Landweber tracks changes in genetic code

Steven Schultz

Princeton NJ -- As biologists begin to interpret the data revealed by the human genome project, Laura Landweber is asking a more basic question: Where did the genetic code itself come from?

Landweber, an assistant professor of ecology and evolutionary biology, is one of the leading researchers in breaking down the long-held belief that all organisms, from humans to bacteria, follow the same rules in reading the instructions encoded in their DNA. The rules, it turns out, have changed throughout the course of evolution, so that the same DNA sequence can mean one thing in one organism and something else in another.

"It has been misnamed the universal code, but there are variations," said Landweber.

That realization, however, has caused evolutionary biologists to wonder how the code could change -- even a little -- without severe consequences for the organism that experiences the change. "It's like someone rewiring the keyboard on your computer," said Landweber. What if pressing the period key suddenly started to result in Rs instead of periods?

In a paper in a recent issue of Current Biology, Landweber, along with research assistant Catherine Lozupone and graduate student Rob Knight, revealed a molecular mechanism that allows such changes to happen. They showed how a few mutations in a single protein clear the way for a major rewiring of an organism's genetic code.

In addition to shedding light on how code changes occur, the finding is intriguing because it offers insight into the process of evolution in general. Landweber's group found that the same mutations show up in many distantly related species. That means that the same mechanism has evolved independently at different times, sometimes several millions of years apart -- a process called convergent evolution.

"To me, it's a surprisingly clear case of convergent evolution at the molecular level," said Landweber.

Landweber's group focused on DNA sequences that tell cells when to stop building the protein described by one gene and move on to the next. In the standard genetic code, there are three ways of writing such "stop" instructions. In some organisms, however, one of these DNA sequences means "add" instead of stop -- it tells the cell to attach one of 20 chemical building blocks to a growing chain of protein.

To track down the source of this change, Landweber's group studied ciliates -- single-celled organisms that propel themselves by moving hairlike appendages and that tend to have unusual genetic codes. The researchers looked in particular at the ciliate version of a protein called eRF1 (short for eukaryotic release factor 1), which is responsible for reading stop instructions. They discovered specific mutations that cause eRF1 to lose the ability to recognize one of the three possible stop instructions.

Landweber notes that organisms may sometimes survive this mutation because eRF1 would still recognize one or two of the other stop commands. In addition, stop commands, occurring only once per gene, are rarer than other instructions. Once the mutation is established, the DNA sequence that used to mean "stop" can now be gradually adopted for another purpose.

Now that she has a clue as to how the code changes, Landweber is looking for further details of eRF1's evolution and firmer explanations for how organisms survive the change.

Future experiments could involve taking the eRF1 gene from an organism with the standard genetic code, purposefully making alterations in it, then reinserting it into different organisms and seeing how it affects the interpretation of the genetic code.

Another key task will be to find the eRF1 protein in many other organisms with standard and variant genetic codes to compare its structure and function. She and others will be looking at a wide range of eukaryotes -- the large class of organisms from ciliates to mammals whose cells have nuclei and the similar kinds of genes.

"I am hoping that, with the genome of our favorite big eukaryote (humans) complete, we'll be able to foment enough excitement to plunder the genomes of some of nature's fantastic unicellular inhabitants," she said.

With a better understanding of the molecular machinery underlying the evolution of the genetic code in different organisms, biologists may gain a clearer picture of how simple genomes first evolved and how they gave rise to more complex genomes, like our own.


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