Contiguously hydrophobic sequences are functionally significant throughout the human exome

Hydrophobic interactions have long been established as essential for stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genomewide context. Here we test the role of hydrophobicity on functional impact across 70,000 disease-and non-disease-associated single-nucleotide polymorphisms (SNPs), using enrichment of disease association as an indicator of functionality. We find that functional impact is uncorrelated with hydrophobicity of the SNP itself and only weakly correlated with the average local hydrophobicity, but is strongly correlated with both the size and minimum hydrophobicity of the contiguously hydrophobic sequence (or blob) that contains the SNP. Disease association is found to vary by more than sixfold as a function of contiguous hydrophobicity parameters, suggesting utility as a prior for identifying causal variation. We further find signatures of differential selective constraint on hydrophobic blobs and that SNPs splitting a long hydrophobic blob or joining two short hydrophobic blobs are particularly likely to be disease associated. Trends are preserved for both aggregating and nonaggregating proteins, indicating that the role of contiguous hydrophobicity extends well beyond aggregation risk. 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.

Automated summary

This study investigates the role of hydrophobicity on the functional impact of sequence variants in a genomewide context. The findings indicate that the functional impact is not correlated with the hydrophobicity of the SNP itself, but is strongly correlated with the size and minimum hydrophobicity of the contiguous hydrophobic sequence. The study also suggests that longer unbroken hydrophobic sequences are more likely to be under selection, leading to improvements in genomic tools and understanding of protein-aggregation disease etiology and protein evolutionary history.