Fertility Relevance Probability Analysis Shortlists Genetic Markers for Male Fertility Impairment

Abstract

Impairment of male fertility is one of the major public health issues worldwide. Nevertheless, genetic causes of male sub- and infertility can often only be suspected due to the lack of reliable and easy-to-use routine tests. Yet, the development of a marker panel is complicated by the large quantity of potentially predictive markers. Actually, hundreds or even thousands of genes could have fertility relevance. Thus, a systematic method enabling a selection of the most predictive markers out of the many candidates is required. As a criterion for marker selection, we derived a gene-specific score, which we refer to as fertility relevance probability (FRP). For this purpose, we first categorized 2,753 testis-expressed genes as either candidate markers or non-candidates, according to phenotypes in male knockout mice. In a parallel approach, 2,502 genes were classified as candidate markers or non-candidates based on phenotypes in men. Subsequently, we conducted logistic regression analyses with evolutionary rates of genes (<i>dN</i>/<i>dS</i>), transcription levels in testis relative to other organs, and connectivity of the encoded proteins in a protein-protein interaction network as covariates. In confirmation of the procedure, FRP values showed the expected pattern, thus being overall higher in genes with known relevance for fertility than in their counterparts without corresponding evidence. In addition, higher FRP values corresponded with an increased dysregulation of protein abundance in spermatozoa of 37 men with normal and 38 men with impaired fertility. Present analyses resulted in a ranking of genes according to their probable predictive power as candidate markers for male fertility impairment. Thus, <i>AKAP4</i>, <i>TNP1</i>, <i>DAZL</i>, <i>BRDT</i>, <i>DMRT1</i>, <i>SPO11</i>, <i>ZPBP</i>, <i>HORMAD1</i>, and <i>SMC1B</i> are prime candidates toward a marker panel for male fertility impairment. Additional candidate markers are <i>DDX4</i>, <i>SHCBP1L</i>, <i>CCDC155</i>, <i>ODF1</i>, <i>DMRTB1</i>, <i>ASZ1</i>, <i>BOLL</i>, <i>FKBP6</i>, <i>SLC25A31</i>, <i>PRSS21</i>, and <i>RNF17</i>. FRP inference additionally provides clues for potential new markers, thereunder <i>TEX37</i> and <i>POU4F2</i>. The results of our logistic regression analyses are freely available at the PreFer Genes website (https://prefer-genes.uni-mainz.de/).