Friday, 19 December 2014

Hidden viral DNA prompts immune system into action

If our DNA is the essence, the blueprint, of what we are as human beings, then it may be time for a bit of a rethink. Just 2% of our DNA codes for proteins that assemble and maintain our bodies. Of the noncoding DNA, a whopping 45% of isn’t of animal origin at all. It’s viral, and it has been with us for a very long time.

Endogenous retroviruses (ERV) have been hiding in our genomes for millions of years doing what DNA does best – replicate. As survival strategies go, being a dormant virus in another creature’s genome is pretty solid. However, as time goes by, DNA shifts and breaks while preferentially maintaining the useful regions (like our 2% of coding DNA) and mutilating the noncoding regions. ERV DNA should, after all this time hiding in our genomes, be completely useless by now, shuffled ever closer into an oblivion of tandem repeats and useless features from so many generations of meiotic cell division. So, why is about 8% of our DNA very obviously identified as ERV? And, more importantly, what is it doing?

[caption id="attachment_116" align="alignleft" width="590"]Scanning electron micrograph, if you're interested. Very nice indeed. HIV (green) attacking a lymphocyte. Photo credit: C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus, CDC. CC2.0[/caption]

When we think of the term “retrovirus”, HIV is usually the first thing to spring to mind. Disease causing viruses, retroviruses invade cells and can insert themselves into the DNA. If this occurs in a cell involved in sexual reproduction, like a sperm or an egg, then the virus can be passed on to the next generation hidden among the parental DNA.

A new study published in Science from researchers at the University of Texas Southwestern Medical Center and the Karolinska Institutet in Stockholm suggests that ERVs play an important immunological role in humans.

They found that ERV DNA is expressed in B cells activated by common bacterial and viral pathogens. B cells are a type of white blood cell of the immune system and are involved in producing antibodies. In activated B cells, the ERV is first expressed as RNA. This RNA is recognised by a protein called RIG-I, which recognises the ERV RNA as not being human. Some of the ERV RNA will be converted to DNA during this process, and another protein in the B cell, cGAS, will recognise that as being non-human DNA.

RIG-I and cGAS signal other proteins in the B cell, telling it to remain active and allowing it to multiply and produce antibodies against the original threat that triggered the activation of the B cell in the first place. This is the first known incidence of ERV playing a beneficial role in the human immune system.

Dr Zhijian "James" Chen, author on the study, said “These findings suggest that both the RNA and DNA sensing pathways play an important role in detecting ERV and activating adaptive immune responses.”

This beneficial response may explain why ERVs haven’t all been lost in our genomes, despite millennia of cohabiting with our coding DNA. Dr Gunilla Karlsson Hedestam of the Karolinska Institutet adds, “Once retroviruses have become part of the host germline, they are subject to selection for beneficial effects just like any other part of the genome, and their ability to activate an innate immune response seems to have been utilized to the benefit of the host.”

It remains to be seen whether this is an isolated incident of helpful junk DNA, but certainly given the vast amount of DNA “spare parts” floating around in our genome it stands to reason that much of it still serves a purpose.

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