遗传密码子及其应用

作为生命信息的基本遗传单位,基因组遗传密码的破译对于人们加深对生命本质的认识具有重要的理论价值和现实意义.目前,遗传密码子的研究重心已由遗传密码子的破译及反常密码子的发现转入到遗传密码子的起源与进化及扩张等研究.遗传密码子的起源与进化是当今基因组学研究的热点命题之一,相关的学说、假设层出不穷,但尚未取得实质性突破.另一方面,无义密码子的再定义及遗传密码的扩张等研究却极大的丰富和发展了遗传密码子的科学内涵,推动了生命科学研究的发展.文章综述了遗传密码子的多态性、起源与进化、无义密码子的再定义及遗传密码的扩张等方面的研究进展,并就其应用价值作了评述,期待为其在基因组学、医学等相关领域的应用研究提供参考.     

遗传密码的新排列和起源探讨

根据DNA核苷酸组分的动态变化规律将遗传密码的传统排列按密码子对GC和嘌呤含量的敏感性进行了重排.新密码表可划分为2个半区（或1/2区）和4个四分区（或1/4区）.就原核生物基因组而言,当GC含量增加时,物种蛋白质组所含的氨基酸倾向于使用GC富集区和嘌呤不敏感半区所编码的氨基酸,它们均使用四重简并密码,对DNA序列的突变具有相对鲁棒性（Robustness）.当GC含量降低时,大多数密码子处于AU富集区和嘌呤敏感半区,这个区域编码的氨基酸具有物理化学性质的多样性.因为当密码子第三位核苷酸（CP3）在嘌呤和嘧啶之间发生转换时,密码子所编码的氨基酸也倾向于发生变化.关于遗传密码的进化存在多种假说,包括凝固事件假说、共进化假说和立体化学假说等,每种假说均试图解释遗传密码所表现出来的某些化学和生物学规律.基于遗传密码的物理化学性质、基因组变异的规律和相关的生物学假说,本研究提出了遗传密码分步进化假说（The Stepwise Evolution Hypothesis for the Genetic Code）.在人们推断的最原始的RNA世界里,原初（Primordial）遗传密码从只能识别嘌呤和嘧啶开始,编码一个或两个简单而功能明确的氨基酸.由于胞嘧啶C的化学不稳定性,最初形成的遗传密码应该仅仅由腺嘌呤A和尿嘧啶U来编码,却可得到一组7个多元化的氨基酸.随着生命复杂性的增加,鸟嘌呤G从主载操作信号的功能中释放出来,再伴随着C的引入,使遗传密码逐步扩展到12,15和20个氨基酸,最终完成全部进化步骤.遗传密码的进化过程同时也伴随以蛋白质为主体的分子机制和细胞过程的进化,包括氨酰tRNA合成酶（AARS）从初始翻译机器上的脱离、DNA作为信息载体而取代RNA以及AARS和tRNA共进化等基本过程.分子机制和细胞过程是生命的基本组成元件,它们不但自己不断地趋于完善,也促使生命体走?     

终止密码的多种解读方式——延伸还是终止?

在大多数生物体中,核遗传密码是通用的。真核生物核基因组中已发现的非标准遗传密码的使用非常少。大多数非标准遗传密码通常是将1种或者2种终止密码子重新分配为有义密码子,至少保留1种密码子作为翻译终止信号。然而,近期有研究发现,在2种纤毛虫中,所有3种终止密码子既可编码氨基酸,又可作为翻译终止信号;此外,基于转录组的分析表明,在游仆虫的读码框内终止密码子处存在广泛的编程性核糖体移码现象。这些发现提示,终止密码子具有多种解读方式,其翻译终止过程可能依赖某些未知的调控元件。本文基于近期发现的纤毛虫中终止密码子模糊使用的现象,重点讨论了这些生物区分有义"终止"密码子和真正终止密码子的分子机制。对于这些生物体中终止密码子使用的特殊性及翻译终止的研究,将有助于深入理解真核生物中的翻译终止及基因表达调控的分子机制。     

