“Nothing in Biology Makes Sense Except in the Light of Evolution”

I’m a Mobilitas-funded post-doc in Tartu University, working in the lab of Tanel Tenson in the Institute of Technology. I write a blog about my research, and I’ve been kindly invited to write a guest post for the UT blog. I have very few opportunitites to explain my work to people outside of my immediate research areas, so I thought it might be a great chance to try introducing the research in a way that’s (hopefully!) accessible and (this is probably a long shot, I know!) interesting to people outside of biology.

The title is a quote from a 1973 essay by the evolutionary biologist Theodosius Dobzhansky. Although Dobzhansky was a theist, he understood that evolution and not creation is the only way to explain the weird and wonderful processes of Biology, and he was an advocate for the teaching of evolution in schools. Understanding the process of evolution can help us explain Biology on all scales, from molecules, to cells, to metabolic networks, to organs to whole organisms and to populations of organisms. I work on the small end of the scale, on evolution of molecules, proteins to be specific. Proteins are made up of chains amino acids, which are coded for in DNA.

You might be wondering why protein evolution is interesting or important. Of course every scientist thinks theirs is the coolest field (just like every parent thinks their child is the cutest), but it is pretty cool! I work on some of the most ancient proteins that function in some of the most fundamental processes in all life, and I’m trying to piece together what proteins were present in our ancestors and how they’ve evolved into their modern forms. It’s sort of like molecular archaeology, digging around for evidence of tools and mechanisms used by our ancestors or distant cousins. Like classical archaeology, we only have very few clues to go on. Only a fraction of genomes have been “excavated”, and many lineages have become extinct. But from those clues, we can retrace evolutionary histories and pinpoint significant events like gene duplication or horizontal gene transfer.

So I can use my evolutionary research to look into the past, but perhaps the most important application of my work is to predict functional aspects of modern proteins. I will discuss this below, but I’ll first very briefly describe the methods.

Mutations happen at the DNA level, sometimes causing changes in the amino acid sequence of a protein. It’s these changes that allow the relationships between the proteins to be recovered in the form of a phylogenetic tree. First, a multiple sequence alignment is made, stacking the protein sequences on top of each other, so to visualize the amino acid differences between them. These similarities and differences are what are used to compute the phylogenetic tree. The patterns of mutations can be used to resolve the relationships among organisms, but that’s not what I’m interested in. I’m interested in how the patterns of mutations can give us clues about protein function.

The most important residues are more likely to be kept unchanged through evolution, and appear as invariant in the alignment (the conserved sites pointed out in the figure). In the case of enzymes, these are often amino acids found in the active site and are important for catalysis. Other conserved sites may be involved in inter-molecular interactions, or are important for maintaining the integrity of the three dimensional structure of the protein.

I get all my sequences from publically available sequences from genome projects, writing programming scripts in Python to sort my data, and making alignments and trees with various programs run either locally or on a server in the States. I write other programming scripts to analyse patterns of conservation. Since all my work is done on my laptop and the web, I can work from virtually anywhere if I need to. Today, I’m working from a couch in Sweden!

I mostly work on proteins that interact with the ribosome, the molecular machine for making more proteins (translation). So I’m lucky to be working in Tanel Tenson’s lab, which has expertise in the ribosome and translation. Along with Tanel, I work with my partner Vasili Hauryliuk (he has a blog too), who’s a senior scientist with his own sub-lab within Tanel’s… um… not sure of the correct terminology for this kind of lab hierarchy, so let’s call it motherlab! Vasili and I met in Uppsala, Sweden though working on the same proteins, translational GTPases. Vasili was working there on their biochemistry and I was starting a post doc there on their evolution. It was a very serendipitous meeting for many reasons!

My main project in Tartu is on a superfamily of proteins that produce a stress “alarmone” molecule called ppGpp in response to adverse environmental conditions. I’ve found how these proteins are distributed across the tree of life, and in some of the most interesting subgroups of this family, I’ve used conservation patterns to identify amino acids that seem to be involved in “cross-talk” from one end of the protein to the other, and are potentially important for regulating the protein’s function. We are writing up the results now, with the aim of submitting it for publication some time in the next few months. As Vasili and his students also work on the biochemistry of one of these alarmone synthetases, we plan to test my predictions of functionally important amino acids by mutating them and measuring the activity of the protein. That will be in that strange funny smelling place they call the lab!

So, that’s my research in a nutshell. Get in touch if you’re interested in hearing more! And if there are any enthusiastic students who are interested in Masters or summer projects, drop me a line!


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