Inferring the gene coevolution network from deep comparative genomics

从深度比较基因组学推断基因协同进化网络

• 批准号: 2241312
• 负责人: Gavin Conant
• 金额: $ 49.96万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2241312&HistoricalAwards=false
• 关键词: Inferring; gene; coevolution; network; deep

It is not surprising that a missing or damaged gene can be detrimental to the organism possessing it. It is more surprising that having extra copies of genes can also be harmful, as is the case with Down syndrome, where an extra, undamaged, copy of chromosome 21 is responsible for the syndrome’s symptoms. Geneticists believe that these extra genes are harmful because they encode proteins that need to work in concert with the proteins made by genes on other chromosomes. If these interacting proteins are not present in the correct numbers relative to each other, they can disrupt cellular activities. Unfortunately, no simple experiments can identify all the pairs of genes that need to work in balance with each other. Curiously however, there are also cells that have entire extra copies of the genome in their cells, possessing not two but four or more copies. Despite the extra copies, these polyploid cells are healthy and can be found in many forms of life. In fact, over evolutionary time, several important groups of organisms, including the vertebrates and all flowering plants, have undergone such polyploidy events and transmitted the resulting extra genes to their descendants. Importantly though, not all of the extra (or duplicated) genes are kept. As a result, the patterns of gene loss and survival seen after a polyploidy can be used to identify the pairs of genes that have dosage interactions with each other. In other words, by studying evolution after polyploidy across many different genomes, it will be possible to identify the interactions driving effects like those of Down syndrome, and to shed light on gene interactions in general.This project will use evolutionary modeling software developed by the investigators to analyze duplicate gene loss and retention after more than a dozen independent polyploidies. The team will improve this tool by adding the capacity to model polyploidies that occurred “on top of” other polyploidies. Then, using more than 60 individual genomes, the investigators will infer a network of genes where the connections between those genes represent dosage interactions. In this framework, pairs of interacting genes will be those for which differences in copy number between the pair is evolutionarily costly. With the network in hand, the researchers will use existing large-scale datasets on physical interactions between proteins, regulatory connections between genes and other biochemical information to understand why certain pairs of genes need to be maintained in similar copy number in order to function correctly.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.

毫不奇怪的是，缺失或受损的基因可能对拥有的生物有害。更令人惊讶的是，拥有额外的基因副本也可能是有害的，就像唐氏综合症一样，在唐氏综合症中，额外的未切割，染色体21染色体的副本负责综合征的症状。遗传学家认为这些额外的基因是有害的，因为它们编码需要与基因在其他染色体上产生的蛋白质一起工作的蛋白质。如果这些相互作用的蛋白质不存在于彼此相对于正确的数字，它们可能会破坏细胞活性。不幸的是，没有一个简单的实验可以识别所有需要彼此平衡的基因对。然而，奇怪的是，也有一些细胞在其细胞中具有全部额外的基因组副本，而不是两个或更多的副本。尽管有额外的副本，但这些多倍体细胞仍然健康，可以在多种形式的生活中找到。实际上，在进化时期，包括脊椎动物和所有开花植物在内的几个重要的生物群已经发生了这种多倍事件，并将所得的额外基因传播到其后代。但是，重要的是，并非所有额外的（或重复）基因都保留。结果，可以使用多倍体后观察到的基因丧失和生存模式来识别彼此相互作用的基因对。换句话说，通过研究多倍体在许多不同基因组上的进化，可以鉴定驱动驱动效应（如唐氏综合症的相互作用），并阐明一般的基因相互作用。该项目将使用研究人员开发的进化建模软件来分析多Zen独立的多倍型的重复基因丧失和重复。该团队将通过增加“在”其他多倍体上的多倍体建模的多倍体来改善此工具。然后，使用60多个基因组，研究人员将推断一个基因网络，其中这些基因之间的连接代表剂量相互作用。在此框架中，相互作用的基因将是对两对拷贝数差异的差异在进化上昂贵的。借助网络，研究人员将使用现有的大规模数据集进行蛋白质之间的物理相互作用，基因与其他生化信息之间的监管连接，以了解为什么需要在相似的副本中维持某些基因以正确运行以正确运行。该奖项颁发了NSF的法定任务，反映了通过评估的概念来评估众所周知的支持者。