Potential Impact of Genetic-Code Mutations on Medicine and Health

T. Wong, Hong Xue
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Abstract

The genetic code encoding amino acid sequences in ribosomal translation consists of an alphabet of 61 triplet codons for 20 amino acids and three chain termination signals. Basically the same universal code is employed by all organisms from the Last Universal Common Ancestor (LUCA)-proximal Methanobacter kandleri (Mka) to humans. This universal code, which has remained invariant for all living species, enables the transplantation of protein-coding genes between different species without loss of function, and constrains the chemical diversity of the encoded amino acids. Over the initial decades following the discovery of the code, its invariance coupled with the lack of any information regarding its origin have led to the view that the code might represent an inexplicable ‘frozen accident’ in the history of life. However, with the formulation of the coevolution theory of the genetic code and its multifaceted supporting evidence, this view has become untenable. Instead, the encoded amino acids are known to comprise two different classes: ten Class 1 amino acids available on prebiotic Earth were incorporated into the protocells as they evolved into life forms, while the ten Class 2 amino acids were produced by early life through biosynthesis. Thus, the later entry of the Class 2 amino acids identified them as end products of cellular evolution, which suggests the plausibility of continuing alterations of the encoded amino acids after an eons-long pause. Accordingly, attempts were made by our group to replace Trp by 4-fluroTrp (4FTrp) from the proteome of Bacillus subtilis. The targeted replacement obtained proved the inherent mutability of the code, and this has stimulated the development of a wide range of mutated codes through a variety of approaches. Hundreds of genetic code mutants have now been successfully isolated from microbes to animals, transforming the code from an immutable construct to a highly malleable molecular device. The effects of such new codes on medicine and health range from treatments for a variety of diseases to the alleviation of food crisis arising from the degradation of the environment and devastation due to natural disasters.
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遗传密码突变对医学和健康的潜在影响
编码核糖体翻译氨基酸序列的遗传密码由20个氨基酸的61个三重密码子和3个链终止信号组成。基本上,从最后的普遍共同祖先(LUCA)-近端坎德利甲烷杆菌(Mka)到人类的所有生物都使用相同的通用代码。这一普遍编码在所有现存物种中都保持不变,使得蛋白质编码基因在不同物种之间移植而不丧失功能,并限制了编码氨基酸的化学多样性。在密码被发现后的最初几十年里,它的不变性加上缺乏关于其起源的任何信息,导致人们认为密码可能代表了生命历史上一个无法解释的“冻结事故”。然而,随着遗传密码的共同进化理论及其多方面的支持证据的形成,这种观点已经变得站不住脚。相反,已知编码的氨基酸由两类不同的氨基酸组成:10种1类氨基酸在生命起源前的地球上可用,在它们进化成生命形式的过程中被整合到原始细胞中,而10种2类氨基酸是由早期生命通过生物合成产生的。因此,后来进入的第2类氨基酸将它们确定为细胞进化的最终产物,这表明经过长时间的停顿后,编码氨基酸继续改变的可能性。因此,本研究组尝试用枯草芽孢杆菌蛋白质组中的4-氟Trp (4FTrp)代替Trp。所获得的有针对性的替换证明了编码的内在可变性,这刺激了通过各种方法开发各种变异编码。数以百计的遗传密码突变体已经从微生物和动物中成功分离出来,将密码从一个不可变的结构转变为一个高度可塑的分子装置。这些新守则对医药和健康的影响范围广泛,从治疗各种疾病到缓解因环境退化和自然灾害造成的破坏而引起的粮食危机。
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