遗传密码子研究进展

作为生命信息的基本遗传单位,基因组遗传密码的破译对于人们加深对生命本质的认识具有重要的理论价值和现实意义。目前,遗传密码子的研究重心已由遗传密码子的破译及反常密码子的发现转入到遗传密码子的起源与进化及扩张等研究。遗传密码子的起源与进化是当今基因组学研究的热点命题之一,相关的学说、假设层出不穷,但尚未取得实质性突破。另一方面,无义密码子的再定义及遗传密码的扩张等研究却极大的丰富和发展了遗传密码子的科学内涵,推动了生命科学研究的发展。文章综述了遗传密码子的多态性、起源与进化、无义密码子的再定义及遗传密码的扩张等方面的研究进展,并就其应用价值作了评述,期待为其在基因组学、医学等相关领域的应用研究提供参考。     

基于密码子偏性的置换模型估计正向选择

由于遗传密码子的简并性特征,大多氨基酸由多于一种密码子编码.在蛋白质编码过程中,同义密码子间的使用有着较显著的偏差,即同义密码于使用频率不等.应用CUSP软件对数据集H3N2和MHC进行同义密码子使用偏性的分析,然后基于同义密码子的使用偏性建立新的密码子置换模型,并在此模型的基础上分析物种的正向选择性.分析结果表明新的密码子置换模型能更好地拟合数据,由此可得到更加可靠的参数估计值.     

遗传密码的高维空间对称性

对称性是由均衡比例产生的匀称美。对称性和对称破缺在自然界和生命现象中普遍存在。20种氨基酸和终止码共有64个遗传密码子,组成一个6维的编码空间。遗传密码空间以对称轴将空间分成对称的两大部分：嘌呤空间和嘧啶空间。遗传密码子的简并以对称轴为参考轴,呈平行排列。高简并度氨基酸（6,4,3,简并度）和低筒并度氨基酸（1,2简并度）的简并子空间近似呈周期性的双方错方式排列。遗传密码的简并与4种核苷酸的二进制数字编码,具有密切的关系。经过分析,可得出遗传密码的连通性λλ简并法则：“除丝氨酸的密码子分成两个与对称轴平行的,分离的子空间之外,其余氨基酸和终止密码的密码子,都通过与空间对称轴平行的λλ平面或λ边简并,组成独立的,单一的连通子空间。”并对氨基酸密码子的惯用率与编码空间的对称关系,以及数字生物学的意义进行了分析和讨论。     

遗传密码格式的组合编码数分析

用N个密码子对m个编码对象进行编码的编码格式是m元N维空间中的一个顶点。64个密码子对20种氨基酸和终止密码子进行编码格式的组合编码数是一个十分巨大的数字。对多元高维编码空间的拓扑特性进行了分析和研究 ,并由此推导出m -N空间的特性三角的排列方式以及给出特性三角公式的数学证明。指出 ,目前的遗传密码的编码格式是21元64维编码空间的一个顶点。应用组合数学分析的方法 ,计算了遗传密码格式的最大组合编码数CM =4.19×1084 ,基因组遗传密码的组合编码数CG =1.13×1080 以及线粒体遗传密码的组合编码数CT =1.38×1079 等。分析结果表明 ,遗传密码的指定是一个小概率事件 ,可能来源于λ简并后的偶数三联密码配对的组合编码的对称破缺     

简并性还是多态性?——遗传密码子设定的进化特点的剖析(英文)

