Q & A with Joel McManus-Department of Biological Sciences - Carnegie Mellon University

Thursday, September 1, 2011

Q & A with Joel McManus

Biological Sciences Newest Assistant Professor

The Department of Biological Sciences is proud to introduce their newest assistant professor, Dr. Joel McManus. Dr. McManus comes to Carnegie Mellon from the University of Connecticut Health Center, where he was a postdoctoral research fellow. He also received his doctorate in biomolecular chemistry from the University of Wisconsin, Madison.

Tell us a little about the research that you plan to conduct at Carnegie Mellon.
I plan to have two research projects at CMU. The first project is aimed at understanding how genomic differences affect gene expression. Gene expression involves transcription of DNA into mRNA, alternative splicing of mRNA, translation of the mRNA into proteins, and regulation of mRNA and protein levels through degradation pathways. Differences in the networks controlling these processes lead to gene expression variation, which is an important source of phenotypic diversity. Most research in this area has focused on transcription networks and mRNA abundance, because these are the easiest to study. At Carnegie Mellon, I plan to investigate changes in splicing and translation regulatory networks using high throughput sequencing and bioinformatics. The second project will use these same tools to investigate mRNA secondary structure genome wide. mRNA structures play a large role in gene expression, yet very little is known about the structures of most mRNAs.

What are some potential implications from your work?The main implication of my postdoctoral work is that many gene expression differences, between individuals and species, are caused by differences in trans-acting regulatory factors, e.g. transcription factors and miRNAs. This was surprising, as these factors each tend to control multiple genes, and trans-acting changes are expected to be detrimental to organisms through pleiotropic effects.  Consequently, most of the differences in gene expression between species were thought to come from changes in cis-regulatory sequence elements, e.g. promoter sequences, which typically just affect single genes. I found that the networks regulating mRNA abundance in closely related Drosophila species have diverged through changes in both cis- and trans-acting network components. In fact, more genes are affected by differences in trans-acting factors than through changes in the sequences of cis-acting elements, however trans-acting changes are generally smaller in magnitude. This implies that pleiotropy may not be as extensive as was assumed. Additionally, small differences in mRNA abundance caused by trans-acting changes may be compensated by other factors in regulatory networks.

I have also begun investigating alternative splicing regulatory networks and find that exon-skipping is more prone to trans-regulatory changes than intron retention. The work of other investigators suggests that exon-skipping is controlled by more trans-acting factors than intron retention. This implies that the structure of splicing regulatory networks pre-disposes them to different kinds of evolutionary changes, since splicing events with more regulators are more likely to evolve trans-acting regulatory differences. 

In general, where is your field of research heading?
Up to now, the field has been really centered on understanding the cis-regulatory elements that control mRNA abundance. The goal has long been to predict gene expression differences by simply comparing genome sequences. It’s becoming clear that differences in trans-acting factors also play a substantial role in gene expression variation, especially between individuals within a species. Thus predicting gene expression differences will require a thorough understanding regulatory network structure and the roles of trans-acting factors. Also, I think the field is moving towards investigating variation in other regulatory processes, not just transcript abundance. We need to know how it all fits together, because it is clear from basic molecular biology that much of gene expression is regulated post-transcriptionally.

Can you tell us about your current collaborations as well as your plans for future collaborations?
Currently, I have been collaborating with Dr. Joe Coolon, a postdoc in Dr. Patricia Wittkopp’s lab at the University of Michigan. We have been working on the evolution of gene expression networks together for a couple of years now.  We are now expanding our work from whole animals to specific tissues in Drosophila. I think this will be very insightful, as many genes are only expressed in certain tissues.  I’ve also been involved in sequencing the genomes of multiple Drosophila cell lines with the modENCODE project, with the goal of understanding how differences in genome sequence compare to differences in mRNA abundance.

At Carnegie Mellon, there are a number of people that I look forward to working with. I’m really excited about the computational and the gene expression network communities at Carnegie Mellon, including Dr. Xing, Dr. Russell Schwartz and Dr. Ziv Bar-Joseph as well as Dr. Veronica Hinman, Dr. Javier Lopez, and Dr. Chuck Ettensohn. In addition, I plan to compare protein abundance in the different species of and hope to work with Dr. Jon Minden using the DIGE system that he developed. There’s also a great RNA community at CMU. For the RNA structure project, I think that I’ll interact substantially with the Woolford, Macbeth, and Chakrabarti groups.

What do you think makes a good grad student? What will you be looking for in a graduate student?
I think there are at least two vital characteristics in good graduate students – curiosity and perseverance. I will be looking for students who are highly motivated, interested in trying new things, and willing to keep trying.  My work is very interdisciplinary, and students who work in my lab will be exposed to both molecular biology techniques and computer programming for data analysis. I am really excited about students who are interested in bioinformatics, genomics and gene regulatory networks.

What part of coming to Pittsburgh and the Department are you most excited about?
There are great network, computational, RNA and fly research communities in Pittsburgh and at Carnegie Mellon that I think I can fit with really well. Another thing that excites me is that the department does a lot of basic research and that is really where I have been intellectually.

What do you like to do for fun?
I like to read and spend time with my family.  I have a three-year-old son and my wife and I hope, when he is a little older, to turn him into an outdoor enthusiast like ourselves. We plan to take him camping, canoeing and more.