How similar are humans and chimpanzees in expressed proteins as estimated by mass spectrometry–based serum proteomics?

• A state-of-the-art MS-based 4-D proteome analysis of bona-fide proteins from serum — the most comprehensive human proteome groups. • Humans and chimpanzees are found to be 66% similar (44% dissimilar) in unique proteins or 44% similar (66% dissimilar) in unique plus differentially expressed proteins. • Protein-protein interaction networks revealed contrasting sets of physically/functionally connected proteins for humans and chimpanzees. • Chimpanzee serum displays increased abundance of six insulin-like growth-factor binding proteins. • This large protein divergence between humans and chimpanzees likely results from different levels and strategies of the exquisite gene expression mechanisms. The question of how similar humans are to chimpanzees and other primates has been central in investigations of our origins. Genomically, they were initially shown to be 98.5% similar, but this similarity has been diminishing. Physiologically, both species are substantially different, and efforts have focused on determining the sources of such contrasts. Linear arrangements of ATGC nucleotides may look similar, but variations in processing of such complex, interconnected and large genomes may result in substantially different species. A milestone goal in chimpanzee versus human comparison would be therefore to map most, ideally all their expressed proteins and functions. A pioneering, but limited, theoretical study concluded that humans and chimpanzees are as much as 80% different in proteins. To assess more comprehensively the level of such differences, we performed a state-of-the-art MS-based 4-D proteome analysis of bona-fide proteins from serum — the most comprehensive human proteome groups. Of the identified proteins, we found that humans and chimpanzees are 66% similar. If we include shared but differentially expressed proteins in a less strict evaluation, this similarity decreases to 44%. Protein-protein interaction networks further revealed contrasting sets of physically/functionally connected proteins, providing insights into immune response, and species-specific disease susceptibility, highlighting possible trends for much more reactive immune response for humans. The chimpanzee serum also displays increased abundance of six insulin-like growth-factor binding proteins, which may point to substantial differences in muscle development and energy metabolisms. Overall, our exploratory findings on serum proteins indicate that MS-based proteomics can indeed contribute to improved understanding of the molecular basis for the divergences between humans and chimpanzees, signaling that they occur essentially at the level of expressed proteins. This large protein divergence, as indicated by serum proteins, compared to a more similar genetic content, therefore likely results from different levels and strategies of gene expression, as well as from post-transcriptional and post-translational protein modifications.