Inferring the gene coevolution network from deep comparative genomics

缺失或受损的基因对拥有它的生物体是有害的，这并不奇怪。更令人惊讶的是，拥有额外的基因拷贝也可能是有害的，就像唐氏综合症的情况一样，额外的、未受损的21号染色体拷贝导致了综合症的症状。遗传学家认为，这些额外的基因是有害的，因为它们编码的蛋白质需要与其他染色体上的基因合成的蛋白质协同工作。如果这些相互作用的蛋白质彼此之间的数量不正确，它们就会破坏细胞活动。不幸的是，没有一个简单的实验可以确定所有需要相互平衡的基因对。然而，奇怪的是，也有一些细胞的细胞中有完整的额外的基因组拷贝，拥有的不是两个，而是四个或更多的拷贝。尽管有额外的拷贝，这些多倍体细胞是健康的，可以在许多形式的生命中找到。事实上，在进化过程中，包括脊椎动物和所有开花植物在内的几个重要生物群体都经历了这种多倍体事件，并将由此产生的额外基因传给了后代。但重要的是，并不是所有额外的（或复制的）基因都被保留下来。因此，多倍体发生后基因丢失和存活的模式可以用来识别彼此之间有剂量相互作用的基因对。换句话说，通过研究许多不同基因组的多倍体后的进化，将有可能确定像唐氏综合症这样的相互作用驱动效应，并阐明一般的基因相互作用。该项目将使用由研究人员开发的进化建模软件来分析十多个独立多倍体后重复基因的丢失和保留。研究小组将通过增加多倍体模型的能力来改进这个工具，这些多倍体发生在其他多倍体的“顶部”。然后，利用60多个个体基因组，研究人员将推断出一个基因网络，这些基因之间的联系代表了剂量的相互作用。在这个框架中，相互作用的基因对将是那些拷贝数差异在进化上代价高昂的基因对。有了这个网络，研究人员将利用现有的大规模数据集来研究蛋白质之间的物理相互作用、基因之间的调节连接和其他生化信息，以理解为什么某些基因对需要保持相似的拷贝数才能正常工作。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。

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.