Testis-Specific Y-Centric Protein-Protein Interaction Network Provides Clues to the Etiology of Severe Spermatogenic Failure

Pinpointing causal genes for spermatogenic failure (SpF) on the Y chromosome has been an ever daunting challenge with setbacks during the past decade. Since complex diseases result from the interaction of multiple genes and also display considerable missing heritability, network analysis is more likely to explicate an etiological molecular basis. We therefore took a network medicine approach by integrating interactome (protein-protein interaction (PPI)) and transcriptome data to reconstruct a Y-centric SpF network. Two sets of seed genes (Y genes and SpF-implicated genes (SIGs)) were used for network reconstruction. Since no PPI was observed among Y genes, we identified their common immediate interactors. Interestingly, 81% (N = 175) of these interactors not only interacted directly with SIGs, but also they were enriched for differentially expressed genes (89.6%; N = 43). The SpF network, formed mainly by the dys-regulated interactors and the two seed gene sets, comprised three modules enriched for ribosomal proteins and nuclear receptors for sex hormones. Ribosomal proteins generally showed significant dys-regulation with RPL39L, thought to be expressed at the onset of spermatogenesis, strongly down-regulated. This network is the first global PPI network pertaining to severe SpF and if experimentally validated on independent data sets can lead to more accurate diagnosis and potential fertility recovery of patients.