Contiguously hydrophobic sequences are functionally significant throughout the human exome

Abstract

Significance Proteins rely on the hydrophobic effect to maintain structure and interactions with the environment. Surprisingly, natural selection on amino acid hydrophobicity has not been detected using modern genetic data. Analyses that treat each amino acid separately do not reveal significant results, which we confirm here. However, because the hydrophobic effect becomes more powerful as more hydrophobic molecules are introduced, we tested whether unbroken stretches of hydrophobic amino acids are under selection. Using genetic variant data from across the human genome, we find evidence that selection increases with the length of the unbroken hydrophobic sequence. These results could lead to improvements in a wide range of genomic tools as well as insights into protein-aggregation disease etiology and protein evolutionary history.