遗传密码子的设定表现出令人困惑的多态性特点 :不同氨基酸拥有的密码子的数目 ,除 5个外 ,从 1个到 6个都有 .这种特点显示出密码子无论在翻译行为还是进化轨迹上 ,都存在诸多的异质性 .因此 ,简并性一词的收敛含义 ,并不能表征这种多态性的进化内涵 .没有同义密码子的AUG(Met)和UGG (Trp)并无简并现象 .其余的密码子则可分为两大类 :一类是 ,4个同义密码子为 1组 ,具有相同的第 1、2位碱基 ,并遵循“3中读 2”的读出规则 .同组的 4个同义密码子 ,不过是来自同一个双字母原始密码子 (XYN)的孑遗物 ,从这个意义上讲 ,也不宜视为简并现象 ;另一类则主要是 ,2个同义密码子为一组 ,并遵循“3中读 3”读出规则 .它们是由编码 2个氨基酸的双义原始密码子 ,第 3位的未定碱基N进一步设定形成 .至于有 6个同义密码子的 ,特别令人困感不解的组别 ,实际上是 4 + 2个 ,这启示它们可能源于上述两大类 .遗传密码子多态性的起源 ,可能始于最初阶段 ,氨基酸同某类寡核苷酸的起始二联体的相互作用 ,而完成于所有的双义原始密码子的第 3位碱基的分化 .这种进化轨迹被传统的简并性一词所模糊 ,并导致鉴定各有关理论可信性的坚实依据和令不同观点取得共识的基础被掩盖起来 .这可能就是在遗传密码子起源领域里 ,长期存在着众     

线粒体遗传密码及基因组遗传密码的对称分析

病毒、细菌和真核生物的氨基酸编码都使用相同的遗传密码,表明它们可能有共同的来源。但人和牛的线粒体的遗传密码和基因组的遗传密码相比,出现以下不同;（1）ATA编码甲硫氮酸M而不是异亮氨酸I。（2）TGA不再是终止密码子X而编码色氨酸W。（3）AGA和AGG不再是精氨酸R的密码子而变为终止密码子X。应用高维空间拓扑分析的方法,对线粒体遗传密码和基因组遗传密码的6维编码空间进行对称性分析,得到如下结果：（1）线粒体遗传密码的起始密码子是2个而不是1个。（2）线粒体遗传密码的终止密码子是4个而不是3个。（3）线粒体遗传密码空间只有2、4、6三种偶数简并度而没1、3两种奇数简并度,表明其对称度较高。（4）线粒体遗传密码空间除丝氨酸S分成两个平行的子空间之外,终止密码子X亦分成两个平行的子空间,表明其连通度较低。（5）线粒体遗传密码一基因组遗传密码相比,共有3个简并平面出现变异,即：1001λλ（M和I）,011λ1λ（W和X）,以及1011λλ（S和X或S和R）。（6）基因组遗传密码的1、3两种奇数简并度可能来源于线粒体遗传密码的1001λλ平面和011λ1λ平面的对称性破缺。对线粒体遗传密码变异的生物学意义及遗传密码的起源进行了分析和讨论。     

硒代半胱氨酸(selenocysteine):密码表中第二十一个氨基酸?

已知所有的氨基酸中,只有遗传密码表内的20种基本氨基酸才能在核糖体中直接掺入肽链;但最近发现于原核、真核生物中的含硒酶里的硒代半胱氨酸(Se-Cys)似亦有此特点。生化、遗传实验均表明Se-Cys对应于终止密码子UGA;相应的tRNA(95bp)基因已经找到。但其转录产物上所携的Se-Cys很可能由原先携带着的Ser经O-磷酰Ser而来。上述发现显示了UGA作为有义密码子的保守性:也许它正处于从有义密码子变为无义密码子的进化过程中。     

