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

合作研究：GCR：了解上位性：基因型到表型作图的关键

• 批准号: 1934848
• 负责人: Sudhir Kumar
• 金额: $ 320.22万
• 依托单位: Temple University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1934848&HistoricalAwards=false
• 关键词: Collaborative; Research; GCR; Understanding; Epistasis

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.

这个不断增长的融合研究项目正在寻求通过功能上位性来解释基因型-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组中的意外变化。 这些关于变异的大量数据对（几乎）中性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纯化选择来解释种群中新突变的命运。 研究团队将采用上位性、共同进化过程和深度学习的机械模型。 跨学科的深度整合将是探索上位论的关键作用的关键，最终也是质疑生命最基本规则的关键。该研究小组提出了一个跨学科的项目，为分子进化的新中性上位理论奠定基础。 该团队假设，绝大多数的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，即使每一种突变都可能是有害的。 新的中性上位论结合了中性和近中性的分子进化理论，并有可能实现范式转变，其中位置之间的上位相互作用，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NSF的法定使命，并被认为值得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来支持。

项目成果

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.

• DOI: 10.1371/journal.pcbi.1010006
• 发表时间: 2022-04
• 期刊: PLoS computational biology
• 影响因子: 4.3

An Evolutionary Portrait of the Progenitor SARS-CoV-2 and Its Dominant Offshoots in COVID-19 Pandemic.

• DOI: 10.1093/molbev/msab118
• 发表时间: 2021-07-29
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Kumar S;Tao Q;Weaver S;Sanderford M;Caraballo-Ortiz MA;Sharma S;Pond SLK;Miura S
• 通讯作者: Miura S

Insights into the energy landscapes of chromosome organization proteins from coevolutionary sequence variation and structural modeling

从共同进化序列变异和结构建模洞察染色体组织蛋白的能量景观

• DOI: 10.1073/pnas.1921727117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Levy, Ronald M.

Investigations of water/oxide interfaces by molecular dynamics simulations

• DOI: 10.1002/wcms.1537
• 发表时间: 2021-06
• 期刊: Wiley Interdisciplinary Reviews: Computational Molecular Science
• 作者: Ruiyu Wang;M. Klein;V. Carnevale;E. Borguet

Mi3-GPU: MCMC-based inverse Ising inference on GPUs for protein covariation analysis

• DOI: 10.1016/j.cpc.2020.107312
• 发表时间: 2021-01-06
• 期刊: COMPUTER PHYSICS COMMUNICATIONS
• 影响因子: 6.3
• 作者: Haldane, Allan;Levy, Ronald M.
• 通讯作者: Levy, Ronald M.