A central goal of evolutionary biology is to elucidate the genetic architecture of adaptation. In humans, this question is of interest both for what it will reveal about our species-specific traits and because of the emerging links between adaptation and disease susceptibility. To date, however, there are only a handful of examples of human regulatory adaptations, such that many outstanding questions remain open. Among these: Which pathways have been remodeled in human evolution? Do adaptive changes in the regulation of entire pathways involve changes to many genes, or to few? What is the relative importance of changes in cis (e.g., promoter regions) vs. trans (e.g., transcription factors) regulatory elements? How prevalent are compensatory changes in regulatory pathways? As a first step towards answering these questions, we propose to identify transcriptional pathways that have been adaptively remodeled in humans and to examine their evolution across three primate species. Specifically, we plan to focus on five transcription factors that have been shown previously (in our work and by others) to be the target of positive selection in the human lineage. Through a combination of siRNA knockdowns, gene expression profiles, ChIP-seq, and reporter gene experiments, we will identify the genes that are directly regulated by these transcription factors, not only in humans but also in two close evolutionary relatives, chimpanzees and rhesus macaques. The proposed combination of approaches will lead to the reliable annotation of direct regulatory targets of five transcription factors in three species and facilitate the identification of transcriptional pathways that underlie human-specific adaptation. Comparison of regulatory networks in the three species will reveal the genetic basis for a large set of regulatory differences between humans and closely related species, enabling us to address many of the above questions. To our knowledge, this research represents the first genome-wide exploration of differences in regulatory pathways across species. In addition to identifying pathways that have been adaptively remodeled in the human lineage, it will yield unprecedented insights into the genetic basis of regulatory change at the transcription level.

Public Health Relevance

The goal of the proposed study is to identify a first set of regulatory pathways that have been remodeled in humans, and learn about the genetic basis of gene regulatory changes in primates.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Blekhman, Ran; Perry, George H; Shahbaz, Sevini et al. (2014) Comparative metabolomics in primates reveals the effects of diet and gene regulatory variation on metabolic divergence. Sci Rep 4:5809
Pai, Athma A; Gilad, Yoav (2014) Comparative studies of gene regulatory mechanisms. Curr Opin Genet Dev 29:68-74
Zhou, Xiang; Cain, Carolyn E; Myrthil, Marsha et al. (2014) Epigenetic modifications are associated with inter-species gene expression variation in primates. Genome Biol 15:547
Gilad, Yoav (2012) Using genomic tools to study regulatory evolution. Methods Mol Biol 856:335-61
Romero, Irene Gallego; Ruvinsky, Ilya; Gilad, Yoav (2012) Comparative studies of gene expression and the evolution of gene regulation. Nat Rev Genet 13:505-16
Perry, George H; Reeves, Darryl; Melsted, Pall et al. (2012) A genome sequence resource for the aye-aye (Daubentonia madagascariensis), a nocturnal lemur from Madagascar. Genome Biol Evol 4:126-35
Veyrieras, Jean-Baptiste; Gaffney, Daniel J; Pickrell, Joseph K et al. (2012) Exon-specific QTLs skew the inferred distribution of expression QTLs detected using gene expression array data. PLoS One 7:e30629
Tung, Jenny; Barreiro, Luis B; Johnson, Zachary P et al. (2012) Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proc Natl Acad Sci U S A 109:6490-5
Cain, Carolyn E; Blekhman, Ran; Marioni, John C et al. (2011) Gene expression differences among primates are associated with changes in a histone epigenetic modification. Genetics 187:1225-34
Pai, Athma A; Bell, Jordana T; Marioni, John C et al. (2011) A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genet 7:e1001316

Showing the most recent 10 out of 11 publications