Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity
Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity
复制标题
DOI：
10.1101/gr.3804205
复制
发表时间：
2005-07-01
期刊：
影响因子：
7
通讯作者：
Sidow, A
中科院分区：
文献类型：
--
作者：
Stone, EA;Sidow, A
我们发现，错义变体对蛋白质功能的损害程度仅通过比较序列分析即可预测。损害的适用范围并不局限于区分正常与有害变异的二元预测，而是从轻度到重度影响不断延伸。预测的准确性强烈依赖于序列变异，并且当不同的直系同源物可用时是最高的。通过量化蛋白质每个位置的物理化学特征，基于观察到的进化变异，实现了高预测准确性。错义变体的物理化学特征与蛋白质功能受损之间的密切关系延伸到人类疾病。通过使用四种不同的蛋白质，其中有足够的比较序列数据，我们表明，疾病的等级，或发展癌症的可能性，强烈相关的物理化学约束违反致病氨基酸变异。
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.