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【bio-news】基因组为何支离破碎

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Science (318):405; 19 October 2007

Why Genomes in Pieces?
Laura F. Landweber

Some microorganisms are evolutionary puzzles in that their genomes contain encrypted genes that are descrambled into gene products.

Microbial eukaryotes take ample detours along the route from DNA to messenger RNA (mRNA) and protein.Some of their tricks continue to erode the notion of a gene beyond its natural subdivision into functional exons and noncoding introns . Two discontinuous genetic systems described in this issue further challenge this dogma. On page 415 of this issue, Marande and Burger report a fully scrambled mitochondrial genome in Diplonema papillatum, a free-living relative of disease-causing trypanosomes , and on page 450, Soma et al. describe a set of scrambled transfer RNA (tRNA) genes in the nuclear genome of the red alga Cyanidioschyzon merolae . The findings are reminders that a genome sequence can be a far cry from knowledge of gene products.

Marande and Burger explode the notion of a gene with mRNA building blocks present as “modules” of ~165 base pairs, each on a sepa separate chromosome in the mitochondria of the protist D. papillatum. Construction of a complete mRNA requires joining up to nine modules through a mechanism that appears distinct from known forms of RNA splicing, the processes that join exons in eukaryotic mRNA. Although split genes occur in other systems (including Chlamydomonas, Euglena, Alveolata, plants, and Diptera), rarely are the scrambled pieces “sewn” back together to create a contiguous gene or RNA. Some exceptions are gene unscrambling in ciliates and the bursicon gene in mosquitoes . Transsplicing of RNA and even proteins can also merge functional regions located on dispersed elements of prokaryotic or eukaryotic genomes.

The pathway for gene assembly in diplonemid mitochondria may provide a clue to the origin of U-insertional RNA editing, which makes a modest appearance in the report by Marande and Burger as six non–DNA-encoded uracil (U) residues that join two RNA modules. Perhaps the ancestral role of guide RNAs that direct U insertion and deletion in the related kinetoplastid protozoa was to provide a template scaffold to link modules. Such small antisense RNAs may later have gained a role in RNA editing, possibly under selective pressure to repair a region or restore a reading frame after loss or erosion of a module.

Soma et al. describe a new layer of tRNA processing in the red alga C. merolae: circularly permuted tRNAs, with the coding region for the RNA 3' end located upstream of the coding region for its 5' end. Although circular permutation has been a laboratory tool for the study of RNA structure and function for years, true biological occurrences were previously known only in phage and ciliate mitochondria . Maturation of tRNA is an elaborate RNA- and protein-driven cascade of clipping, coiffing, and adorning an initial RNA transcript . Soma et al. add one more decryption step to this assembly line.

Why do quirky genetic architectures emerge and persist? Some genetic systems may provide a source of evolutionary novelty. For example, module recycling or shuffling could generate new gene products without destroying the old ones or requiring duplication . So far, the gene products in D. papillatum seem conventional, but examination of the mitochondrial proteome may tell otherwise Some genetic systems may be molecular fossils— neutral vestiges of the past without any special benefits. It is parsimonious to assume that the earliest organisms had split genes, for instance , but because all extant life has been evolving for the same length of time from a common ancestor, one cannot infer the preservation of ancestral genome organization without detailed mapping of ancestral and derived characters on a reliable phylogeny.

Another possible explanation for rococo genetic systems is atavism, in which some biological mechanisms revert back to an ancestral state, although presumably with modification, in a new, derived genetic background. Some of these events may appear to recapitulate features of primitive genomes,providing indirect clues as to how early genetic systems could have functioned.

There is also pure chance, a scenario that is probably slightly deleterious. Unconstrained by dogma and size, why shouldn’t microbial life explore a broad range of possibilities? Protists, often reproducing asexually in the wild, would gradually accumulate small mutations and genome rearrangements that would be crippling without a mechanism to mitigate the effect. Acquisition of a new mechanism may be successful if the organism can recruit a preexisting cellular function or template for repair or rearrangement and then elaborate on the basic mechanism, leading to fixation and expansion of a complex genetic system.

Reductive evolution could account for the svelte genome size (16.5 Mb) of C. merolae and perhaps even some of its quirky genome architecture, if a few spandrels arose as byproducts of genome compaction. This is consistent with its recent placement as a derived lineage within an outgroup of red algae . Genome reduction may lead to intrachromosome rearrangement or overlapping genes in related protists , as either a consequence of, or adaptation to, small size. Germ-line rearrangements can also yield gene duplications .which would be trimmed back under the sword of reductive evolution. Thus, the model that Soma et al. propose for the origin of a permuted tRNA gene is feasible, albeit via secondary acquisition: tRNA gene duplications could emerge along with other germ-line rearrangements, and then the 5' end of the upstream gene would be lost, as well as the 3' end of a downstream gene, leaving the organism no choice but to exploit such a resulting permuted gene, if it can. The only option would be to rescue it by adding a few more acrobatic steps to the already-complex tRNA-processing cascade. Clearly there is a need for a suite of tRNA sequences, or better yet, comparative genomes, both closely and distantly related to C. merolae, to decipher the evolutionary history of its permuted tRNA genes.

