee promoters had significantly different activity in four cases, three of which recapitulated the gene expression difference seen in the microarray experiment. For these three genes, we were therefore able to demonstrate that a change in cis influences expression differences between humans and chimpanzees. Moreover, using site-directed mutagenesis on one construct, the promoter for the DDA3 gene, we were able to identify three nucleotides that together lead to a cis regulatory difference between the species. High-throughput application of this approach can provide a map of regulatory element differences between humans and our close evolutionary relatives.

Motivation: Comparisons of gene expression levels within and between species have become a central tool in the study of the genetic basis for phenotypic variation, as well as in the study of the evolution of gene regulation. DNA microarrays are a key technology that enables these studies. Currently, however, microarrays are only available for a small number of species. Thus, in order to study gene expression levels in species for which microarrays are not available, researchers face three sets of choices: (i) use a microarray designed for another species, but only compare gene expression levels within species, (ii) construct a new microarray for every species whose gene expression profiles will be compared or (iii) build a multi-species microarray with probes from each species of interest. Here, we use data collected using a multi-primate cDNA array to evaluate the reliability of each approach.Results: We find that, for inter-species comparisons, estimates of expression differences based on multi-species microarrays are more accurate than those based on multiple species-specific arrays. We also demonstrate that within-species expression differences can be estimated using a microarray for a closely related species, without discernible loss of information.Contact: A.O. (oshlack@wehi.edu.au) or Y.G. (gilad@uchicago.edu)Supplementary information: Supplementary data are available at Bioinformatics online.

The images for Figures 4 and 5 were mistakenly swapped. The titles and legends for both figures are correct, but the image for Figure 4 should be the image for Figure 5, and vice versa.

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p, Author Summary Development of vaccines for HIV/AIDS is a pressing global issue. The rhesus monkey remains the primary model for testing potential human vaccines; however, little is known about similarities and differences in host genes involved in HIV/AIDS response in humans and rhesus monkeys. Understanding these similarities and/or differences should allow more efficient testing of vaccines beneficial to humans. Here we describe the role that variation in the number of copies of CCL3-like genes (CCL3L) plays in SIV progression rates in rhesus monkeys. Copy number variation (CNV) of these genes has previously been shown to play a role in susceptibility and progression of HIV in humans. Our results suggest that individual monkeys with lower CCL3L copy number progress more rapidly. Accounting for CCL3L CNV in rhesus vaccine trials will improve researchers' abilities to interpret survival data.

Regulatory changes have long been hypothesized to play an important role in primate evolution. To identify adaptive regulatory changes in humans, we performed a genome-wide survey for genes in which regulation has likely evolved under natural selection. To do so, we used a multi-species microarray to measure gene expression levels in livers, kidneys, and hearts from six humans, chimpanzees, and rhesus macaques. This comparative gene expression data allowed us to identify a large number of genes, as well as specific pathways, whose inter-species expression profiles are consistent with the action of stabilizing or directional selection on gene regulation. Among the latter set, we found an enrichment of genes involved in metabolic pathways, consistent with the hypothesis that shifts in diet underlie many regulatory adaptations in humans. In addition, we found evidence for tissue-specific selection pressures, as well as lower rates of protein evolution for genes in which regulation evolves under natural selection. These observations are consistent with the notion that adaptive circumscribed changes in gene regulation have fewer deleterious pleiotropic effects compared with changes at the protein sequence level., Author Summary It has long been hypothesized that in addition to structural changes to proteins, changes in gene regulation might underlie many of the anatomic and behavioral differences between humans and other primates. However, to date, there are only a handful of examples of regulatory adaptations in humans. In this work, we present a genome-wide study of gene expression levels in livers, kidneys, and hearts from three species: humans, chimpanzees, and rhesus macaques. These data allowed us to identify genes and entire pathways in which regulation evolved under natural selection and therefore are likely to be functionally important. Our results provide some of the first examples of pathways that have been remodeled specifically in the human lineage. In particular, we find that the regulation of a large number of genes involved in metabolic pathways evolved under lineage-specific directional selection. This result is intriguing, because, in addition to the obvious cognitive and linguistic differences between humans and non-human apes, a clear lifestyle shift between us and other primates can be found in our diet. We also found evidence for tissue-specific selection pressures on gene regulation, an observation that provides strong support to the notion that adaptive circumscribed changes in gene regulation have fewer deleterious pleiotropic effects compared with changes at the protein sequence level.