Collaborative Research: GCR: Understanding Epistasis: the Key for Genotype to Phenotype Mapping

这个不断增长的趋同研究项目旨在通过三个重叠的研究领域：分子进化、数据科学和统计物理学的融合，通过功能上位性来解释基因型-表型图谱的弹性。该项目的动机是通过基因、个体和物种的DNA测序揭示的种群、基因家族和系统发育群体中意想不到的数量变化。这些关于变异的大量数据对（几乎）中立的分子进化理论提出了意想不到的挑战，该理论通过随机遗传漂变和净化选择来解释群体中新突变的命运。研究团队将采用上位、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性的关键作用，并最终对生命最基本的规则进行质疑的关键。研究小组提出了一个跨学科项目，为分子进化的新中性上位理论奠定基础。该团队假设，绝大多数种群变异和物种差异是由于突变的随机遗传漂变，这些突变通过上位性是中性的，尽管每个突变都可能是有害的。新的上位性中立理论结合了中性和接近中性的分子进化理论，具有范式转变的潜力，其中位置之间的上位性相互作用，而不是任何单个位置，是比较分析的主要单位。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识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.