The goal of this study is to identify proteins whose expression levels have evolved under natural selection in humans and non-human primates. Variation in gene regulation, both at the transcriptional and translational levels, is thought to be involved in human phenotypic diversity including disease susceptibility, and is hypothesized to have played an important role in human evolution. Although most previous work in this area has focused on mRNA levels, proteins are usually more directly involved in biological processes. Moreover, complex translational regulatory mechanisms can influence protein levels independent of transcript abundance. Therefore, the characterization of variation in protein levels in humans and non-human primates is expected to provide considerable insight into the genomic mechanisms that may have played important roles in our evolutionary history. In this study, I will (i) develop an antibody microarray platform for highthroughput measurements of steady-state protein expression levels in multiple primate species, (ii) use this platform for comparisons of human, chimpanzee (Pan troglodytes), and rhesus macaque (Macaca mulatta) liver, kidney, heart, lung and testis tissues, and (iii) examine ratios of intra- and inter-specific variation to identify proteins whose expression levels have evolved under stabilizing selection across primates or directional selection in the human lineage. These proteins may be involved in human diseases, for example when expression levels are perturbed. Furthermore, proteins with adaptive changes in steady-state expression levels may have been important in the evolution of human-specific traits, which will be explored using analyses of protein functions and patterns of expression and natural selection by tissue. Variation in protein expression levels is thought to be involved in human phenotypic diversity including disease susceptibility, and may have played an important role in human evolution. This study will use highthroughput technologies to compare protein expression levels across five different tissues from humans, chimpanzees, and rhesus macaques, to identify proteins with expression levels that (i) are highly similar among the three primate species, and (ii) have significantly increased or decreased along the human lineage. Such proteins may be involved in human diseases, for example when expression levels are perturbed, and proteins with significant human lineage changes in expression levels may have been important in the evolution of physical traits that are unique to our species.

F32GM085998

2008-08-11

2011-08-10