An often-wondered question about evolution is 'Where do new forms and functions come from?' Understanding the source of novelty in evolution is key to understanding how life got from its simplest precursors to the complex panoply of biodiversity we observe in the world today.

Charles Darwin's theory of evolution by natural selection is a powerful mechanism for improving existing functions, in a step-by-step, mutation-by-mutation fashion, but it is unable to explain how those functions first arose. In other words, "Natural selection may explain the survival of the fittest, but it cannot explain the arrival of the fittest," quoted in Hugo DeVries's 1904 book, Species and Varieties Their Origin by Mutation. 

New insight into this question comes from experimental results observing the evolution of a modern virus in the laboratory. Viruses infect their hosts by attaching to molecular receptors on the outer layer of cells. These receptors are the locks that viruses' must open to enter the cell. The keys to the locks are viral proteins called host-recognition proteins. 

Scientists have known for years that viruses could gain new keys with relatively few mutations. They also knew that these mutations readily evolve. However, they did not understand how these mutations worked. The answer to this question led an international group of researchers from UC San Diego, Earth Life Research Institute in Tokyo, and Yale University to reveal a surprising new mechanism of evolution.

EON Research Fellow Katherine Petrie, working in the laboratory of Justin Meyer at UC San Diego, studied a harmless virus named bacteriophage lambda. They found that lambda overcomes the challenge of using a new receptor by violating a well-accepted rule of molecular biology. The rule, also known as the central dogma, is something everyone learns (and forgets) in high school biology. It's a multistep mechanism for how DNA produces living organisms. Genetic information is stored as pieces of DNA or genes, genes are deciphered into another molecule called mRNA, this molecule is translated into a protein, and proteins are the molecules that make up living cells and viruses.

Dr. Katherine Petrie (Photo credit: Nerissa Escanlar)

Petrie and colleagues found that a single gene sometimes yields multiple different proteins. The virus evolved a protein sequence that was prone to structural errors that result in the creation of at least two different host-recognition proteins. Fortuitously for the virus, but not its host, the different types of the proteins can exploit different locks. The protein mistakes allowed the virus to infect its normal host, as well as new host cells. 

Petrie and her coauthors' work shows that new functions can arise by chance differences in the creation of proteins. With this initial step taken by the protein, natural selection can then take it from there and drive genetic changes that enhance the virus's ability to use the new receptor. These protein errors allow evolution to be much more flexible than previously anticipated.

Dr. Meyer compares lambda's evolution to visiting local breweries. 'There are so many great brews to choose from that it's best to sample a few before committing to a single pint.' The virus can taste different molecules and explore a range of possible hosts.

'It was remarkable watching Katie and the Lab unveil these truly extraordinary results, one successful experiment after another,' proclaimed Professor Meyer. The project started serendipitously by the observation that some data seemed off'. Meyer and Petrie came up with a radical hypothesis to explain this discrepancy and then set up a series of experiments to falsify it. One after another the hypothesis stood up to the toughest scrutiny.

Justin explains one of his favorite aspects of conducting the research, 'it was rewarding to work with some of the younger researchers on the project and to explain this cool hypothesis. We designed experiments so that data acquisition was completely blind and upon entering the data, our computer would automatically generate a graph that revealed whether or not the hypothesis made the correct prediction." Biology undergraduate Sarah Medina says that, "seeing the graph fill with data felt like hitting the jackpot. All of our hard work was paying off in a big way."

How exactly do these mutations work? A molecular machine inside of cells called a ribosome translates RNA molecules into a polypeptide chain. This long chain then folds in on itself to create a three-dimensional structure. This structure is a protein. Different polypeptide sequences yield different structures with unique functions. It turns out that viruses can evolve polypeptide chains that can fold into multiple different structures. This means that one virus can produce multiple offspring with different host targets. 

This nongenetic variation in the protein is a way to access more functions from a single DNA gene sequence. 'It's like a buy-one-get-one-free special for the protein,' says Dr. Petrie, the lead author on the study. 

What does this research mean for the larger picture? The research reveals a new, general, mechanism for evolution and helps scientists understand how organisms quickly adapt to their environments. Additionally, even though this discovery was made in a modern organism; the mechanism of using non-genetic variation to explore multiple functions with a single sequence may be especially important for the first biomolecules of life, which were likely constrained in their length and complexity. This example of 'messy' biology, where there is an imperfect sequence-function relationship, illustrates how 'messiness' - the mistakes and side-products that are often considered a problem to be solved in prebiotic chemistry - may actually be an opportunity to exploit. 

Link to Katherine Petrie's paper: http://science.sciencemag.org/content/359/6383/1542

DOI: 10.1126/science.aar1954