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Q&A: Scientists Discovered Somatic Recombination in the Brain. Now What?

Wednesday, January 16, 2019

Jerold Chun

The recent Nature paper describing the first evidence of somatic gene recombination in the human brain has been getting so much attention that we went back to the lab’s PI to learn more. Jerold Chun is Professor in the Degenerative Diseases Program and Senior Vice President of Neuroscience Drug Discovery at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif. He spoke with us about this remarkable discovery in the APP gene in patients with sporadic Alzheimer’s disease, the decades-long hunt for somatic recombination in genes active in the brain, and how SMRT Sequencing made a difference.

Previous efforts to find somatic recombination in the human brain failed. Why did you continue the hunt?

This goes way, way, way back. Anyone who knew about V(D)J recombination that was originally reported in the ’70s and knew something about the nervous system has been intrigued by that possibility. It was the seed for trying to identify some type of similar recombination in the brain. But back then ideas were very vague; it was simply trying to take what we knew about the immune system and projecting what might occur in the nervous system. Nevertheless, the concept remained compelling and our studies on genomic mosaicism that occurred in the interim supported something interesting going on.  As it turns out, the thought was good but the details were quite different from what we originally thought. We’re now at the point where we can talk about it not as a phantom but as reality.

After all those years of looking for this evidence, what was it like to finally find it?

You kind of scratch your head about the vagaries of science. This is a concept that was written off by almost any sane scientist years ago because so much effort had gone into chasing it and nothing emerged.

In the paper, you noted that short-read sequencing had been used for these efforts in the past but wasn’t successful. Why was that?

We had originally thought that if we could use single-cell technologies which rely on short-read sequencing, it would open this area up. The challenge is that the resolution of the sequencing technology is not sufficient even to interrogate the wild type locus. Even under the best circumstances we’re pretty much around 1 million base pairs. That’s not going to allow us to see 300 kilobases, which is where the APP locus is. That was a major limitation. Also, most short-read sequencing approaches require mapping to a reference genome. If there were inversions, insertions, or deletions, they may well be missed or be filtered out because they don’t map to what was expected in the reference. As soon as PacBio came onto the scene for our work, it just became absolutely clear that this was the way to pursue it so we could look at the complete sequence of what we now know are variants.

How did your team use SMRT Sequencing for this project?

There’s a really cool and special kind of sequencing with PacBio — circular consensus sequencing, or CCS. If you have a small enough piece — say, in the 3 kb to 5 kb range — the polymerase can go around and around and around the template. As a result, you can get many, many reads of the same template, so you can line those up and take the consensus read by looking at which of the residues show up most often. This is a way to get around the inherent polymerase error rates. In so doing, you get enormously high Phred scores as well as certainty levels. I think in this case we had a median Phred score of around 93 and a certainty of 99.999999%. It was actually approaching Sanger sequencing levels of certainty.

In the publication you speculated that HIV antiretroviral therapies might be used for patients with sporadic Alzheimer’s disease. Do you see that as near-term or will it take a long time to assess the possibility?

I think this is now. What we need to do is convince the clinical community to embark on it. The epidemiological signals are some of the most compelling of any that one could hope for. The total number of individuals in the United States who have HIV, are being treated with these antiretrovirals, and are at risk of Alzheimer’s disease because they are 65 or older is more than 120,000. The projections for developing Alzheimer’s in that age group is about 3% to 10%. But in 2016 the first reported case of an HIV patient with Alzheimer’s appeared in the literature, and as of now that’s the only case. I think it would be to everyone’s benefit to look at whether we can recapitulate that signal in a controlled, prospective clinical trial. Importantly, these are FDA-approved agents, some of which have been in humans since the 1980s, and thus there is sufficient proven safety to use these agents over long periods of time. Based on the science, we now have an explanation for why this might work.

This discovery must open new doors for your lab. What’s next?

There’s a new universe that’s been accessed here. It should impact both other forms of Alzheimer’s disease as well as other brain diseases and perhaps even other diseases that involve cells with a long life span. I think we’re in a position to search for and test whether gene recombination producing genomic cDNAs are more prevalent and involving other genes, and PacBio is certainly going to be a big part of that analysis.

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