Inter-species comparisons of gene expression levels will increase our understanding of the evolution of transcriptional mechanisms and help to identify targets of natural selection. This approach holds particular promise for apes, as many human-specific adaptations are thought to result from differences in gene expression rather than in coding sequence. Expression differences have also been associated with phenotypes of medical importance, including numerous diseases as well as differential drug response. ? ? To identify genes whose regulation is likely to be of functional importance in humans, we propose to compare gene expression levels in liver and kidney within and between five humans, five chimpanzees, five orangutans, and five rhesus macaques. To do so, we will develop and use multi-species cDNA arrays that enable the measurement of genes expression differences between species, while accounting for the effect of sequence divergence on hybridization intensity. We will focus on two sets of genes: first, those whose expression levels are approximately constant across individuals from all four species, and whose regulation is therefore likely to be under stabilizing selection. This set will represent promising candidates for disease-association studies. Using a new population genetic approach that we developed, we will use polymorphism and divergence data from these genes to infer the strength and mode of natural selection acting on their upstream regulatory regions. We will also identify genes whose expression levels are constant in the three non-human primates, but consistently elevated or reduced in humans. These regulatory changes are likely to underlie human-specific adaptations. Finally, to enable this type of study for any tissue, we will design and optimize genome-wide multi-species oligonucleotide arrays. ? ? In summary, the proposed research will lead to the identification of the first set of genes whose expression regulation is likely to evolve under natural selection in humans and will shed light on the relationship between gene expression patterns and the evolution of cis-regulatory regions. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Genetic Variation and Evolution Study Section (GVE)
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Eckstrand, Irene A
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University of Chicago
Schools of Medicine
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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
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
Pai, Athma A; Gilad, Yoav (2014) Comparative studies of gene regulatory mechanisms. Curr Opin Genet Dev 29:68-74
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
Perry, George H; Melsted, Páll; Marioni, John C et al. (2012) Comparative RNA sequencing reveals substantial genetic variation in endangered primates. Genome Res 22:602-10

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