A long-standing hypothesis is that changes in regulation play an important role in adaptive evolution, notably in primates. Consistent with this theory, the past decade of research has yielded an increasing number of cases where regulatory changes contribute to species-specific adaptations and to reproductive isolation. Nonetheless, to date, there are still only a handful of examples of regulatory adaptations in primates and even fewer cases where the underlying regulatory mechanisms have been resolved. In this application, we propose to continue our work towards understanding the evolutionary processes that shape gene regulation in primates, and in particular, to study the mechanisms of regulatory change in humans and close evolutionary relatives. By using RNA sequencing instead of traditional microarrays, we propose to study and compare gene expression phenotypes in multiple tissues and across species, at unprecedented resolution, as well as to characterize exon usage and alternative splicing patterns. Moreover, by using a combination of genomic approaches that will allow us to characterize histone modification marks and methylation profiles at genome-wide scale, we propose to move beyond simple characterization of gene expression levels to the study the underlying regulatory mechanisms such as chromatin state and epigenetic markers. Specifically, we propose to: (i) Use RNA sequencing to identify genes whose transcript regulation likely evolves under natural selection, (ii) compare promoter methylation states across tissues and species in order to increase our understanding of the mechanisms of regulatory change, and (iii) compare profiles of two histone modifications across tissues and species in order to increase our understanding of the mechanisms of regulatory change. At the conclusion of this work, we will have high-resolution gene and exon expression data, methylation state, and histone modification profiles from a set of five tissues from multiple human, chimpanzee, and rhesus macaque individuals. These data will allow us to explore conserved inter-tissue regulatory differences in the three species, as well as identify genes and pathways whose regulation evolved under natural selection in primates, including human-specific regulatory adaptations. In addition, our data will allow us to determine the mechanisms that explain, at least in part, regulatory differences between the species.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077959-09
Application #
8635359
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2006-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
9
Fiscal Year
2014
Total Cost
$292,314
Indirect Cost
$102,314
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Wang, Sidney H; Hsiao, Chiaowen Joyce; Khan, Zia et al. (2018) Post-translational buffering leads to convergent protein expression levels between primates. Genome Biol 19:83
Battle, Alexis; Khan, Zia; Wang, Sidney H et al. (2015) Genomic variation. Impact of regulatory variation from RNA to protein. Science 347:664-7
Tung, Jenny; Zhou, Xiang; Alberts, Susan C et al. (2015) The genetic architecture of gene expression levels in wild baboons. Elife 4:
Gallego Romero, Irene; Pavlovic, Bryan J; Hernando-Herraez, Irene et al. (2015) A panel of induced pluripotent stem cells from chimpanzees: a resource for comparative functional genomics. Elife 4:e07103
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
Schwalie, Petra C; Ward, Michelle C; Cain, Carolyn E et al. (2013) Co-binding by YY1 identifies the transcriptionally active, highly conserved set of CTCF-bound regions in primate genomes. Genome Biol 14:R148
Khan, Zia; Ford, Michael J; Cusanovich, Darren A et al. (2013) Primate transcript and protein expression levels evolve under compensatory selection pressures. Science 342:1100-4
Tung, Jenny; Gilad, Yoav (2013) Social environmental effects on gene regulation. Cell Mol Life Sci 70:4323-39
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

Showing the most recent 10 out of 39 publications