Origination of LTR Retroelement–Derived NYNRIN Coincides with Therian Placental Emergence

Abstract

The emergence of the placenta is a revolutionary event in the evolution of therian mammals, to which some LTR retroelement-derived genes, such as PEG10, RTL1, and syncytin, are known to contribute. However, therian genomes contain many more LTR retroelement-derived genes that may also have contributed to placental evolution. We conducted large-scale evolutionary genomic and transcriptomic analyses to comprehensively search for LTR retroelement-derived genes whose origination coincided with therian placental emergence and that became consistently expressed in therian placentae. We identified NYNRIN as another Ty3/Gypsy LTR retroelement-derived gene likely to contribute to placental emergence in the therian stem lineage. NYNRIN knockdown inhibited the invasion of HTR8/SVneo invasive-type trophoblasts, whereas the knockdown of its non-retroelement-derived homolog KHNYN did not. Functional enrichment analyses suggested that NYNRIN modulates trophoblast invasion by regulating epithelial-mesenchymal transition and extracellular matrix remodeling and that the ubiquitin-proteasome system is responsible for the functional differences between NYNRIN and KHNYN. These findings extend our knowledge of the roles of LTR retroelement-derived genes in the evolution of therian mammals.

A Nuclear Export Signal in KHNYN Required for Its Antiviral Activity Evolved as ZAP Emerged in Tetrapods

“…However, while N4BP1 orthologs are present in birds, KHNYN orthologs are not, suggesting that it has been lost in this lineage. NYNRIN originated as a fusion between KHNYN and a Ty3/Gypsy pol gene in the therian stem lineage and is present in most marsupials and placental mammals ( 24 ). Because it emerged much later than ZAP in tetrapod evolution, we have not considered it further in this study.…”

“…It has 2 human paralogs, NYNRIN and N4BP1. NYNRIN evolved from a KHNYN gene duplication in which the RNase H and integrase domains from an endogenous retrovirus replaced the last exon of KHNYN and it has been suggested to play a role in the regulation of placental development ( 23 , 24 ). N4BP1 is a predominantly nucleolar protein whose expression is induced by type I interferon ( 9 , 25 – 28 ).…”

Birth of protein-coding exons by ancient domestication of LINE retrotransposon

“…The gag genes encoding virus-like capsid proteins of long terminal repeat (LTR) retrotransposons are also co-opted as host genes: ARC for synaptic plasticity (5, 6), Peg10 and Rtl1 for placenta formation (7, 8), and PNMA2 expressed in neurons and related with autoimmune diseases (9). Other examples include ASPRV1/SASPase , derived from a retroviral protease involved in the protease activity for mammalian skin formation (10); NYNRIN , derived from integrase and contributing to placentation (11); and RTOM family, derived from reverse transcriptase in monotremes (12). DNA transposons are also sources of multiple lineage-specific proteins.…”