Abstract
Developments in experimental and computational biology are advancing our understanding of how protein sequence variation impacts molecular protein function. However, the leap from the micro level of molecular function to the macro level of the whole organism, e.g. disease, remains barred. Here, we present new results emphasizing earlier work that suggested some links from molecular function to disease. We focused on non-synonymous single nucleotide variants, also referred to as single amino acid variants (SAVs). Building upon OMIA (Online Mendelian Inheritance in Animals), we introduced a curated set of 117 disease-causing SAVs in animals. Methods optimized to capture effects upon molecular function often correctly predict human (OMIM) and animal (OMIA) Mendelian disease-causing variants. We also predicted effects of human disease-causing variants in the mouse model, i.e. we put OMIM SAVs into mouse orthologs. Overall, fewer variants were predicted with effect in the model organism than in the original organism. Our results, along with other recent studies, demonstrate that predictions of molecular effects capture some important aspects of disease. Thus, in silico methods focusing on the micro level of molecular function can help to understand the macro system level of disease.
Highlights
Protein sequences span three orders of magnitude in their lengths (30-30k residues)
To avoid the overlap of variant sets used for SNAP2 training and those used in this work, we trained a SNAP2 version, using only variants with impact upon molecular function, i.e. leaving out all human disease variants from OMIM or HumVar [28] but keeping the variants from Protein Mutant Database (PMD)
We predicted the effect of disease-causing single amino acid variants (SAVs) from OMIM through PolyPhen-2, SIFT and the re-trained version of SNAP2
Summary
Protein sequences span three orders of magnitude in their lengths (30-30k residues). OMIM, the database of Online Mendelian Inheritance in Man [5], archives thousands of SAVs that cause Mendelian diseases. Databases such as the Protein Mutant Database (PMD) catalogue tens of thousands SAVs altering molecular function; many of those have not been observed to cause a phenotype on the level of the organism. Sequencing everyone on this globe, will we observe almost all possible SAVs? Obvious exceptions include embryonically lethal variants and not all variants will occur in germ lines
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