A Compendium of ERVs in the Genomes of Major Primates

Summary

ERVs integrate into host DNA, forming vertically inherited proviral sequences. These sequences not only record the historical imprints of ancient retroviruses but also play significant biological roles in modern host genomes. The widespread distribution of ERVs in primate genomes suggests that constructing a unified system for ERV site distribution would facilitate the study of their impact on host genomic biology and evolution. In this study, we utilized LTR_harvest to predict candidate ERV sequences in primate genomes and further identified and annotated the characteristics of these candidate sequences using LTR_digest software. We have compiled a comprehensive and well-annotated database (http://ervsdb.omics.henbio.com/home/index/index.html?idx=1). This database enables the acquisition of ERV data and corresponding neighboring genes for 61 primate species, characterization of ERV proviral structures, assessment of integration sites, and prediction of potential regulatory gene functions associated with ERV-LTRs. Using Trachypithecus francoisi as an example, we have preliminarily explored the potential influence of ERVs on host resistance or susceptibility to diseases, providing a theoretical reference for further research on ERVs in other animals.

Keywords

Primates; ERVs; Trachypithecus francoisi

Introduction

ERVs are special genetic elements that represent the remnants of ancient interactions between retroviruses and vertebrates, which have been preserved in host genomes and are vertically transmitted through Mendelian inheritance mechanisms

¹

. These viral remnants are widely present in the genomes of various species, including mammals, birds, reptiles, and amphibians, exhibiting distinct distribution and expression patterns across different species

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.To date, approximately 43 viral families have been identified in eukaryotes that have formed endogenous relationships with their hosts. ERVs serve as important tools for studying the co-evolution of hosts and retroviruses, providing a genomic perspective on the roles of infection and immunity in the evolutionary history of retroviruses

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Throughout their evolutionary history, ERVs have undergone a series of events such as replication, recombination, mutation, and insertion, leading to a diversity in their sequence quantity, distribution, and expression patterns within host genomes

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.For instance, a solo-LTR arises from homologous recombination between the 5' and 3' LTRs of ancestral viruses, with the intervening protein-coding sequences being deleted

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.ERVs that contain the three major protein-coding domains of retroviruses—gag, pol, and env—are defined as complete ERVs

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.In fact, at least 85% of ERVs exist in reference genomes as isolated LTRs

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.ERVs are classified into three major categories based on differences in their reverse transcriptase polymerase, ranging from Class I (gamma-like retroviruses) to Class III (spumaretrovirinae), and extending to the more diverse Class 16, encompassing a wide range of ERV sequence diversity

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The regulatory sequences provided by ERVs play a crucial role in altering genetic networks, cellular functions, and gene regulation. Studies have shown that RNA, cDNA, and protein products encoded by ERVs are closely associated with the occurrence of various diseases, including cancer, aging, chronic inflammation, and neurological disorders

^8,

^9,

^10,

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.Given the importance of primates in medical research, exploring their genomics and epigenomics is particularly critical, as primate genomics is a golden key to understanding the fundamental aspects of human evolution and disease

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.The genetic, neuroanatomical, physiological, and immunological similarities between primates and humans make them ideal preclinical models

^13,

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. Therefore, computational identification of transposable elements, especially ERVs, has become an urgent need. With the advancement of high-throughput sequencing technologies, we have the opportunity to deeply explore the distribution and activity of these ancient viral remnants in primate genomes. Our goal is to map the landscape of ERVs in primates. Through this information, we can more accurately assess the extent of ERV invasion and replication in the genome, as well as their potential impacts on the structure and function of the host genome.

Our research also focuses on the biological functions of ERV-encoded products, including investigating potential gene fusions between ERVs and host genes, and how these fusion events regulate the expression of host genes, affect cellular functions, and contribute to disease development. By analyzing ERV expression data and their interactions with host genes, we can better understand the new roles that these ancient viral remnants play in modern organisms. These findings not only help us comprehend the evolutionary history of ERVs but may also reveal their potential impacts on human health and disease, providing new insights for future medical research and therapeutic strategies.

Materials and Methods

Results

Discussion

In the vast field of life sciences, ERVs, as ancient and enigmatic components of the genome, have consistently been a focal point of research. They are not only key players in genome evolution but may also profoundly influence the physiological and pathological processes of their hosts. This study employs bioinformatics methods to thoroughly investigate the distribution of ERVs across the entire genome in major primate species.

Previous studies on ERVs in primate genomes have revealed the following findings: 425 full-length ERVs containing reverse transcriptase (RT) sequences were identified in the gorilla genome

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, 284 ERVs were detected in the golden snub-nosed monkey (Rhinopithecus roxellana), with 85 structurally intact; the black snub-nosed monkey (Rhinopithecus bieti) harbored 56 intact ERVs; while the François' langur (Trachypithecus francoisi) exhibited 160 structurally complete ERVs, accounting for 40% of its total ERV content

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.Concurrently, ERVs constitute approximately 8% of the human genome

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and about 10% in mice. However, discrepancies exist between these findings and the results of the present study, which may be attributed to methodological variations and parameter settings across different studies. In previous research, gorilla ERVs were identified using LTR_struc combined with BLAST alignment of conserved RT sequences, whereas ERVs in golden snub-nosed monkeys, black snub-nosed monkeys, and François' langurs were screened through BLAST analysis using gibbon leukemia virus gag and env sequences as probes, followed by RetroTecter software validation. In contrast, our study employed LTR_harvest for candidate ERV prediction and performed comprehensive sequence characterization and annotation using LTR_digest, enabling a more systematic and exhaustive screening and analysis of ERVs across genomes.

