Collaborative Research: GCR: Functional Epistasis - the Key for Understanding the Rules of Life

这个不断增长的收敛研究项目正在寻求通过功能上位性来解释基因-表型图谱的弹性，通过三个重叠的研究领域的融合：分子进化、数据科学和统计物理。该项目的动机是通过对基因、个体和物种进行DNA测序，揭示了种群、基因家族和系统发育群体中意想不到的数量的变异。这些关于变异的海量数据正在对(几乎)中性的分子进化理论提出意想不到的挑战，该理论通过随机遗传漂移和净化选择来解释种群中新突变的命运。研究团队将采用上位论、共同进化过程和深度学习的机制模型。跨学科的深度整合将是探索上位的关键作用，并最终询问最基本的生活规则。研究小组提出了一个跨学科的项目，为分子进化的新的中性上位论奠定基础。该团队假设，绝大多数种群变异和物种差异是由于上位性中性突变的随机遗传漂移，即使每种突变都可能对个人有害。新的中性-上位性理论统一了中性和近中性的分子进化理论，并有可能实现范式转变，将位置之间的上位相互作用而不是任何个人位置作为比较分析的主要单位。这一奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Growing Convergence Research project is seeking to explain the resilience of genotype-phenotype maps through functional epistasis via a convergence of three overlapping fields of investigation: molecular evolution, data science and statistical physics. The project is motivated by an unanticipated amount of variation in populations, gene families, and phylogenetic groups revealed by DNA sequencing of genes, individuals, and species. These voluminous data on variation are posing unexpected challenges to the (nearly) neutral theory of molecular evolution that explains the fate of new mutations in a population through random genetic drift and purifying selection. The research team will employ mechanistic models of epistasis, co-evolutionary processes, and deep learning. Deep integration across disciplines will be key for exploring the pivotal role of epistasis and, ultimately, for interrogating the most fundamental rules of life. The research team proposes a transdisciplinary project to set the foundations for a novel neutral-by-epistasis theory of molecular evolution. This team hypothesizes that a vast majority of population variation and species differences are due to random genetic drift of mutations that are neutral by epistasis, even though each may be individually detrimental. The new neutral-by-epistasis theory unites both neutral and nearly-neutral theories of molecular evolution and has the potential for a paradigm shift in which epistatic interactions between positions, rather than any individual position are the primary unit of comparative analysis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.