CAREER: Fluctuations and fitness - fundamental limits and selection conflicts

自然选择发生在生物组织的所有层面上。在较高级别，它有利于较低级别单位之间的合作，在较低级别，它有利于利用共同利益谋取自身利益的作弊者。在面临两个不同水平选择的大肠杆菌中，质粒的复制控制基因的相应分子机制得到了最好的表征：相对于细胞伙伴系统地过度复制的质粒拷贝在后代细胞中固定的机会较高，但这些细胞在群体中固定的机会通常较低。为了分析冲突，多尺度选择和细胞漂移的数学框架将被扩展，重点放在冲突抑制机制，自私的元控制，以及如何通过克隆干扰来阻止合作。此外，还将开发一个实验平台，以测试不同的条件如何选择利他主义或自私，并通过将产生的突变映射到已知的控制系统来监测冲突的动态。所有社会元素--从微生物到人类--都可以从合作和自私中受益，而最成功的行为取决于社会场景的参数。研究人员在细菌细胞中最简单、研究最充分的过程之一中发现了自私和利他主义因素之间的明显冲突：自我复制的DNA片段通过自私的过度繁殖获得直接优势，但随后却间接受到影响，因为它们给它们所依赖的细胞带来了更大的负担。由于这个系统的其他方面都得到了很好的研究，这为从分子机制和物理化学的角度严格分析合作等复杂现象提供了一个独特的机会。这类冲突的一般规则将通过数学推导和实验测试，确定利他主义行为的条件，并确定增强或抑制自私的机制。通过专注于可检验的定理和广泛的直觉原理，结果对教育和研究同样重要。

Natural selection occurs at all levels of biological organization. At higher levels it favors cooperation between lower-level units and at lower levels it favors cheaters that exploit the common good for their own interests. The corresponding molecular mechanisms are best characterized for the replication control genes of plasmids in Escherichia coli that face selection at two distinct levels: plasmid copies that systematically over-replicate relative to their cellmates have a higher chance of fixing in descendent cells, but these cells typically have a lower chance of fixing in the population. To analyze the conflict, the mathematical frameworks for multi-scale selection and drift in cells will be extended, focusing on conflict suppression mechanisms, meta-control of selfishness, and how cooperation is prevented by clonal interference. In addition, an experimental platform will be developed to test how different conditions select for altruism or selfishness, and monitor the dynamics of the conflict by mapping arising mutations to the known control systems. All social elements--from microorganisms to humans--can benefit from both cooperation and selfishness, and the most successful behavior depends on the parameters of the social scene. The investigators have identified a clean-cut conflict between selfish and altruistic elements in one of the simplest and best studied processes in bacterial cells: Self-replicating pieces of DNA get an immediate advantage by selfishly over-reproducing, but then instead indirectly suffer because they impose a larger burden on the cells upon which they rely. Because other aspects of this system are so well-studied, this provides a unique opportunity to rigorously analyze a complex phenomenon like cooperation in terms of molecular mechanisms and physical chemistry. General rules for such conflicts will be mathematically derived and experimentally tested, determining conditions for altruistic behavior and identifying mechanisms that enhance or suppress selfishness. By focusing on testable theorems and broad intuitive principles, the results are equally important for education and research.