The study revealed that ERVs are classified into intact and various fragmented types based on their canonical structural features (5' LTR-gag-pol-env-3' LTR), exhibiting significant distribution disparities across primate genomes. The François' langur (Trachypithecus francoisi) displayed the highest ERV content at 14.2%, whereas the siamang (Symphalangus syndactylus) genome contained the lowest proportion at merely 2.78%. This divergence likely stems from the combined effects of evolutionary history, genome size and complexity, ecological pressures, and genetic variation, collectively driving heterogeneous patterns of ERV insertion, deletion, rearrangement, and population distribution

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.Notably, ERVs predominantly exist in fragmented forms among primates, with solo-LTRs constituting the primary remnants, while pol genes remain most prevalent. The pol gene, encoding reverse transcriptase and integrase—core components for ERV replication and genomic integration—suggests these fragmented sequences may retain residual functionality or regulatory potential within host genomes

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.Conversely, the widespread loss of env genes correlates with their distinct evolutionary fate and potential detrimental impacts on both ERVs and hosts. Further analysis demonstrated that most ERVs in François' langur genomes are incomplete, with env gene absence correlating with a 30-fold increase in ERV proliferation rates, rendering them genomic super-spreaders. Additionally, the potential immunosuppressive properties of Env proteins may disadvantage both ERVs and hosts, leading to gradual evolutionary devaluation and subsequent loss of env gene functionality through natural selection.

From a geographic distribution perspective, Old World monkeys and New World monkeys—separated by continental drift—exhibit distinct ERV sequence divergence. However, the similarity between human ERV sequences and those of Old World monkeys, particularly in terms of quantity and structural integrity, supports their shared ancestral origin. In this study, we conducted detailed classification of ERVs within the François' langur genome, revealing their predominant classification into Class I and Class II ERVs, with balanced numerical distribution between these two categories. Notably, while Cui et al. identified 412 foamy viruses (Class III) representing six distinct lineages in amphibians—demonstrating their broad distribution in certain species—our analysis failed to detect Class III sequences in François' langurs, suggesting either extreme rarity or complete absence of foamy viruses in this species

^25,

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.Different ERV classes exhibit distinct amplification and retention mechanisms during evolution, potentially explaining their variable genomic abundance, distribution patterns, and evolutionary trajectories.

Research indicates that ERV LTRs frequently demonstrate promoter or enhancer activity, functioning as cis-regulatory elements to modulate host gene expression near integration sites. Wang et al. demonstrated that p53 binding sites within HERV LTRs regulate host gene expression, with over one-third of p53 binding sites originating from ERV LTRs

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.Furthermore, ERV-host gene fusion events can alter transcriptional regulation, exemplified by ERV9 insertions upstream of human TP63 that enhance specific p63 isoform expression—a critical mechanism for germline stability

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.Among the 358 protein-coding genes potentially fused with intact ERVs in François' langurs, enriched signaling pathways suggest that ERVs may significantly influence host gene expression through either fusion events or cis-regulatory mechanisms. These interactions likely participate in regulating fundamental cellular processes, environmental adaptation, disease pathogenesis, and complex behavioral modulation in the host species.Taking immune-related genes as an example, the NF-κB binding sites within ERV-LTRs can bidirectionally regulate the expression of TLR5 (the bacterial flagellin receptor), PGLYRP4 (a peptidoglycan recognition protein), and BRCA2 (a core factor in homologous recombination repair), providing a testable molecular model for "ERV-immune co-evolution".

ERVsDb compiles the first comprehensive atlas of endogenous retroviruses (ERVs) across 61 primate species, couples deep annotation of adjacent genes with data-driven prediction of ERV activation potential, and delivers all analyses through a zero-code interface—thereby closing a long-standing gap for a dedicated, systematic yet user-friendly resource. By systematically mining the regulatory power of long terminal repeats (LTRs), the database converts ERVs from “fossil sequences” into “functional elements”. Each ERV is assigned a quantifiable and experimentally addressable identity, propelling the field from descriptive correlation to mechanistic validation and providing a sustainable, expandable data foundation for deciphering how ERVs continuously reshape primate genome evolution, immune networks and disease susceptibility.

Authors’contributions

YFL, CLJ and LXL designed the research and provided relevant knowledge; ZNZ, YLH download the required data; ZWL, YJH generated the Figures and tables; BYL wrote and edited the manuscript. All of the authors read and approved the final manuscript.

Data and Code Availability

The primate genomic data used in this project were obtained from the public database NCBI, the analysis code is provided within the main text, and the database information is publicly accessible free of charge.

Funding

This work is supported by the Natural Science Foundation(2025KY0127).

Acknowledgments

The authors express their gratitude to the data providers and to all participants in this study.

Ethics Statement

It is not applicable.

Consent for publication

It is not applicable.

Competing interests

All authors declared no competing interests.

References