Evolution is a tinkerer, and its products are not necessarily neat or elegant. Like a Rube Goldberg invention, it builds upon existing parts, embracing all their gawkiness but grad Gradually smoothing out operations with optimization over time. The biological results are often robust systems that, in the case of protists, may not seem so at first glance.

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Why Genomes in Pieces?
基因组为何支离破碎？

Some microorganisms are evolutionary puzzles in that their genomes contain encrypted genes that are descrambled into gene products.

一些微生物基因组中包含的排列杂乱的基因密码会重新整合并生成相应产物，这是一个进化之谜。

Microbial eukaryotes take ample detours along the route from DNA to messenger RNA (mRNA) and protein.Some of their tricks continue to erode the notion of a gene beyond its natural subdivision into functional exons and noncoding introns . Two discontinuous genetic systems described in this issue further challenge this dogma. On page 415 of this issue, Marande and Burger report a fully scrambled mitochondrial genome in Diplonema papillatum, a free-living relative of disease-causing trypanosomes , and on page 450, Soma et al. describe a set of scrambled transfer RNA (tRNA) genes in the nuclear genome of the red alga Cyanidioschyzon merolae . The findings are reminders that a genome sequence can be a far cry from knowledge of gene products.

除了拥有从DNA到信使RNA再到蛋白的经典遗传途径外，真核微生物还采取许多其他方式来表达其遗传信息。而这些不同于经典途径的表达基因的方式正继续改变着人们对基因概念即基因可分为有功能的外显子和无编码能力的内含子的认识。而本期杂志刊登的文章中描述的两个非连续性遗传系统进一步对这一权威概念提出了挑战。杂志的415页里，Marande和Burger报道了Diplonema papillatum体内的一个完全杂乱的线粒体基因组，该是与致病睡虫有亲缘关系的自由生物，在450页，Soma等描述了红藻核基因组中一系列杂乱的转运RNA基因。这些发现提醒我们，基因序列与我们所认识的基因产物相差甚远。

Marande and Burger explode the notion of a gene with mRNA building blocks present as “modules” of ~165 base pairs, each on a sepa separate chromosome in the mitochondria of the protist D. papillatum. Construction of a complete mRNA requires joining up to nine modules through a mechanism that appears distinct from known forms of RNA splicing, the processes that join exons in eukaryotic mRNA. Although split genes occur in other systems (including Chlamydomonas, Euglena, Alveolata, plants, and Diptera), rarely are the scrambled pieces “sewn” back together to create a contiguous gene or RNA. Some exceptions are gene unscrambling in ciliates and the bursicon gene in mosquitoes . Transsplicing of RNA and even proteins can also merge functional regions located on dispersed elements of prokaryotic or eukaryotic genomes.

Marande和Burger通过探究mRNA的生成过程推翻了人们对基因的认识。该mRNA的基本成分是一些含有约165个碱基对的模块，每一个模块位于原生动物D. papillatum线粒体中相互分离的染色体中。构建一个完整的mRNA需将9段模块连接在一起，而采取的机制则不同于已知的RNA拼接过程，即将外显子连接为真核mRNA。尽管断裂基因见于其他生物系统（包括衣滴虫目，裸藻属，Alveolata，植物和双翅目），但将杂乱的片段“缝合”在一起而创造出一个连续的基因或RNA则较为少见。而纤毛虫和蚊子的粘液素基因所表现出的基因整合则是一些例外。RNA乃至蛋白的反式拼接可以将原核和真核生物基因组中相互远离的功能区整合起来。

The pathway for gene assembly in diplonemid mitochondria may provide a clue to the origin of U-insertional RNA editing, which makes a modest appearance in the report by Marande and Burger as six non–DNA-encoded uracil (U) residues that join two RNA modules. Perhaps the ancestral role of guide RNAs that direct U insertion and deletion in the related kinetoplastid protozoa was to provide a template scaffold to link modules. Such small antisense RNAs may later have gained a role in RNA editing, possibly under selective pressure to repair a region or restore a reading frame after loss or erosion of a module.

