Science2014-06-11 1:11 PM

一个国际研究组首次合成真核细胞——酵母的染色体 Total Synthesis of a Functional Designer Eukaryotic Chromosome

论文摘要 

据一项新的研究报告,研究人员第一次合成了一个真核细胞染色体。该染色体来自一种在地球上被研究得最透彻的生物之一:发面酵母或酿酒酵母。酵母已被用来制造啤酒、生物燃料及药物,但它们一旦配备了全套合成的且可变的染色体时,比如在此项研究中所设计的染色体,这种单细胞生物就可以生产出这些重要商品的更好的版本,其中包括新的抗生素或对环境更友善的生物燃料。

尽管研究人员在该研究中仅仅合成了该酵母菌的16条染色体中的1条,但他们的努力是通往构建一个完整的真核细胞生物基因组的关键性的一步。这样一种基因组不仅可作为一种高度灵活的工具并用于生产商业物质,它也可帮助研究人员更多地了解基因组生物学--其中包括基因组是如何构建的、它们是如何组织的,以及是什么让它们能够运作。

在近些年中,DNA合成技术得到了快速地改善。凭借这些技术,科学家们能够组装原核生物的基因组(如细菌),但组装真核生物基因组在此之前仍然是一个未完成的工作。作为真核生物的发面酵母的基因组是由1200万个核苷酸组成的;核苷酸是基因字母,它们以一种特别的顺序被串在一起。

由Jef Boeke和Narayana Annaluru领导的一个小组将目标对准该酵母菌的染色体III,后者由超过2.5%的这些核苷酸所组成。他们用软件来对其做出小的变动;尤其是移除某些基因间重复及较少使用的DNA区域。接着他们通过将个体核苷酸串联在一起而构建了一种真实的染色体版本;核苷酸是基因的构建模块。重要的是,他们在被认为不重要的基因旁边放置了小的被称作loxPsym位点的标记,这样他们便能改变或删除被标注的基因以观察该酵母菌是否能够存活。

研究人员在活体酵母菌细胞内放入他们的人工合成的染色体并测试了这些改变的细胞在不同营养物及在不同条件下生长的能力。在每种情况下,配备有某种合成染色体版本的酵母菌功能与天然酵母菌的功能没有差别。研究人员通过激活不同的loxPsym位点以改变或删除基因,从而进一步地操纵酵母菌细胞。

他们发现,某些细胞的生长会更为缓慢。而其它某些具有不同基因组合的细胞则会非常快速地生长。例如,通过以不同方式重组DNA,研究人员希望能够设计出可比天然酵母菌制造更多乙醇的或在困难的环境中生长得更好的酵母菌。这项工作确立了酵母菌这种选定的真核生物可作为设计合成真核生物基因组生物学的基础。


Abstract 

Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. Here, we report the synthesis of a functional 272,871–base pair designer eukaryotic chromosome, synIII, which is based on the 316,617–base pair native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, transfer RNAs, transposons, and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling. SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in a-mater derivatives resulting from loss of the MATα allele on synIII. The complete design and synthesis of synIII establishes S. cerevisiae as the basis for designer eukaryotic genome biology.

Editor's Summary

Designer Chromosome

One of the ultimate aims of synthetic biology is to build designer organisms from the ground up. Rapid advances in DNA synthesis has allowed the assembly of complete bacterial genomes. Eukaryotic organisms, with their generally much larger and more complex genomes, present an additional challenge to synthetic biologists. Annaluru et al. (p. 55, published online 27 March) designed a synthetic eukaryotic chromosome based on yeast chromosome III. The designer chromosome, shorn of destabilizing transfer RNA genes and transposons, is ∼14% smaller than its wild-type template and is fully functional with every gene tagged for easy removal.

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