The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity

Almost half of the human genome consists of retrotransposons, ‘parasitic’ sequences that insert themselves into the host genome via an RNA intermediate. While most of these sequences are silenced or mutationally deactivated, they can present opportunities for evolutionary innovation: mutation of a deteriorating retrotransposon can result in a gene that provides a selective advantage to the host in a process termed domestication1–3. The PNMA family of gag-like capsid genes were domesticated from an ancient vertebrate retrotransposon of the Metaviridae clade at least 100 million years ago4,5. There are six full-length PNMA genes in humans and five in mice5. PNMA1-3 were originally identified as autoantigens that cause paraneoplastic neurological syndrome (PNS). PNMA4-6 were identified based on homology with PNMA1-3 but are not implicated in PNS6,7. We reasoned that the conservation of PNMA genes is unlikely to be based on their autoantigenic properties. While Pnma5 is implicated in oocyte development via an unknown mechanism8, little is known about the non-pathological roles of the other genes. PNMA1 and PNMA4 are positively regulated by the master germ cell transcription factors MYBL1 and STRA8, and their transcripts are bound by the translational regulator DAZL during gametogenesis9. This developmental regulation of PNMA1 and PNMA4 expression in gonadal tissue suggested to us that they might serve a reproductive function. Through the analysis of donated human ovaries, genome-wide association studies (GWAS), and genetic mouse models, we find that PNMA1 and PNMA4 are necessary for the maintenance of a normal reproductive lifespan. These proteins self-assemble into capsid-like structures that exit human cells, and we observed large PNMA4 particles in mouse male gonadal tissue that are consistent with capsid formation. Lysate was prepared from eight testes (collected at 3 months) from either wild type or control (lacking Pnma4) mice (3 biological replicates each). Lysate was fractionated by velocity (38,000 rpm, 3 hours) over a double sucrose cushion (25% and 70%). The 70% meniscus was further fractionated by isopycnic centrifugation on an iodixanol step gradient. PNMA4 was IPed from iodixanol fractions 8 and 9, RNA was extracted IP beads, and sequenced.