Systemic evolutionary changes in mammalian gene expression

Abstract

Changes in gene expression play an important role in evolution and can be relevant to evolutionary medicine. In this work, a strong relationship was found between the statistical significance of evolutionary changes in the expression of orthologous genes in the five or six homologous mammalian tissues and the across-tissues unidirectionality of changes (i.e., they occur in the same direction in different tissues -- all upward or all downward). In the area of highly significant changes, the fraction of unidirectionally changed genes (UCG) was above 0.9 (random expectation is 0.03). This observation indicates that the most pronounced evolutionary changes in mammalian gene expression are systemic (i.e., they operate at the whole-organism level). The UCG are strongly enriched in the housekeeping genes. More specifically, in the human-chimpanzee comparison, the UCG are enriched in the pathways belonging to gene expression (translation is prominent), cell cycle control, ubiquitin-dependent protein degradation (mostly related to cell cycle control), apoptosis, and Parkinson's disease. In the human-macaque comparison, the two other neurodegenerative diseases (Alzheimer's and Huntington's) are added to the enriched pathways. The consolidation of gene expression changes at the level of pathways indicates that they are not neutral but functional. The systemic expression changes probably maintain the across-tissues balance of basic physiological processes in the course of evolution (e.g., during the movement along the fast-slow life axis). These results can be useful for understanding the variation in longevity and susceptibility to cancer and widespread neurodegenerative diseases. This approach can also guide the choice of prospective genes for studies aiming to decipher cis-regulatory code (the gene list is provided).

Keywords: Carcinogenesis; Cis-regulation; Evolution; Gene expression; Human; Longevity; Mouse; Neurological diseases; Organismal integrity; Primates; Protein interaction networks; Translation.