One of the problems with studying the origin of life is that nearly 4 billion years' worth of evolution have happened since, and the changes that came with that evolution obscure much of what we might otherwise learn from the DNA sequences that now exist. Horizontal gene transfer also makes a mess out of many attempts at tree building. Does that mean we can never hope to understand what the first few proteins were? A paper that should appear at PNAS this week argues that the answer is an emphatic "no."
The basics of the problem are two-fold: changes on the DNA sequence level have obscured physical similarity in the proteins, and the original protein structures have been borrowed by and adapted to a range of cellular processes. The authors reason around these challenges in a number of ways. They point out that the first organisms were almost certainly simple energy-processing machines, and so they focus on basic metabolism. To avoid the issues with DNA sequences, they take advantage of the fact that there are now many three-dimensional structures for proteins described.
The authors used the scientific community's identification of a number of small structural units, termed "folds," that appear in a number of metabolic enzymes (there are currently 776 folds known). They were used to produce a mathematical test (called a "hidden Markov model") that can identify similar folds in other proteins. They then set the model loose on all the genomes, allowing it to pull out all the proteins where that fold appears. With a huge collection of representatives from those 776 folds in hand, they engaged in the standard practice of tree building, both based on the folds themselves and on some of their metabolic activities.
Of those 776, only 16 appeared throughout the tree of life, suggesting that these existed at the time of the last common ancestor. Of those 16, the nine most ancient appeared to be used in a wide variety of metabolic pathways. Repeating the tree building with the metabolic functions revealed the pathways in which these folds started out.
So, what does this tell us about how life as we know it began? For starters, it appears that life could have built up a pretty complex metabolism based on a relatively small number of protein folds. For another, the two most ancient metabolic pathways point to what came before our current, protein-focused world: they're both involved in producing the nucleotides of DNA and RNA from less complex organic molecules. This, to the authors, supports the view that life began with an RNA world.
It's difficult to tell how solid this analysis is; it seems to connect and build upon earlier work that is presented in a number of references, and I'm not in a position to evaluate them all. If nothing else, however, the paper is important for presenting an interesting approach to a problem that might have recently been considered impossible to solve.