  Darwin's theory of evolution emphasized that positive selection of functional
proficiency provides the fitness that ultimately determines the structure of
life, a view that has dominated biochemical thinking of enzymes as perfectly
optimized for their specific functions. The 20th-century modern synthesis,
structural biology, and the central dogma explained the machinery of evolution,
and nearly neutral theory explained how selection competes with random fixation
dynamics that produce molecular clocks essential e.g. for dating evolutionary
histories. However, the quantitative proteomics revealed that fitness effects
not related to functional proficiency play much larger roles on long
evolutionary time scales than previously thought, with particular evidence that
some universal biophysical selection pressures act via protein expression
levels. This paper first summarizes recent progress in the 21st century towards
recovering this universal selection pressure. Then, the paper argues that
proteome cost minimization is the dominant, underlying "non-function" selection
pressure controlling most of the evolution of already functionally adapted
living systems. A theory of proteome cost minimization is described and argued
to have consequences for understanding evolutionary trade-offs, aging, cancer,
and neurodegenerative protein-misfolding diseases.
