Endogenous retrovirus sequences can be transcriptionally active: the reality vs. the hype

A recent paper on characterizing endogenous retrovirus sequences has attracted some attention because of a press release from Kyoto University that focused on refuting junk DNA. But it turns out that there's no mention of junk DNA in the published paper.

Let's start with a little background. Retroviruses are RNA viruses that go though a stage where their RNA genomes are copied into DNA by reverse transcriptase. The virus may integrate into the host genome and be carried along for many generations producing low levels of virus particles [Retrotransposons/Endogenous Retroviruses]. The integrated copies are called endogenous retroviruses (ERVs).

Our genome contains about 31 different families of ERVS that have integrated over millions of years. Most of the original virus genomes have acquired mutations, including insertions and deletions, and they are no longer active. These sequences account for about 8% of our genome.

Retroviruses contain a strong promoter at the 5′ end in a region called a long terminal repeat (LTR). These promoters can still be quite active in the human genome unless they have acquired silencing mutations. This causes spurious transcription of what's left of the original retrovirus or adjacent genomic DNA.

Most of the LTR fragments in our genome come from much more abundant transposon-related sequences but ERVs make a substantial contribution. This means that there are thousands of sites in the human genome where degenerate LTRs are still capable of promoting transcription and this is a major source of pervasive transcription.

The LTR promoters will have many of the characteristics of functional regulatory sites including the presence of chromatin markers such as modified histones and lack of methylation. In a small number of cases, these promoter regions have become co-opted as genuine regulatory sites in the human genome but the vast majority are not associated with the regulation of any human genes.

Unfortunately, most of the papers in the scientific literature do not distinguish between functional regulatory sites and fossil ones derived from ERVs and transposons—they are all called "regulatory sites" even if they don't actually regulate any genes. [Endogenous retroviruses and junk DNA]

Now let's get to a paper published on July 18,2025 in the journal Science Advances

Chen, X., Zhang, Z., Yan, Y., Goubert, C., Bourque, G. and Inoue, F. (2025) A phylogenetic approach uncovers cryptic endogenous retrovirus subfamilies in the primate lineage. Science Advances 11:eads9164. [doi: 10.1126/sciadv.ads9164]

Current approaches for classifying and annotating endogenous retroviruses (ERVs) and their long terminal repeats (LTRs) have limited resolution and are inaccurate. Here, we developed an annotation approach based on phylogenetic analysis and cross-species conservation. Focusing on the evolutionarily young LTR subfamilies known as MER11A/B/C, we revealed the presence of four “new subfamilies,” suggesting a new annotation for 412 (19.8%) of these repeat elements. We then validated their regulatory potential using a massively parallel reporter assay. We further identified motifs associated with their differential activities including an ape-specific gain of SOX-related motifs through a single-nucleotide deletion. By applying our approach across 53 simian-enriched LTR subfamilies, we defined 75 new subfamilies and found a novel annotation for a total of 3807 (30.0%) instances from 26 subfamilies. With this refined annotation of simian-enriched LTRs, it will be possible to better understand the evolution in primate genomes and potentially identify critical roles for ERVs and their LTRs in the hosts.

This is a complicated paper full of details and retrovirus jargon. It's not of much interest to the average person unless you are passionate about the various MER11 subfamilies or the number of degenerate LTRs that retain the characteristics of retrovirus promoters. The authors isolated many of the promoter regions and showed that they still retain promoter activity in a reporter gene assay but this is not surprising.

It's unfortunate that the authors refer to all of these sites as regulatory sites and note that they are active in some tissues. It's not clear whether they think of these as true regulatory sites that have a biological function or whether they recognize that many of them are nonfunctional. There's no discussion of spurious transcription or junk DNA/RNA.

Now let's look a how the work is covered in the popular press based on a press release from Kyoto University.

New study reveals hidden regulatory roles of ‘junk’ DNA

A new international study suggests that what was once dismissed as “junk DNA” may actually play a crucial role in regulating gene expression....

'Junk DNA' is not actually junk, it's found to play a powerful role in the human body

For decades, scientists regarded large portions of our DNA as genetic junk – useless remnants of ancient viruses that invaded our ancestors’ genomes. These segments, known as transposable elements (TEs), were long dismissed as evolutionary fossils with no present-day function....

However, a new international study challenges the view that ancient viral DNA in our genome is useless. Researchers from Japan, China, Canada, and the US focused on a DNA family called MER11. These sequences influence when and where genes turn on, especially during early human development.

Study reveals hidden regulatory roles of 'junk' DNA

A new international study suggests that ancient viral DNA embedded in our genome, which were long dismissed as genetic "junk," may actually play powerful roles in regulating gene expression. Focusing on a family of sequences called MER11, researchers from Japan, China, Canada, and the US have shown that these elements have evolved to influence how genes turn on and off, particularly in early human development....

We really need to put a stop to this kind of ridiculous hype. It's contributing to the spread of misinformation and the mistrust of science. I've addressed this issue before where I quoted Stuart Ritchie from his book Science Fictions. [University press releases are a major source of science misinformation]

In an age of 'churnalism', where time-pressed journalists often simply repeat the content of press releases in their articles (science news reports are often worded vitrually identically to a press release), scientists have a great deal of power—and a great deal of responsibility. The constraints of peer review, lax as they might be, aren't present at all when engaging with the media, and scientists' biases about the importance of their results can emerge unchecked. Frustratingly, once the hype bubble has been inflated by a press release, it's difficult to burst.

There's no easy solution but I did repeat a suggestion in that earlier post.

Press releases of all sorts are failing us but university press releases are the most disappointing because we expect universities to be credible sources of information. It's obvious that scientists have to accept the blame for deliberately distorting their findings but surely the information offices at universities are also at fault? I once suggested that every press release has to include a statement, signed by the scientists, saying that the press release accurately reports the results and conclusions that are in the published article and does not contain any additional information or speculation that has not passed peer review.

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