# Veterinary Herpesviruses: Experimental Tools for Transcriptomics and Neuroscience

## TL;DR

Veterinary herpesviruses are used as models to study gene complexity and brain connectivity, revealing new insights into transcriptomics and neuroscience.

## Contribution

The paper highlights how veterinary herpesviruses have advanced transcriptomics and neuroscience through long-read sequencing and neural tracing.

## Key findings

- Long-read sequencing revealed extensive gene message overlaps and diverse transcript isoforms in veterinary herpesviruses.
- Pseudorabies virus is used as a tool to map brain circuits and study neural network function.
- Veterinary herpesvirus datasets have improved transcript annotation practices in mammalian genomics.

## Abstract

This review provides an overview of how veterinary herpesviruses—pseudorabies virus of pigs, equine herpesvirus of horses, bovine herpesvirus of cattle, and caviid gammaherpesvirus of guinea pigs—have become powerful research models that advanced two major areas of science. Using a technology called long-read sequencing, which can read complete gene messages from start to stop, scientists discovered that these messages overlap with each other far more extensively than previously known, and that each gene produces many more message variants than expected. These discoveries revealed fundamental principles of how genes are controlled—principles that extend beyond viruses to eukaryotic genomes, including our own. They can also benefit both human and veterinary medicine by providing insights applicable to a broad range of pathogens. Additionally, pseudorabies virus has been repurposed as an essential neurological research tool. Its ability to travel between connected nerve cells makes it uniquely suited for mapping brain circuits, helping scientists visualize brain connectivity with unprecedented precision. Importantly, the virus can also be engineered to carry activity sensors into the brain, allowing direct recording of not only the physical connections between neurons but also their electrical activity—enabling simultaneous study of both the anatomy and the function of neural networks.

Here we discuss three veterinary alphaherpesviruses—pseudorabies virus, equid alphaherpesvirus 1, and bovine alphaherpesvirus 1—that were instrumental in uncovering the true extent of transcriptome complexity through long-read RNA sequencing, which earlier short-read approaches could not resolve. We focus on three major transcriptomic features whose discovery and characterization relied heavily on these viral models: (i) widespread transcriptional overlaps that complicate read assignment and may drive transcriptional interference; (ii) diverse transcript isoforms arising from alternative 5′ and 3′ transcript termini, as well as splicing; and (iii) non-coding RNAs clustered near replication origins that illuminate potential replication–transcription interactions on a shared nuclear template. Long-read viromics in these veterinary systems has additionally served as a stringent benchmark for transcript callers and annotation pipelines, because the extreme density of overlaps and co-terminal transcript families exposes errors that often go unnoticed in typical mammalian transcriptomes. This has made veterinary herpesvirus datasets disproportionately influential in shaping best practices for full-length isoform calling, transcript end mapping, and artifact-robust cDNA library handling. We also discuss animal gammaherpesviruses as proxies for human gammaherpesviruses, allowing experimental investigation of viral programs difficult to study in human infection. Finally, we describe pseudorabies virus applications as a retrograde transneuronal tracer.