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The Ancient Viruses Lurking in our Genome

Gayathri Chandran
BSc Life Sciences
Sophia College for Women

For the past few months, most of us have been stuck at home and spent our time collectively hating the very existence of viruses. It is easy to do so, considering the intensity with which the Covid-19 pandemic has taken over our lives. However, what if we ourselves are, in part, viruses?! This statement is not far-fetched, particularly when we consider the facts we know so far. The Human Genome Project revealed that merely 1-2% of our genome consisted of genes, on the other hand, it is known that 5-8% of our genome consists of viruses! These viruses which have been sewn into our genome after they infected our ancestors are referred to as human endogenous retroviruses

Retroviruses are RNA viruses which integrate into the host genome using an enzyme called reverse transcriptase, to translate its RNA genome into DNA. When the germline of the host is infected, the integrated retroviral elements are inherited in a Mendelian fashion. In very simple terms- HERVs are acquired from past infections caused by exogenous retroviruses which had affected the germ cells. They have the same structure as exogenous retroviruses (shown below).

Generally, the expression of these viruses is very tightly regulated. Most HERVs in the genome have accumulated mutations over the years which prevent their retrotransposition in the cell and they are further silenced by epigenetic mechanisms (such as DNA methylation). This ensures that they are
transcriptionally silent. However, evidence has showed that there are certain HERVs families which are highly transcriptionally active in healthy human tissues. Uncontrolled activation of these retroviral elements could cause diseases, right from autoimmune diseases to schizophrenia, and thus, they have garnered significant interest over the years.

Various HERV env genes (envelope genes forming the viral envelope) exist such as HERV-K, HERVH etc. In breast cancer patients, higher levels of the mRNAs of these genes have been seen. Similarly, the overexpression of HERV proteins has been reported in cancer tissues. For example, the expression of the HERV-K Env protein is particularly higher in metastatic tumors as compared to benign lesions. Higher levels of HERVs have also been implicated in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

This is connected with changes in the epigenetic silencing mechanisms, notably lower methylation causing an increased gene expression of the HERVs. Similarly, even the onset of schizophrenia is linked to the transcriptional activation of certain retroviral elements in the brain. For example, the HERV-W gene products were high in the plasma of patients with schizophrenia. Overall, the exact link of the HERVs with various diseases is yet to be established. Deciphering the same could help us understand mechanisms underlying various diseases. This could in turn, help develop therapeutic targets to alleviate the symptoms of the diseases or possibly stop its progression.

However, there is no reason to be alarmed. The very fact that the HERVs are around, despite entering our genome several years ago, means that they are not very disadvantageous as they would have otherwise been eliminated in the course of evolution. This indicates that the HERVs have largely been neutral to our genome. There is an increasing amount of evidence which points to these ‘fossil viruses’ directing our evolution. Since they are dispersed all over our genome, they act as repositories of regulatory elements and can change the way genes are expressed. The long terminal repeats (LTRs) flanking the HERVs contain cis-regulatory sequences and they could influence the gene expression levels or the gene activity of the nearby genes. Evidence has also emerged suggesting that HERVs may be advantageous to our genome. HERVs block the replicative processes of viral invaders similar to them, conferring a degree of antiviral resistance in the host. Very interestingly, some HERVs expressed in the placenta function to promote maternal tolerance to the
developing fetus.

It is evident that HERVs have multifaceted roles in the human body, in health and disease. It is essential that we make an effort to understand these ancient viruses with diverse roles to eventually get a better understanding of ourselves!

Reference (Dec-20-A2)

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