线粒体中基因的组装途径或许为插入尿嘧啶式的RNA拼接的起源提供了一个线索，该拼接方式也适度的出现在Marande和Burger的研究中，并导致出现了6个非DNA编码的且连接两个RNA模块的尿嘧啶残基。或许，与动基体目原生动物有亲缘关系的原生动物体内的引导尿嘧啶插入及缺失的指导RNA的古老作用就是为模块的连接提供一个模板支架。之后，这些小的反义RNA可能会在RNA拼接中发挥作用，如在选择压力下修复基因组中一个区域，抑或在丧失或损坏一个模块后恢复一个读码框。

Soma et al. describe a new layer of tRNA processing in the red alga C. merolae: circularly permuted tRNAs, with the coding region for the RNA 3' end located upstream of the coding region for its 5' end. Although circular permutation has been a laboratory tool for the study of RNA structure and function for years, true biological occurrences were previously known only in phage and ciliate mitochondria. Maturation of tRNA is an elaborate RNA- and protein-driven cascade of clipping, coiffing, and adorning an initial RNA transcript . Soma et al. add one more decryption step to this assembly line.

Soma等描述了红藻体内的一个新的tRNA加工过程：将其编码区的3’端置于5’端上游后形成环状排列的tRNA。尽管环化排列作为实验室研究RNA结构和功能的工具已有数年，但是目前仅在噬菌体和纤毛虫线粒体中观察到了这一真实的生物学现象。tRNA的成熟是一个由RNA和蛋白驱动的，对初始RNA转录体进行剪切、拼接和修饰的过程。Soma等的研究更进一步阐明了这个组装线的机制。

Why do quirky genetic architectures emerge and persist? Some genetic systems may provide a source of evolutionary novelty. For example, module recycling or shuffling could generate new gene products without destroying the old ones or requiring duplication. So far, the gene products in D. papillatum seem conventional, but examination of the mitochondrial proteome may tell otherwise Some genetic systems may be molecular fossils— neutral vestiges of the past without any special benefits. It is parsimonious to assume that the earliest organisms had split genes, for instance, but because all extant life has been evolving for the same length of time from a common ancestor, one cannot infer the preservation of ancestral genome organization without detailed mapping of ancestral and derived characters on a reliable phylogeny.

为何会出现这种奇特的遗传学体系并延续了下来？一些遗传学系统可能会成为进化上不断呈现新变化的源泉。例如，模块的重新利用或迁移会在不破坏旧有模块或无须其有拷贝的情况下生成新的基因产物。到目前为止，……的基因产物似乎都是通过常规途径产生的，但是对线粒体蛋白质组的考察可能会告诉我们事物的另一面。一些遗传学系统可能是分子化石--- 无任何特殊利益的过去曾有的遗传学系统的中立性遗迹。

例如，推测最早的生物含有断裂基因，但是，因为所有现存的生物都是由共同的祖先经相同的时间进化而来，那么在缺乏详细的有关可靠的系统发生方面的祖先及其衍生特征的图谱时，就无法推断出祖先的基因组组织结构的保守性。

Another possible explanation for rococo genetic systems is atavism, in which some biological mechanisms revert back to an ancestral state, although presumably with modification, in a new, derived genetic background. Some of these events may appear to recapitulate features of primitive genomes, providing indirect clues as to how early genetic systems could have functioned.

有关旧式遗传学系统的另一个可能的解释是隔代遗传，在此过程中一些生物学机制恢复到一种原始生物才有的状态，尽管该状态可能会在一种新的衍生遗传学背景下发生改变。隔代遗传中的一些事件可能会再次反映出原始基因组的特征，从而为早期遗传学系统是如何拥有功能提供间接的线索。

There is also pure chance, a scenario that is probably slightly deleterious. Unconstrained by dogma and size, why shouldn’t microbial life explore a broad range of possibilities? Protists, often reproducing asexually in the wild, would gradually accumulate small mutations and genome rearrangements that would be crippling without a mechanism to mitigate the effect. Acquisition of a new mechanism may be successful if the organism can recruit a preexisting cellular function or template for repair or rearrangement and then elaborate on the basic mechanism, leading to fixation and expansion of a complex genetic system.

