Any two unrelated people differ by about 20,000 missense mutations (also referred to as SAVs: Single Amino acid Variants or missense SNV). Many SAVs have been predicted to strongly affect molecular protein function. Common SAVs (> 5% of population) were predicted to have, on average, more effect on molecular protein function than rare SAVs (< 1% of population). We hypothesized that the prevalence of effect in common over rare SAVs might partially be caused by common SAVs more often occurring at interfaces of proteins with other proteins, DNA, or RNA, thereby creating subgroup-specific phenotypes. We analyzed SAVs from 60,706 people through the lens of two prediction methods, one (SNAP2) predicting the effects of SAVs on molecular protein function, the other (ProNA2020) predicting residues in DNA-, RNA- and protein-binding interfaces. Three results stood out. Firstly, SAVs predicted to occur at binding interfaces were predicted to more likely affect molecular function than those predicted as not binding (p value < 2.2 × 10–16). Secondly, for SAVs predicted to occur at binding interfaces, common SAVs were predicted more strongly with effect on protein function than rare SAVs (p value < 2.2 × 10–16). Restriction to SAVs with experimental annotations confirmed all results, although the resulting subsets were too small to establish statistical significance for any result. Thirdly, the fraction of SAVs predicted at binding interfaces differed significantly between tissues, e.g. urinary bladder tissue was found abundant in SAVs predicted at protein-binding interfaces, and reproductive tissues (ovary, testis, vagina, seminal vesicle and endometrium) in SAVs predicted at DNA-binding interfaces. Overall, the results suggested that residues at protein-, DNA-, and RNA-binding interfaces contributed toward predicting that common SAVs more likely affect molecular function than rare SAVs.

中文翻译：

---

蛋白质-蛋白质和蛋白质-核酸结合残基对人类常见和稀有序列变异很重要

任何两个无关的人之间的差异约为20,000个错义突变（也称为SAV：单个氨基酸变体或错义SNV）。预测许多SAV会强烈影响分子蛋白质功能。预计平均SAV（占人口的5％）比罕见SAV（占人口的1％）对分子蛋白质功能的影响更大。我们假设，普通SAV比罕见SAV普遍具有这种效应，部分原因是普通SAV经常在蛋白质与其他蛋白质，DNA或RNA的界面处发生，从而产生亚组特异性表型。我们通过两种预测方法对60706人的SAV进行了分析，其中一种（SNAP2）预测SAV对分子蛋白质功能的影响，另一种（ProNA2020）预测DNA，RNA和蛋白质结合界面中的残基。三个结果突出。首先，预计在结合界面上发生的SAV比未结合的预测更可能影响分子功能（p值<2.2×10-16）。其次，对于预测在结合界面处发生的SAV，与稀有SAV相比，对常见SAV的蛋白质功能影响更强（p值<2.2×10-16）。对带有实验注释的SAV的限制确认了所有结果，尽管所得子集太小而无法为任何结果建立统计学意义。第三，在结合界面处预测的SAV分数在组织之间存在显着差异，例如，发现在蛋白质结合界面预测的SAV和生殖组织（卵巢，睾丸，阴道，精囊中的精囊和子宫内膜）在DNA结合界面预测。总体而言，结果表明蛋白质，DNA和RNA结合界面处的残基有助于预测常见SAV比稀有SAV更可能影响分子功能。