Bioinformatic prediction of sperm protein relevance and validation of the parameters network centrality and substitution rate in men and bulls

本项目的目的是评估网络中心性和替换率是否是推断蛋白质与精子功能相关的合适参数。在PPI网络中结合高中心性和低替换率的精子蛋白质将被认为是高度相关的。磷酸化和参与精子发生、精子成熟和精子组装将被视为增加功能相关性的支持性证据。反之亦然。分析将基于人类精子蛋白质组的PPI网络，使用自己的数据以及其他工作组公布的数据。我们将确定&gt；100精子蛋白的中心性水平和替换率，这些蛋白的功能和表达或变异已知与男性不育和不育有关。这些数据将与精子蛋白的中心性水平和替换率进行比较，目前已知的精子蛋白与男性生育力下降无关。编码DNA(六个哺乳动物物种的DNA)和关于序列进化的数据以及关于磷酸化状态和蛋白质功能的支持性数据将从公开的数据库中检索到。这些数据将允许评估与男性生育力降低有关的精子蛋白是否比在男性亚不育或不育中没有已知作用的精子蛋白更常被归类为高度必需的。此外，我们将调查PPI网络中的高重要性和低替换率是否适合作为预测人类和生活质量的生育标记的参数。因此，我们将检验被归类为高度必需的20种精子蛋白的编码单核苷酸多态(CSNPs)是否比被视为非必需的20种精子蛋白的cSNP更频繁地与男性(n=96)和公牛(n=100)的生育水平不同有关。这项研究的一个潜在的次要结果将是识别新的候选基因/蛋白质，用于a)畜牧业的遗传评估，b)男性生育力下降的诊断和治疗，以及c)男性免疫避孕药的开发。最后，我们将编写一个软件应用程序，允许使用网络中心性和替换率作为参数来自动评估精子蛋白质的重要性。从长远来看，这一应用将扩展到不同器官、组织和细胞类型的蛋白质。该应用程序将通过网络服务器向公众开放。所有数据、分析和结论都将发表在国际期刊上。

The aim of the present project is to evaluate if network-centrality and substitution rates are suitable parameters to infer the relevance of a protein for sperm functioning. Sperm proteins that combine high centrality in PPI networks with low substitution rates will be regarded as highly relevant. Phosphorylation and involvement in spermatogenesis, sperm maturation and sperm assembly will be taken as supportive evidence for increased functional relevance. Less relevant sperm proteins are defined vice versa.Analyses will be based on a PPI network of the human sperm proteome using own data as well as published data of other working groups. We will determine centrality levels and substitution rates of > 100 sperm proteins whose function and expression or variants are known to associate with sub- and infertility in men. These data will be compared with centrality levels and substitution rates of > 100 sperm proteins without, so far known, involvement in reduced fertility in men. Coding DNAs (cDNAs of six mammalian species) and data on sequence evolution as well as supportive data on phosphorylation status and protein function will be retrieved from publicly available databases. These data will allow for an assessment if sperm proteins involved in reduced male fertility are more frequently classified as highly essential than the sperm proteins without a known role in male sub- or infertility. Additionally, we will investigate if high essentiality in PPI network and low substitution rates are suitable parameters to predict fertility markers in humans and lifestock. Therefore, we will examine if coding single nucleotide polymorphisms (cSNPs) of 20 sperm proteins categorized as highly essential associate more frequently with differential fertility levels in men (n = 96) and bulls (n = 100) than cSNPs of 20 sperm proteins regarded as less essential. A potential secondary outcome of the study will be the identification of new candidate genes/proteins for a) genetic evaluations in animal husbandry, b) diagnosis and therapy of reduced male fertility and c) development of immunocontraceptives for men.Finally, we will write a software application that will allow for an automated assessment of sperm protein essentiality employing network-centrality and substitution rates as parameters. In the long run the application will be extended to proteins of diverse organs, tissues and cell types. The application will be made available to the public via a web-server. All data, analyses, and conclusions will be published in international journals.