在此过程中也完全有可能给生物体带来轻微损伤。

为何微生物不能在不受条条框框约束的条件下去尝试更多的可能性？原生动物在野生条件下通常为无性繁殖，这一过程会逐渐积累小的突变并发生基因组重排，如果没有一种缓和机制的话，该过程最终会破坏基因组的稳定。如果生物体能够对业已存在的细胞功能或模板进行修复或重组，然后对基本的机制进行完善加工，从而固定或扩展一个复杂的遗传学系统，那么就可能成功获得新机制。

Reductive evolution could account for the svelte genome size (16.5 Mb) of C. merolae and perhaps even some of its quirky genome architecture, if a few spandrels arose as byproducts of genome compaction. This is consistent with its recent placement as a derived lineage within an outgroup of red algae . Genome reduction may lead to intrachromosome rearrangement or overlapping genes in related protists,as either a consequence of, or adaptation to, small size. Germ-line rearrangements can also yield gene duplications .which would be trimmed back under the sword of reductive evolution. Thus, the model that Soma et al. propose for the origin of a permuted tRNA gene is feasible, albeit via secondary acquisition: tRNA gene duplications could emerge along with other germ-line rearrangements, and then the 5' end of the upstream gene would be lost, as well as the 3' end of a downstream gene, leaving the organism no choice but to exploit such a resulting permuted gene, if it can. The only option would be to rescue it by adding a few more acrobatic steps to the already-complex tRNA-processing cascade . Clearly there is a need for a suite of tRNA sequences, or better yet, comparative genomes, both closely and distantly related to C. merolae, to decipher the evolutionary history of its permuted tRNA genes.

还原式进化（规模减小的进化方式）或许能解释为何 C. merolae 拥有短的基因组（16.5Mb），

甚至还可能解释为何在基因组压缩后会出现一些三角拱肩这种奇特的基因组结构。这也与近期将 C. merolae 归类为红藻的一类外群衍生谱系一致。基因组规模的减少可能会导致染色体内部的重排或出现与相关原生动物重叠的基因，这可能是小规模基因组的结果，或者是为小规模基因组做出的适应性调节。生殖种系的重排也能产生重复基因，后者会在还原式进化的利剑下重新被修剪为单拷贝。因此，Soma等为序列变化的tRNA的来源提出的模型是可行的，
即使是通过二级获得的方式（secondary acquisition）完成的：
tRNA基因会随着其他种系的重排而产生多拷贝，之后上游基因的5’末端和下游基因的3’末端发生丢失，这样，如果可以的话生物体只能去开发这一序列重排的基因而别无他选。唯一的选择就是在已有的复杂的tRNA加工级联通路中再增加一些“杂技般精巧”的步骤来拯救该基因。显然需要一系列的tRNA基因序列，情况好的话，比较与 C. merolae 近缘和远缘的生物体的基因组，以此阐明该生物序列变化的tRNA基因的进化史。

Evolution is a tinkerer, and its products are not necessarily neat or elegant. Like a Rube Goldberg invention, it builds upon existing parts, embracing all their gawkiness but gradually smoothing out operations with optimization over time. The biological results are often robust systems that, in the case of protists, may not seem so at first glance.

进化是一位修补匠，其产物不必完美无暇。就像Rube Goldberg发明的一样，进化是在已有物种的基础上来完成其建造，期间包容物种的所有瑕疵，但是以最优方式来完善其建造工艺。

以原生动物为例，其出现的生物学结果常常是其所拥有的生命力顽强的生物学系统的体现，而这种顽强的特性乍看并非如此。

2007-10-25 08:36

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npng 编辑于 2007-10-25 08:40

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基因组为何支离破碎？

一些微生物基因组中包含的排列杂乱的基因密码会重新整合并生成相应产物，这是一个进化之谜。

除了拥有从DNA到信使RNA再到蛋白的经典遗传途径外，真核微生物还采取许多其他方式来表达其遗传信息。而这些不同于经典途径的表达基因的方式正继续改变着人们对基因概念即基因可分为有功能的外显子和无编码能力的内含子的认识。而本期杂志刊登的文章中描述的两个非连续性遗传系统进一步对这一权威概念提出了挑战。杂志的415页里，Marande和Burger报道了Diplonema papillatum体内的一个完全杂乱的线粒体基因组，该是与致病睡虫有亲缘关系的自由生物，在450页，Soma等描述了红藻核基因组中一系列杂乱的转运RNA基因。这些发现提醒我们，基因序列与我们所认识的基因产物相差甚远。

