Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity

被引:301
作者
Stone, EA
Sidow, A [1 ]
机构
[1] Stanford Univ, Dept Stat, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA
[3] Stanford Univ, Dept Genet, Stanford, CA 94305 USA
关键词
D O I
10.1101/gr.3804205
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We find that the degree of impairment of protein function by missense variants is predictable by comparative sequence analysis alone. The applicable range of impairment is not confined to binary predictions that distinguish normal from deleterious variants, but extends continuously from mild to severe effects. The accuracy of predictions is strongly dependent on sequence variation and is highest when diverse orthologs are available. High predictive accuracy is achieved by quantification of the physicochemical characteristics in each position of the protein, based oil observed evolutionary variation. The strong relationship between physicochemical characteristics of a missense variant and impairment of protein function extends to human disease. By using four diverse proteins for which sufficient comparative sequence data are available, we show that grades of disease, or likelihood of developing cancer, correlate strongly with physicochemical constraint violation by causative amino acid variants.
引用
收藏
页码:978 / 986
页数:9
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