Progressively more subtle aggregation avoidance strategies mark a long-term direction to protein evolution

To detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare to less entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes have a hydrophilic amino acid composition, which is presumably the simplest solution to the aggregation problem. Young genes9 few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. Later evolution increases hydrophobicity, increasing aggregation risk. This risk is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more dispersed than if distributed randomly. This dispersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years.