Since the discovery of transposable elements in maize by Barbara McClintock in the 1950s, the perception of these mobile genetic elements has seen a major shift from relative obscurity to the realisation of their ubiquity across eukaryotic genomes. One class, the retrotransposons, make up around a third of the human genome and at least half of the maize genome. The latest advances in retrotransposon research were one of the topics of discussion at the 2014 Mobile Genetic Elements and Genome Evolution Keystone Symposium, organised by the Editors-in-Chief of Mobile DNA. In an Opinion article in Mobile DNA leading researchers attending the symposium present their thoughts on where mobile DNA research is going, including opinions from Jef Beoeke of the NYU Langone University School of Medicine, USA. Journal Development Editor for Mobile DNA Sam Rose (@Rosenovich) spoke further to Boeke to find out more about his take on current open questions in the field, exciting developments, and what led to his interest in retrotransposons.
What got you interested in mobile genetic elements?
As a graduate student I studied bacteriophage genetics and I was interested in moving up to eukaryotes – because that was a very popular thing to do – and I was looking at a bunch of different yeast labs. I actually had one goal in life at that point, which was that my postdoc had to be in California. Unfortunately, in the middle of all that, this guy called Gerry Fink came through and gave a lecture on Ty1 and suppressors of Ty insertions. It was a very inspiring talk so, in spite of the fact that he wasn’t anywhere near California – he was in Cornell, Ithica, New York at the time – I said I would be interested.
I was very interested in this idea of transcriptional control of transposons. At the time, the word retrotransposon hadn’t been coined. I was really more interested in what goes on in the nucleus and how an insertion could change expression of genes. I thought that was an interesting question. Of course it still is an interesting question. But when I got to the lab, I came to learn that the project I had written my fellowship proposal on was already being done by another postdoc. I was quite taken aback when my new supervisor called me into his office and said, “Well, I don’t really want you to work on that project because Fred Winston’s working on that project.” I was disappointed, but then he outlined another project, which was basically to develop an assay for movement of the transposon itself.
I remember thinking: “Gee, that’s a much better idea than the original idea, this is really exciting and it sounds fantastic.” I knew about transposable elements, but I hadn’t really thought that I would be studying the transposition part until that day. I guess the rest is history; the project was a success and we coined the term retrotransposon as a result of those experiments and I’ve been in the field ever since.
What’s been the highlight of your career since?
That’s a tough one. I don’t know if I would pick one. It’s been a distributive process, rather than one big eureka moment, about picking apart the many interactions that host proteins have with transposons and this dynamic interaction between the host and the parasite, and the insights that’s given into mechanism.
What’s been the most exciting advance recently, in your opinion?
I think for me some of the work that’s coming out suggesting somatic activation of transposable elements on a grand scale in unlikely places – well, some perhaps more likely than others. Cancer cells seemed like an obvious place to look and many people, including us, have looked – sometimes very successfully and other times much less successfully – but it does seem quite clear now that it’s happening. The jury is still out on whether it’s cause or consequence. Similarly, I think the work that’s emerging on transposition in the brain and transposition as a function of aging, are really exciting areas with quite a bit of potential.
What are the big questions at the moment?
I think some of these questions about cause or consequence and really speaking now about the somatic transposition: what’s really the extent of it and what’s the biological significance of it at the end of the day? I confess I’m still a sceptic on some aspects of the findings and the way that people like to interpret them.
As one example, I think the work from Gage, Moran, Faulkner and others, at this point has clearly demonstrated that there is hopping going on in neurons. We’re beginning to get some sense of what the numbers are. But I’m fundamentally a selfish DNA guy, and the idea that these elements would be jumping around to provide a function is still very difficult to swallow. I think an alternative explanation for those findings, that needs to be considered, is that in the brain and in the testes – in the germ line – many, many genes are expressed. It’s a very permissive environment for expression. So perhaps this is a common feature of the transcriptional environment between these two tissues – they’re both permissive for transposition. Perhaps some of the same transcription factors are used. This might explain why we see it in these very selected environments.
Is there a worry that people will try too hard to find function in things where there is none?
Of course it’s clear that transposable elements can generate diversity, and if you can really make a compelling case that random insertion can somehow generate phenotypic diversity, that’s great. But I haven’t really seen that yet in the brain. I think all the theoretical parts are there but it hasn’t quite been put together in a way that I find satisfying.
What directions can you see the field going in?
One of the other areas that I’m personally very excited about – and a road that we’ve decided to go down – is to build genomes from scratch where every last nucleotide of mobile DNA has been ruthlessly exterminated by synthesis. That is one of the goals of our synthetic yeast genome project. We’re doing the experiment that we’ve talked about at the bar at every transposon meeting, which is: taking out all the transposon DNA from an organism and asking what will happen. Now, I’m betting that we will get away with it in yeast and we won’t see any phenotype that we can attribute to that. I would not be so sanguine about saying that about humans or mammals; I think we would definitely see phenotype differences.
Find out what other leading researchers in mobile DNA think about this evolving field in this Mobile DNA Opinion article, which includes thoughts from Marlene Belfort, Luciano Marraffini, Todd Macfarlan, Keith Slotkin, Harmit Malik, Lynne Maquat. Highlights of this article can be found here.