Van Norden Melissa, Falls Zackary, Mandloi Sapan, Segal Brahm, Baysal Bora, Samudrala Ram, Elkin Peter L
Department of Biomedical Informatics, University at Buffalo, Buffalo, NY, USA.
Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
bioRxiv. 2023 Jul 31:2023.07.31.550344. doi: 10.1101/2023.07.31.550344.
Intra-organism biodiversity is thought to arise from epigenetic modification of our constituent genes and post-translational modifications after mRNA is translated into proteins. We have found that post-transcriptional modification, also known as RNA editing, is also responsible for a significant amount of our biodiversity, substantively expanding this story. The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosines to uracils (C>U) in specific stem-loop structures. We used RNAsee (RNA site editing evaluation), a tool developed to predict the locations of APOBEC3A/G RNA editing sites, to determine whether known single nucleotide polymorphisms (SNPs) in DNA could be replicated in RNA via RNA editing. About 4.5% of non-synonymous SNPs which result in C>U changes in RNA, and about 5.4% of such SNPs labelled as pathogenic, were identified as probable sites for APOBEC3A/G editing. This suggests that the variant proteins created by these DNA mutations may also be created by transient RNA editing, with the potential to affect human health. Those SNPs identified as potential APOBEC3A/G-mediated RNA editing sites were disproportionately associated with cardiovascular diseases, digestive system diseases, and musculoskeletal diseases. Future work should focus on common sites of RNA editing, any variant proteins created by these RNA editing sites, and the effects of these variants on protein diversity and human health. Classically, our biodiversity is thought to come from our constitutive genetics, epigenetic phenomenon, transcriptional differences, and post-translational modification of proteins. Here, we have shown evidence that RNA editing, often stimulated by environmental factors, could account for a significant degree of the protein biodiversity leading to human disease. In an era where worries about our changing environment are ever increasing, from the warming of our climate to the emergence of new diseases to the infiltration of microplastics and pollutants into our bodies, understanding how environmentally sensitive mechanisms like RNA editing affect our own cells is essential.
生物体内的生物多样性被认为源于我们组成基因的表观遗传修饰以及mRNA翻译成蛋白质后的翻译后修饰。我们发现，转录后修饰，也称为RNA编辑，同样对大量的生物多样性负有责任，极大地拓展了这一认知。载脂蛋白B mRNA编辑催化多肽样（APOBEC）家族的RNA编辑酶APOBEC3A和APOBEC3G催化特定茎环结构中胞嘧啶向尿嘧啶的脱氨基作用（C>U）。我们使用RNAsee（RNA位点编辑评估）这一用于预测APOBEC3A/G RNA编辑位点位置的工具，来确定DNA中已知的单核苷酸多态性（SNP）是否能通过RNA编辑在RNA中重现。约4.5%导致RNA中C>U变化的非同义SNP，以及约5.4%被标记为致病性的此类SNP，被确定为APOBEC3A/G编辑的可能位点。这表明由这些DNA突变产生的变异蛋白也可能由瞬时RNA编辑产生，从而有可能影响人类健康。那些被确定为潜在APOBEC3A/G介导的RNA编辑位点的SNP与心血管疾病、消化系统疾病和肌肉骨骼疾病的关联尤为突出。未来的工作应聚焦于RNA编辑的常见位点、由这些RNA编辑位点产生的任何变异蛋白，以及这些变异对蛋白质多样性和人类健康的影响。传统上，我们的生物多样性被认为来自于我们的组成基因、表观遗传现象、转录差异以及蛋白质的翻译后修饰。在此，我们已证明有证据表明，通常由环境因素刺激的RNA编辑可能在很大程度上导致了引发人类疾病的蛋白质生物多样性。在一个我们对不断变化的环境的担忧与日俱增的时代，从气候变暖到新疾病的出现，再到微塑料和污染物渗入我们的身体，了解像RNA编辑这样对环境敏感的机制如何影响我们自身的细胞至关重要。