Marande和Burger通过探究mRNA的生成过程推翻了人们对基因的认识。该mRNA的基本成分是一些含有约165个碱基对的模块，每一个模块位于原生动物D. papillatum线粒体中相互分离的染色体中。构建一个完整的mRNA需将9段模块连接在一起，而采取的机制则不同于已知的RNA拼接过程，即将外显子连接为真核mRNA。尽管断裂基因见于其他生物系统（包括衣滴虫目，裸藻属，Alveolata，植物和双翅目），但将杂乱的片段“缝合”在一起而创造出一个连续的基因或RNA则较为少见。而纤毛虫和蚊子的粘液素基因所表现出的基因整合则是一些例外。RNA乃至蛋白的反式拼接可以将原核和真核生物基因组中相互远离的功能区整合起来。线粒体中基因的组装途径或许为插入尿嘧啶式的RNA拼接的起源提供了一个线索，该拼接方式也适度的出现在Marande和Burger的研究中，并导致出现了6个非DNA编码的且连接两个RNA模块的尿嘧啶残基。或许，与动基体目原生动物有亲缘关系的原生动物体内的引导尿嘧啶插入及缺失的指导RNA的古老作用就是为模块的连接提供一个模板支架。之后，这些小的反义RNA可能会在RNA拼接中发挥作用，如在选择压力下修复基因组中一个区域，抑或在丧失或损坏一个模块后恢复一个读码框。

Soma等描述了红藻体内的一个新的tRNA加工过程：将其编码区的3’端置于5’端上游后形成环状排列的tRNA。尽管环化排列作为实验室研究RNA结构和功能的工具已有数年，但是目前仅在噬菌体和纤毛虫线粒体中观察到了这一真实的生物学现象。tRNA的成熟是一个由RNA和蛋白驱动的，对初始RNA转录体进行剪切、拼接和修饰的过程。Soma等的研究更进一步阐明了这个组装线的机制。

为何会出现这种奇特的遗传学体系并延续了下来？一些遗传学系统可能会成为进化上不断呈现新变化的源泉。例如，模块的重新利用或迁移会在不破坏旧有模块或无须其有拷贝的情况下生成新的基因产物。到目前为止，……的基因产物似乎都是通过常规途径产生的，但是对线粒体蛋白质组的考察可能会告诉我们事物的另一面。一些遗传学系统可能是分子化石--- 无任何特殊利益的过去曾有的遗传学系统的中立性遗迹。例如，推测最早的生物含有断裂基因，但是，因为所有现存的生物都是由共同的祖先经相同的时间进化而来，那么在缺乏详细的有关可靠的系统发生方面的祖先及其衍生特征的图谱时，就无法推断出祖先的基因组组织结构的保守性。

有关旧式遗传学系统的另一个可能的解释是隔代遗传，在此过程中一些生物学机制恢复到一种原始生物才有的状态，尽管该状态可能会在一种新的衍生遗传学背景下发生改变。隔代遗传中的一些事件可能会再次反映出原始基因组的特征，从而为早期遗传学系统是如何拥有功能提供间接的线索。在此过程中也完全有可能给生物体带来轻微损伤。为何微生物不能在不受条条框框约束的条件下去尝试更多的可能性？原生动物在野生条件下通常为无性繁殖，这一过程会逐渐积累小的突变并发生基因组重排，如果没有一种缓和机制的话，该过程最终会破坏基因组的稳定。如果生物体能够对业已存在的细胞功能或模板进行修复或重组，然后对基本的机制进行完善加工，从而固定或扩展一个复杂的遗传学系统，那么就可能成功获得新机制。

还原式进化（规模减小的进化方式）或许能解释为何 C. merolae 拥有短的基因组（16.5Mb），甚至还可能解释为何在基因组压缩后会出现一些三角拱肩这种奇特的基因组结构。这也与近期将……归类为红藻的一类外群衍生谱系一致。基因组规模的减少可能会导致染色体内部的重排或出现与相关原生动物重叠的基因，这可能是小规模基因组的结果，或者是为小规模基因组做出的适应性调节。生殖种系的重排也能产生重复基因，后者会在还原式进化的利剑下重新被修剪为单拷贝。因此，Soma等为序列变化的tRNA的来源提出的模型是可行的，即使是通过二级获得的方式（secondary acquisition）完成的：tRNA基因会随着其他种系的重排而产生多拷贝，之后上游基因的5’末端和下游基因的3’末端发生丢失，这样，如果可以的话生物体只能去开发这一序列重排的基因而别无他选。唯一的选择就是在已有的复杂的tRNA加工级联通路中再增加一些“杂技般精巧”的步骤来拯救该基因。显然需要一系列的tRNA基因序列，情况好的话，比较与C. merolae近缘和远缘的生物体的基因组，以此阐明该生物序列变化的tRNA基因的进化史。

进化是一位修补匠，其产物不必完美无暇。就像Rube Goldberg发明的一样，进化是在已有物种的基础上来完成其建造，期间包容物种的所有瑕疵，但是以最优方式来完善其建造工艺。以原生动物为例，其出现的生物学结果常常是其所拥有的生命力顽强的生物学系统的体现，而这种顽强的特性乍看并非如此。

2007-10-25 08:39

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