Understanding the molecular mechanisms that correlate pathologies with missense mutations is of critical importance for disease risk estimations and for devising personalized therapies. Thus, we have performed a bioinformatic survey of ClinVar, a database of human genomic variations, to find signals that can account for missense mutation pathogenicity. Arginine resulted as the most frequently replaced amino acid both in benign and pathogenic mutations. By adding the structural dimension to this investigation to increase its resolution, we found that arginine mutations occurring at the protein–DNA interface increase pathogenicity 6.5 times with respect to benign variants. Glycine is the second amino acid among all the pathological missense mutations. Necessarily replaced by larger amino acids, glycine substitutions perturb the structural stability of proteins and, therefore, their functions, being mostly located in buried protein moieties. Arginine and glycine appear as representative of missense mutations causing respective changes in interaction processes and protein structural features, the two main molecular mechanisms of genome-induced pathologies.

中文翻译：

---

疾病诱导错义突变的结构生物信息学调查

了解将病理与错义突变相关联的分子机制对于疾病风险估计和设计个性化治疗至关重要。因此，我们对人类基因组变异数据库 ClinVar 进行了生物信息学调查，以找到可以解释错义突变致病性的信号。精氨酸是良性和致病突变中最常被替换的氨基酸。通过在这项研究中增加结构维度以提高其分辨率，我们发现发生在蛋白质-DNA 界面的精氨酸突变相对于良性变异增加了 6.5 倍的致病性。甘氨酸是所有病理性错义突变中的第二个氨基酸。必然被更大的氨基酸取代，甘氨酸取代扰乱了蛋白质的结构稳定性，因此，它们的功能主要位于隐藏的蛋白质部分。精氨酸和甘氨酸作为错义突变的代表出现，导致相互作用过程和蛋白质结构特征的各自变化，这是基因组诱导病理的两个主要分子机制。