Evolution Reloaded: From Artificial Genes To Novel Biological Functions

进化重装上阵：从人工基因到新的生物功能

• 批准号: 1050510
• 负责人: Michael Hecht
• 金额: $ 70.39万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1050510&HistoricalAwards=false
• 关键词: Evolution; Reloaded; Artificial; Genes; Novel; Evolution; Reloaded; Artificial; Genes; Novel

EVOLUTION RELOADED: FROM ARTIFICIAL GENES TO NOVEL BIOLOGICAL FUNCTIONSIntellectual Merit of the Research Project: Nothing in biology makes sense except in the light of evolution, wrote Theodore Dobzhansky. Accordingly, scientists "make sense" of life by understanding biological traits from metabolism at the molecular level to behavior at the societal level in response to eons of selective pressure for enhanced survival. The diversity of life on earth was enabled by a myriad evolutionary trajectories emanating from starting points defined by ancestral sequences that existed billions of years ago. Might different trajectories have evolved if different ancestral sequences had been available? Until now this question could not be answered; collections of primordial sequences were not available for laboratory experimentation. Now however, novel genes and proteins are available. Sequences unbiased by billions of years of evolutionary history can be designed and constructed de novo. Such sequences provide a novel feedstock to restart evolution in the laboratory. Genes that never existed in nature, but which nonetheless encode biological functions that sustain life will enable experiments to assess whether (i) alternative progenitor sequences might lead to different evolutionary trajectories, and (ii) different molecular ancestors might produce fundamentally different progeny. The current project addresses these issues at the level of genes, proteins, genomes, and proteomes. The aims of this work include the following:(1) Discovery of novel sequences that do not resemble natural genes, but nonetheless enable cell growth. Life-sustaining functions will be passaged in both prokaryotic and eukaryotic cells.(2) Probing the functional promiscuity of novel proteins and delineate the extent to which unevolved sequences are multifunctional "generalists."(3) Determination of the biochemical and biophysical properties of novel proteins; and correlation of structural order with catalytic proficiency in sequences that have not benefited from selection.(4) Restart evolution by selecting novel sequences to further enhance microbial growth. Broader Impacts Resulting from the Research Activity: EDUCATION: Surveys indicate that nearly 50% of Americans do not accept evolution as the overarching theory that "makes sense" of life on earth. Evolution's detractors argue that because it is not possible to go back in time and actually observe evolutionary trajectories from ancestral progenitors to modern organisms, evolution must remain "only" a theory. Although evolution in vitro is now a standard technique for protein engineering in academic labs and biotechnology companies, skeptics argue that such studies rely on feedstocks of sequences provided by nature, and therefore provide only limited support for Darwinian theories about the origin and diversification of life on earth. The current project will provide the first example of laboratory studies demonstrating explicitly that (i) novel genes bearing no sequences resemblance to those from natural organisms can evolve to produce progeny that enhance the fitness of a host organism, and (ii) de novo rather than derived macromolecules can provide essential biological functions. Dissemination of these results will have a broad impact on science education and literacy. This study will provide also multiple research training opportunities for students at all levels and postdoctoral researchers. IMPACTS ON DIVERSITY AND OUTREACH: Woman and minorities play significant roles in this research, and numerous outreach activities are planned.BIOTECHNOLOGY: Current biotechnology relies on genes and proteins isolated (or modified) from natural sequences. Yet the number of sequences in natural genomes and proteomes is dwarfed by the possibilities in all of sequence space. This research project explores the functional potential of novel sequences, thereby laying foundations for new technologies in which novel proteins will be developed for specific applications.

进化重新加载：从人工基因到研究项目的新型生物学功能：除了进化外，生物学中的任何一个没有任何意义。因此，科学家通过理解从分子水平的新陈代谢到社会层面行为的生物学特征来“使生活变得有意义”，以响应选择性压力增强生存的选择。地球上生命的多样性是由从数十亿年前存在的祖先序列定义的起点源自的众多进化轨迹来实现的。如果有不同的祖先序列可用，不同的轨迹会进化吗？到目前为止，这个问题无法回答。原始序列的集合无法进行实验室实验。但是，现在可以使用新颖的基因和蛋白质。可以从头设计和建造数十亿年的进化历史的序列。这样的序列提供了一种新颖的原料，以重新启动实验室的进化。在自然界中从未存在的基因，但它编码维持生命的生物学功能将使实验能够评估（i）（i）（i）替代祖细胞序列是否可能导致不同的进化轨迹，（ii）不同的分子祖先可能会产生根本上不同的后代。当前的项目以基因，蛋白质，基因组和蛋白质组的水平解决了这些问题。这项工作的目的包括以下内容：（1）发现不像天然基因的新型序列，但仍可以启用细胞生长。 （2）探测新型蛋白质的功能杂交，并描述未发展的序列是多功能的“通才”。（3）确定新型蛋白质的生物化学和生物物理学特性的程度；结构顺序与尚未从选择中受益的序列催化能力的相关性。（4）通过选择新序列以进一步增强微生物生长来重新启动进化。 研究活动引起的更广泛的影响：教育：调查表明，近50％的美国人不接受进化作为“具有”地球生命的总体理论。 Evolution的批评者认为，由于无法及时回到祖先祖细胞到现代生物的进化轨迹，因此进化必须保持“仅”理论。尽管体外进化现在是学术实验室和生物技术公司蛋白质工程的标准技术，但怀疑论者认为，这种研究依赖于自然提供的序列的原料，因此仅提供对达尔文关于地球生命的起源和多元化的理论的有限支持。 当前的项目将提供实验室研究的第一个例子，表明（i）（i）具有与天然生物体的序列不相似的新型基因可以发展起来产生后代，从而增强宿主有机体的适应性，（ii）从头而不是衍生的巨粒分子可以提供基本的生物学功能。这些结果的传播将对科学教育和识字产生广泛的影响。这项研究还将为各级和博士后研究人员的学生提供多个研究培训机会。对多样性和外展的影响：妇女和少数民族在这项研究中起着重要作用，并计划了许多外展活动。生物技术：当前的生物技术依赖于从自然序​​列中分离（或修改）的基因和蛋白质。 然而，自然基因组和蛋白质组织中的序列数量与所有序列空间中的可能性相形见war。该研究项目探讨了新序列的功能潜力，从而为新技术的基础奠定了基础，其中将为特定应用开发新的蛋白质。