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

• Applicant: Professor Dr. Holger Herlyn
• Subject Area: Reproductive Medicine, Urology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246175694

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.

• DFG Programme: Research Grants