The evolution of the mitochondrial genetic code in arthropods revisited

A variant of the invertebrate mitochondrial genetic code was previously identified in arthropods (Abascal et al. 2006a, PLoS Biol 4:e127) in which, instead of translating the AGG codon as serine, as in other invertebrates, some arthropods translate AGG as lysine. Here, we revisit the evolution of the genetic code in arthropods taking into account that (1) the number of arthropod mitochondrial genomes sequenced has triplicated since the original findings were published; (2) the phylogeny of arthropods has been recently resolved with confidence for many groups; and (3) sophisticated probabilistic methods can be applied to analyze the evolution of the genetic code in arthropod mitochondria. According to our analyses, evolutionary shifts in the genetic code have been more common than previously inferred, with many taxonomic groups displaying two alternative codes. Ancestral character-state reconstruction using probabilistic methods confirmed that the arthropod ancestor most likely translated AGG as lysine. Point mutations at tRNA-Lys and tRNA-Ser correlated with the meaning of the AGG codon. In addition, we identified three variables (GC content, number of AGG codons, and taxonomic information) that best explain the use of each of the two alternative genetic codes.     

Load minimization of the genetic code: history does not explain the pattern

The average effect of errors acting on a genetic code (the change in amino-acid meaning resulting from point mutation and mistranslation) may be quantified as its ''load''. The natural genetic code shows a clear property of minimizing this load when compared against randomly generated variant codes. Two hypotheses may be considered to explain this property. First, it is possible that the natural code is the result of selection to minimize this load. Second, it is possible that the property is an historical artefact. It has previously been reported that amino acids that have been assigned to codons starting with the same base come from the same biosynthetic pathway. This probably reflects the manner in which the code evolved from a simpler code, and says more about the physicochemical mechanisms of code assembly than about selection. The apparent load minimization of the code may therefore follow as a consequence of the fact that the code could not have evolved any other way than to allow biochemically related amino acids to have related codons. Here then, we ask whether this ''historical'' force alone can explain the efficiency of the natural code in minimizing the effects of error. We therefore compare the error-minimizing ability of the natural code with that of alternative codes which, rather than being a random selection, are restricted such that amino acids from the same biochemical pathway all share the same first base. We find that although on average the restricted set of codes show a slightly higher efficiency than random ones, the real code remains extremely efficient relative to this subset P = 0.0003. This indicates that for the most part historical features do not explain the load- minimization property of the natural code. The importance of selection is further supported by the finding that the natural code''s efficiency improves relative to that of historically related codes after allowance is made for realistic mutational and mistranslational biases. Once mistranslational biases have been considered, fewer than four per 100,000 alternative codes are better than the natural code.     

Comparison of translation loads for standard and alternative genetic codes

Background  

The (almost) universality of the genetic code is one of the most intriguing properties of cellular life. Nevertheless, several variants of the standard genetic code have been observed, which differ in one or several of 64 codon assignments and occur mainly in mitochondrial genomes and in nuclear genomes of some bacterial and eukaryotic parasites. These variants are usually considered to be the result of non-adaptive evolution. It has been shown that the standard genetic code is preferential to randomly assembled codes for its ability to reduce the effects of errors in protein translation.     

Logic of the genetic code: Conservation of long-range interactions among amino acids as a prime factor

Any statement on the optimality of the existing code ought to imply that this code is ideal for conserving a certain hierarchy of properties while implying that other codes may have been better suited for conservation of other hierarchies of properties. We have evaluated the capability of mutations in the genetic code to convert one amino acid into another in relation to the consequent changes in physical properties of those amino acids. A rather surprising result emerging from this analysis is that the genetic code conserves long-range interactions among amino acids and not their short-range stereochemical attributes. This observation, based directly on the genetic code itself and the physical properties of the 20 amino acids, lends credibility to the idea that the genetic code has not originated by a frozen accident (the null hypothesis rejected by these studies) nor are stereochemical attributes particularly useful in our understanding of what makes the genetic code ‘tick’. While the argument that replacement of, say, an aspartate by a glutamate is less damaging than replacement by arginine makes sense, in order to subject such statements to rigorous statistical tests it is essential to define what constitutes a random sample for the genetic code. The present investigation describes one possible specification. In addition to obvious statistical considerations of testing hypotheses, this procedure points to the more exciting notion that alternative codes may have existed.     

