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The unusual ‘mutations’ that protect humans from viruses | Explained

Anyone can access all the research papers in medicine and biology via the free search engine PubMed. Do a PubMed search for “cancer” and you will get links to 4.97 million papers, with the most recent first. Querying for “gene” yields 3.34 million links, “viruses” 1.44 million, and “mutations” 1.27 million. The numbers increase by the day. But search for “paramutations” and you should find only some 220 papers or so. This is because research on paramutations is only just taking off.

Many people know that mutations in genes can cause cancer. And the COVID-19 pandemic heightened people’s awareness of, and dread towards, viruses. In this milieu, paramutations are changes that can protect humans against viruses. Researchers Almoro Scarpa and Robert Kofler, of the Institute for Population Genetics in Vienna, Austria, showed how they do so in a paper published in the journal Genetics on October 11.

Chromosomes and genes

Each cell in our bodies has 23 pairs of chromosomes. One of each pair is inherited from each parent. Every chromosome contains one long DNA molecule plus several chromosomal proteins. The DNA is made of four compounds called bases. A gene is a specific sequence of bases in the DNA.

When a gene is expressed, it means the sequence is copied onto the sequence of bases in a related molecule, called RNA. The RNA base sequence then tells the cell the sequence of amino acids required to make the protein coded by the gene.

In this way, the gene directs the synthesis of a protein, with DNA and RNA as the gene’s master and working copies.

Springing the trap

The piRNA cluster is a different type of gene. The RNA from a piRNA cluster is not used to make a protein. Instead, it is cut into shorter pieces of 23-30 bases called piRNA – short for piwi-interacting RNA.

The piRNA is associated with proteins belonging to the piwi family. The piwi-piRNA complex is a search-and-destroy weapon. The piRNA guides the search for RNA and DNA that have the same sequence as the piRNA, and the piwi proteins destroy the targeted RNA, or simply turn ‘off’ the targeted gene.

Effectively, the piRNA cluster is a virus trap. When a virus infects a cell, its DNA integrates into the host cell’s DNA. If by chance it integrates into a piRNA cluster, the cluster will develop the ability to make piRNA that can identify the same sequence in the host RNA and DNA and destroy it.

Simply put, the host DNA co-opts the trapped virus to make an antiviral agent.

The fruit fly (Drosophila melanogaster) has been the workhorse of genetics research since 1901.  piRNA clusters make up around 3% of its genome. Profs. Scarpa and Kofler used computer simulations to find that the antiviral action of piRNA clusters is amplified manifold by paramutation. That is, paramutations helped fly populations become virus resistant faster.

What are paramutations?

A mutation is any change in the sequence of bases in the DNA of a chromosome. A paramutation is a small chemical modification of a chromosomal protein: it flips a nearby gene into a silenced state. So the active and silenced versions of a paramutated gene share the same DNA sequence but their associated proteins have different modifications.

Paramutation originally referred only to interaction between the maternally and the paternally derived copies of the same gene. The protein modification associated with one copy was copied to the protein associated with the other, and both copies were silenced.  This perpetuated the paramutated state into succeeding generations.

Today, we know that the interaction that triggers the modification involves piRNA and other short RNAs, and thus depends on the DNA sequence. So paramutation now refers to interaction between genes that share the same or similar DNA sequence, regardless of their chromosome location.

Paramutations vs. viruses

The piRNA from one cluster can paramutate viral DNA copies inserted elsewhere in the genome, outside of the clusters. As a result, the paramutated insertion is switched from making viral proteins to making more piRNA. This is the mechanism the new study unearthed.

However, not all insertions of the virus are amenable to being paramutated. We also don’t know why some insertions are more paramutable than others.

Paramutation in plants

William Bateson and Caroline Pellew discovered the first paramutation in the culinary pea (Pisum sativum) and reported it in 1915 in the Journal of Genetics. Bateson was one of the first editors of this journal (the author is the current editor); he also coined the term ‘genetics’ to describe the study of heredity.

Among other differences from cultivated peas, the paramutated plants also made smaller and less sweet seeds. Farmers called them “rogues”. (To rogue is to remove inferior or defective plants or seedlings.) Rogues bred true and had only rogue offspring, and crosses between rogue and the desired variety yielded only rogue offspring.

Agricultural scientists have made great efforts to exterminate rogues, although the first substantive advance in understanding rogue peas came only in 2021. Then, researchers of the University of Algarve, Portugal, reported having isolated a mutant that had lost its rogue characteristics, giving scientists a foot in the door to figure out how rogue and non-rogue plants differ.

Paramutation is arguably one of nature’s more closely guarded secrets. While we now have the complete DNA sequence of hundreds of plants and animals, as well as of tens of thousands of people, the documentation of their myriad chromosomal proteins and RNAs has only just begun. The similarities and differences between animal and plant paramutation is still relatively rudimentary. So we can expect exciting discoveries even before PubMed throws up the 250th link.

The author is a retired scientist.

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