Dr. Maitreya Dunham is an Associate Professor in the Department of Genome Sciences at the University of Washington, Seattle. She was previously a Lewis-Sigler Fellow at Princeton University in the Lewis-Sigler Institute. Dr. Dunham is interested in understanding how aneuploidy (abnormal number of chromosomes) and DNA copy number variation (CNV) (abnormal or varying copy number of genes) can cause disease and aging-related phenotypes. Both types of genome rearrangements result in changed protein expression and imbalances in protein concentrations, which can cause diseases such as cancer, Down’s syndrome, and cognitive disorders. Dr. Dunham’s lab uses yeast to model CNV and aneuploidy and ask if aging-related phenotypes, such as growth rate and replicative lifespan, are caused by specific genes (CNV) or by more integrative effects of multiple genes (aneuploidy).
Dr. Dunham has recently focused her efforts on understanding the role of aneuploidy in aging in collaboration with UW professors Dr. Matt Kaeberlein and Dr. Alex Merz. To study aneuploidy, her lab uses disomic yeast strains, in which each individual chromosome is duplicated, for all the yeast chromosomes (yeast are haploid organisms and normally only have one set of chromosomes). Interestingly, she found that strains with individually duplicated chromosomes had a dramatic decrease in replicative lifespan. Furthermore, her lab identified a suppressor mutation that rescued lifespan decline in these strains. The suppressor mutation was a missense mutation in Bul1, which is part of the Rsp5 E3-ubiquitin ligase complex and is involved in protein quality control. This finding supports a potential mechanism by which aneuploidy effects aging via perturbing protein quality control.
Q: Tell us more about the Bul1 suppressor mutation. Is it specific to a certain chromosome?
MD: That is a great question that I am sure the reviewers on our submission will ask. We are currently in the process of doing those experiments. We haven’t yet put that knockout into the other strain backgrounds, but we have it and we are testing it right now. In wild type yeast, the Bul1 suppressor mutation only marginally improves lifespan; so it’s certainly not a lifespan extender in general. And this is for replicative lifespan. We haven’t tested chronological lifespan yet.
Q: Are you doing additional screens to identify new suppressors based on other phenotypes besides growth rate?
MD: That’s a really good question. I’ve been trying to find a way to do it by developing a screen for long-lived things. But nobody has figured that out in the field yet. You could image using a system like Dan Gottschling’s Mother Enrichment Program. But none of the schemes that are out there are totally full proof yet. The problem is that if a screen is leaky, and the follow up screen of the screen requires the use of the Kennedy lab undergraduate dissection microscope mill, that’s not going to scale. We have to have a pretty good way of selecting for them coupled with a pretty good downstream screen that doesn’t require a ton of extra work. We can’t tolerate a huge false positive rate. So I’ve been hoping that people will stabilize the mother enrichment program system to the degree where it could work for something like this, especially for some of the strains that have very severe defects like the ones that have a replicative lifespan of only five generations. Even if we only get get a little enrichment, if it’s a per generation enrichment, then we should be able to do really well by just taking it out a little longer.
Q: What about studying aneuploidy and aging in other organisms?
MD: We are excited to move into other model organisms such as worms. With worms, it’s not the situation where there’s a mother and you have to figure out how many times she will divide. It’s more like does that worm still move when you poke it over its lifespan? In this case, you can imagine doing a screen where you take the worms that are left when none of the trisomes are viable any longer and study them. That’s a much better selection. That is one reason why moving into other systems could be beneficial.
Q: Why did you move into the aging field?
MD: My lab has already developed tools for studying aneuploidy using genomics and genetics, and the aging phenotype is just another interesting phenotype that we could apply our suite of existing tools too. I’ve always been interested in aging. I did a rotation in an aging genetics lab in graduate school. What I like about the aging field also is that so much fundamental biology is touched on by aging. And I really like studying metabolism. If you ask who is still interested in studying metabolism…the answer is the aging people! They get that metabolism is really cool and fundamental! That was actually one of the other reasons that it was easy to get into the aging field. We’ve done all these evolutionary experiments under nutrient limitation, and we thought that we were already selecting for things that are related to calorie restriction as well, which has been shown to work in yeast too. So we tested some of our suppressor strains and disomic strains for aging phenotypes in yeast and that worked!
Q: What’s the big picture relationship between aneuploidy and aging?
MD: I am interested in what happens in general when you have the wrong number of chromosomes: what things go right, and what things go wrong? Can cells tolerate it, and how do they do so if they can? I think that aging is a good phenotype because it’s another aspect of what the cell has to do. Being able to look at a cell from birth to death and across environments and phenotypes and determine where aneuploidy and CNV can have an effect, this is just one piece of that.
Q: Can you talk about your academic career path and your experience as a Lewis-Sigler Fellow?
MD: The Lewis-Sigler Fellowship is a really interesting program, and it’s one of a number of “postdoc replacement” programs. This program is directed mainly at people coming right out of graduate school. They’re a number of these programs now at places like the Whitehead Institute, UCSF, and Berkeley. The nice thing is that right out of graduate school, you get to be independent and have your own lab. I didn’t hire postdocs or graduate students since I was only there for five years. Instead, I had a lab of great technicians and undergraduates. Lewis-Sigler was designed as a large open lab space environment, which can be distracting. But for a new PI with a small group, it was great because you got to interact with other labs. I didn’t have to worry about grants and was able to focus on research for those years. I learned how to manage other people’s time, and I developed a lot of collaborations so I had more interactions with more senior people. These relationships were very important, especially when I was looking for tenure track faculty jobs and needed people to write letters of recommendation and read my applications. I really loved it though, and it was really fun. I got to mentor students and have my own independent research goals that I got to start from scratch.
Q: Do you have any advice for our postdocs who want to pursue academic careers?
MD: Now that I have postdocs of my own, this is of course on my mind. One of my postdocs just got a job at Dupont, so is going into industry. The other one of my postdocs is exploring the possibility of launching a startup based on an invention in my lab. I’m actually a little jealous of people going into industry. It sounds like a lot of fun! I feel like the training in the postdoc that I’ve hoped I’ve provided is exactly what you need to succeed in industry jobs as well as academic jobs. So I think that this idea that your training is only all about whether you’re going to get a faculty job that may or may not exist, or might not be what you actually want to do, is problematic. I hope people don’t get too discouraged about that and think broadly about their options. I do think it’s totally worth talking about how to better train people who are going into industry. Even about how to get an industry job and what are the skills they want. If you identify the kind of job you want and figure out how people got that job, then that helps you in a training plan. NIH is implementing a new training plan for trainees. I think that is a really good idea to have that conversation with mentors about what your goals are. Then we can actually help you!
To learn more about Maitreya Dunham’s scientific research, visit the Dunham Lab Website.