The genetic analysis of mitosis in Aspergillus nidulans

We describe here recent work on the molecular genetics of mitosis in the filamentous fungus Aspergillus nidulans. Aspergillus is one of three simple eukaryotes with powerful genetic systems that have been used to analyze mitosis. The modern molecular biological techniques available with this organism have made it possible to use mutations to identify genes and proteins that play an important role in mitosis. Three Aspergillus genes that affect mitosis are described. One gene, nimA, is specifically expressed late in the cell cycle and codes for a putative protein kinase that induces mitosis, even in cells blocked in S-phase. The second gene, bimG, codes for a putative phosphatase that interacts functionally with the nimA kinase. The third gene, bimE, codes for a protein that suppresses mitosis during interphase, apparently by keeping nimA turned off. None of these genes appear to be similar to any of the genes affecting mitosis that have been characterized in other eukaryotes, but rather appear to be elements of a system that prevents mitosis from occurring during interphase.     

On the origin and evolution of the genetic code. II. Origin of the genetic code as a primordial collector language. The pairing-release hypothesis.

The genetic code is treated as a language used by primordial “collector societies” of tRNA molecules (meaning: societies of RNA molecules specialized in the collection of amino acids and possibly other molecular objects), as a means to organize the delivery of collected material. Its origin is ascribed to the utilization of the complementarity between each tRNA and the genome segment from which it was originally copied, as a means to identify by annealing operations the tRNA molecules returning from their collection trips, and elicit the release of the amino acids they are carrying (the pairing release hypothesis).The gradual conversion of tRNA complements into codon-triplets in the regions of the primordial RNA genomes which specialized in the task of directing the delivery of amino acids by returning tRNA molecules, is ascribed to the removal of genetic redundancy in a gradual reorganization process.A reconstruction of the codon-triplets in one of the earliest genetic codes is attempted by the wobbling reintroduction procedure used in a preceding paper.     

The organic codes. The basic mechanism of macroevolution.

The origin of the genetic code coincided with the origin of life, while the human codes of cultural evolution emerged almost four billion years later. Modern biology does not recognize any other organic code in nature, and is bound therefore to conclude that the whole of cellular evolution consisted of informational changes. Semantic transformations, natural conventions and biological meaning are things that officially do not exist in the organic world, and play no part in our reconstruction of development and evolution. And yet the properties of organic codes are beginning to emerge in various biological processes. Here it is shown that splicing, signal transduction and pattern formation can be accounted for precisely by the existence of organic codes. It is also shown that those processes were instrumental in bringing about major changes in the history of life, and it is concluded that every main step of macroevolution corresponded to the origin of a new organic code.     

The Genetic Code: What Is It Good For? An Analysis of the Effects of Selection Pressures on Genetic Codes

How did the ``universal' genetic code arise? Several hypotheses have been put forward, and the code has been analyzed extensively by authors looking for clues to selection pressures that might have acted during its evolution. But this approach has been ineffective. Although an impressive number of properties has been attributed to the universal code, it has been impossible to determine whether selection on any of these properties was important in the code's evolution or whether the observed properties arose as a consequence of selection on some other characteristic. Therefore we turned the question around and asked, what would a genetic code look like if it had evolved in response to various different selection pressures? To address this question, we constructed a genetic algorithm. We found first that selecting on a particular measure yields codes that are similar to each other. Second, we found that the universal code is far from minimized with respect to the effects of mutations (or translation errors) on the amino acid compositions of proteins. Finally, we found that the codes that most closely resembled real codes were those generated by selecting on aspects of the code's structure, not those generated by selecting to minimize the effects of amino acid substitutions on proteins. This suggests that the universal genetic code has been selected for a particular structure—a structure that confers an important flexibility on the evolution of genes and proteins—and that the particular assignments of amino acids to codons are secondary. Received: 29 December 1998 / Accepted: 8 July 1999