Background: Amino acid mutations in a large number of human proteins are known to be associated with heritable genetic disease. These disease-associated mutations (DAMs) are known to occur predominantly in positions essential to the structure and function of the proteins. Here, we examine how the relative perpetuation and conservation of amino acid positions modulate the genome-wide patterns of 8,627 human disease-associated mutations (DAMs) reported in 541 genes. We compare these patterns with 5,308 non-synonymous Single Nucleotide Polymorphisms (nSNPs) in 2,592 genes from primary SNP resources.
Results: The abundance of DAMs shows a negative relationship with the evolutionary rate of the amino acid positions harboring them. An opposite trend describes the distribution of nSNPs. DAMs are also preferentially found in the amino acid positions that are retained (or present) in multiple vertebrate species, whereas the nSNPs are over-abundant in the positions that have been lost (or absent) in the non-human vertebrates. These observations are consistent with the effect of purifying selection on natural variation, which also explains the existence of lower minor nSNP allele frequencies at highly-conserved amino acid positions. The biochemical severity of the inter-specific amino acid changes is also modulated by natural selection, with the fast-evolving positions containing more radical amino acid differences among species. Similarly, DAMs associated with early-onset diseases are more radical than those associated with the late-onset diseases. A small fraction of DAMs (10%) overlap with the amino acid differences between species within the same position, but are biochemically the most conservative group of amino acid differences in our datasets. Overlapping DAMs are found disproportionately in fast-evolving amino acid positions, which, along with the conservative nature of the amino acid changes, may have allowed some of them to escape natural selection until compensatory changes occur.
Conclusion: The consistency and predictability of genome-wide patterns of disease- associated and neutral amino acid variants reported here underscores the importance of the consideration of evolutionary rates of amino acid positions in clinical and population genetic analyses aimed at understanding the nature and fate of disease-associated and neutral population variation. Establishing such general patterns is an early step in efforts to diagnose the pathogenic potentials of novel amino acid mutations.