Abstract
Germ cells provide the cellular basis for sexual reproduction in multicellular animals. In males, germ cells differentiate into sperm, one of the most morphologically diverse eukaryotic cell types. Owing both to this remarkable diversity and to the rapid evolution of reproduction-related genes, the transcriptional program of male germ cells is widely regarded as divergent across species1,2. However, the possibility that these cells retain a distinctive evolutionarily-conserved genetic basis remains largely unexplored. Here we show, using phylostratigraphy, that the complex male germ cell transcriptome has an old evolutionary origin shared between vertebrate and invertebrate species. Through multilayer network analysis of the human, mouse and fruit fly meiotic transcriptome, we establish that old genes serve as a genetic scaffold from which complexity has evolved, and identify a core set of 79 ancient functional interactions at the heart of male germ cell identity. By silencing a cohort of 920 candidate genes likely to affect the acquisition and maintenance of this identity, we uncover 164 previously unknown spermatogenesis genes. Integrating this information with whole-exome sequencing data from azoospermic men reveals three novel genetic causes of human male infertility shared between species that have diverged for more than 600 million years. Our results redefine the importance of evolutionary history on human reproductive disease and illustrate the translational potential of a new synergy between comparative network biology and medical genetics. We anticipate that our open-access and easily-adaptable interdisciplinary research platform will be harnessed in the context of other cell types and diseases.
Competing Interest Statement
The authors have declared no competing interest.
