Evidence Found for Origin of Genes

By William J. Cromie

Gazette Staff

Genes make all living things what they are physically; now Harvard researchers have taken a major step toward determining what makes genes what they are.

Evidence compiled by a team, led by Nobel laureate Walter Gilbert, supports the theory that all genes in all organisms that ever lived on Earth consist of a small number of basic building blocks. These blocks were shuffled and recombined during the past 3-4 billion years to form a dazzling variety of simple and complex proteins that make up life as we know it. The genes carry instructions for making proteins that do everything from allowing bacteria to metabolize methane gas to aiding humans to think.

Despite their power, scientists have been mystified by the discovery that genes consist largely of junk, segments of DNA that don't carry any instructions for protein-making. Called introns, these segments alternate with exons, which contain the active code of life. Introns are like connectors on strings of Christmas-tree lights, they can be unplugged and rejoined to create different patterns of exon lights.

If correct, this idea would lead to an understanding of how the ancestor of all modern life on Earth was put together. It would also reveal how all the proteins that make modern life possible are assembled. "Such knowledge has profound consequences for understanding ourselves and treating virtually all of our diseases," says Gilbert, Carl M. Loeb University Professor.

Life's Assembly Line

In a report to be published this week in the Proceedings of the National Academy of Sciences, Gilbert's team describes how 32 three-dimensional proteins are constructed from separate modules that correspond to individual exons in the gene that codes for them.

"The protein building blocks, or modules, correlate with the positions of exons separated from each other by introns," explains Sandro De Souza, a postdoctoral affiliate in molecular and cellular biology. "The boundaries of the modules correspond to the positions of introns."

During the process of protein assembly in a cell, the introns are discarded and the exon modules hooked together. The complex protein thus constructed boasts a function greater than the sum of its parts.

Gilbert believes that our earliest ancestor was put together in much the same way. About 3.5 billion years ago, lifeless combinations of chemicals evolved into molecules that carried instructions for making proteins (see "Creating Life in a Lab," Sept. 12, 1996, Gazette). When such molecules, the first exons, became hooked together by introns, they could produce more complex proteins than when they existed individually. They also could be disconnected from each other and combined into new types of genes.

"Such shuffling must have speeded up evolution," notes Manyuan Long, a postdoctoral fellow. "You don't need to evolve new genes from scratch, rather you can recombine basic modules already available. That would accelerate the diversity of proteins and so of living things."

The Junk Gene Mystery

Scientists were amazed and puzzled when they found, in the 1970s, that 95 percent of the genetic material coiled up inside virtually every cell consists of DNA that apparently serves no purpose. It's not like nature to be so wasteful.

In 1978, Gilbert, who won the 1980 Nobel Prize in Chemistry for his work in genetics, came up with the exon theory of genes to explain why so much junk exists in the cells of all living creatures. Although it's a tidy idea, not everyone accepts it.

To convince doubters, Gilbert has been searching for supporting evidence in the positions and structure of exons and introns. That kind of evidence became available only recently from the Human Genome Project, the herculean effort to map all the chemical bases that make up both exons and introns.

Human genes contain some 3 billion such units arranged in as many as 100,000 genes. They are often referred to as "letters" that spell out our genetic heritage. By 1990, the positions of some 60 million bases had been determined, not enough for what Gilbert wanted to do. By 1995, however, the number reached 600 million.

Long took on the task of searching the entire genetic alphabet, the letters found in every creature from one-celled blobs of life to the most-gifted humans. He found that introns and exons line up in a non-random way in the DNA of most living things. Exons appear in the same patterns in primitive protozoans, worms, flies, and people, as do the introns that separate them.

"This fact can only be explained if introns were present from the beginning of life and not inserted later, as some biologists claim," Long insists.

"That means that ancient regions, which represent genes or portions of genes, have descended in a relatively unchanged manner from a common ancestor," Gilbert adds. "This supports the theory that introns have facilitated the shuffling of exons from the time of the origin of genes. It also means that genes are composed, not of hundreds or thousands of basic building blocks, but of a lot fewer, possibly less than a hundred."

The work on 32 common proteins, conserved from ancient times, adds further evidence in favor of the exon theory of genes.

Lost Introns

Of course, there still are objections to this neat story of life. Bacteria, which evolved before plants and animals, lack introns. If they never possessed them, that undermines Gilbert's theory. But he maintains that bacteria lost their introns during three-plus billion years of shuffling.

"Losing introns would enable bacteria to reproduce faster," Long maintains. "You can think of it as a streamlining process."

Gilbert raises the fascinating possibility that bacteria may be ahead of humans and their junk-laden genes in the evolutionary race. "Maybe we're not as advanced and sophisticated as we would like to believe," he says with a smile.

Skeptics acknowledge that the Harvard team has accumulated strong evidence that new genes can arise from mixing and matching exons. However, that evidence does not prove that the common ancestor of modern life was put together in this fashion.

"Since that occurred between 3 billion and 4 billion years ago, some critics say we will never be able to prove it conclusively," Long admits. He compares the situation to the accepted existence of quarks and other subatomic particles. "We cannot see them, but we believe they exist because they explain the behavior of matter so successfully," he says.

"Our theory demands certain consequences," Gilbert adds. "If we make predictions based upon it and find that the predictions are correct, then we've gone as far as we can."

The practical results of successfully predicting how each protein is assembled could be staggering. Virtually every human disease and defect can be traced to abnormal or missing proteins. Having their blueprints opens up the possibility of designing drugs or replacing defective exons to correct these problems.

"Determining how our common ancestor was put together doesn't promise such practical consequences; it's pure basic research," Gilbert points out. "But history has shown repeatedly that today's basic knowledge becomes tomorrow's electric motor, computer chip, or miracle material. Take flu viruses, as a possibility. New strains arise every year. That's a problem in evolution. If we can understand and predict how viruses evolve, how they shuffle their exons, we could make more effective vaccines. We can never conclusively prove the exon theory of genes, but if we can realize such practical benefits from it, we will never need to do so."