Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases.
Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions (AASs) in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbor the largest proportion of harmful variants (42.1%), whereas the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%). Differences in the proportions of the harmful and benign variants are wide within each group, but they still show clear differences between the groups. Frequently appearing protein domains show a wide spectrum of variant frequencies, whereas no major protein structural class-specific differences were noticed. AAS types in the original and variant residues showed distinctive patterns, which are shared by all the protein groups. The observations are relevant for understanding genetic bases of diseases, variation interpretation, and for the development of methods for that purpose.
['Schaafsma|Gerard C P|GCP|0000-0001-6351-7486', 'Vihinen|Mauno|M|0000-0002-9614-7976']
D019943:Amino Acid Substitution D002875:Chromosomes D019295:Computational Biology D004252:DNA Mutational Analysis D016208:Databases, Factual D014644:Genetic Variation D006801:Humans D016296:Mutagenesis D020125:Mutation, Missense D009369:Neoplasms D011487:Protein Conformation D000072417:Protein Domains D011506:Proteins
proteins sensitivity variation disease groups pathogenicity