A comprehensive annotation of conserved protein domains in human endogenous retroviruses

Human endogenous retroviruses (HERVs) occupy nearly 8% of the human genome, yet their protein-coding potential remains largely unexplored. Originating from ancestral retroviruses that infected germline cells, HERVs typically follow the canonical proviral structure LTR–gag–pol–env–LTR, where gag, pol, and env encode structural, enzymatic, and envelope proteins. We present a comprehensive resource annotating conserved retroviral domains across 120 000 + ORFs derived from internal HERV regions. Using a reproducible pipeline based on HMMER and InterProScan, we identified over 17 000 domain hits—primarily from pol genes such as reverse transcriptase, RNase H, and protease—and quantified their structural conservation. Hundreds of domains exceed 95% alignment coverage, revealing a surprising abundance of full-length retrovirus-like domains in both young and ancient families. The HERVK (HML-2) subfamily retains the most complete polyprotein architecture, including 13 loci with nearly intact Gag, Pol, and Env, but full-length Pol domains are also found in HERVH, HERVW, and HERVE. Our annotations recover conserved catalytic motifs in Pol and transmembrane features in Env, enabling fine-grained functional interpretation. All results—including BED, FASTA, domain sequences, InterProScan outputs, and transmembrane predictions—are provided as an open resource at Zenodo to support downstream analyses of HERV protein expression, immune modulation, and co-option in health and disease.