Fossils, Geological History May Hold Clues For New Cures

May 2, 2002

GAINESVILLE, Fla. — Clues for using the sequence of the human genome to diagnose and treat diseases may lie in our distant past, says a University of Florida professor.

The human genome contains 3 billion letters of DNA sequence and as many as 100,000 genes. Buried within this enormous pile of data is information about why people get sick and what might be done to keep them healthy. Finding this information, however, has proved difficult, with the result that the human genome project has not yet proved to be the medical windfall that was long anticipated.

In an article in Friday’s issue of the journal Science, Steven Benner, a UF distinguished professor of chemistry, writes that a solution may lie in connecting the history of genes and proteins to the geological and the fossil records of our human and pre-human past.

“The past is key to the present,” Benner says. “By understanding how proteins evolved together with the history of the planet, we can better understand how proteins work today.”

Proteins control life functions. To find how they evolved, molecular geneticists extract information about their ancestors by matching up similarities in gene sequences, which provide the recipes for proteins. The process is similar to historical linguistics, which reconstructs ancient languages by finding similarities in their descendent languages. For example, in many European languages, the word for “snow” contains an “n,” which suggests the words stem from another word in a common Indo-European language containing that letter.

Instead of languages, geneticists seek similarities in amino acids denoted by the different letters of the genetic code. They use these similarities to reconstruct the amino acid sequences of ancient proteins and resurrect these ancient proteins in the laboratory, studying them to gain insights about their modern descendants.

The next step is to date the events that produced the proteins and the genes associated with them. Friday’s Science paper reports a new way to date events recorded in genomes from sequence data alone. Benner conducted the research in collaboration with scientists at UF and the Foundation for Applied Molecular Evolution in Gainesville.

With the dates in hand, scientists can then match the events that created genes and proteins with events recorded in the fossil and geological records. This allows scientists to zero in on the genes and proteins they may be hunting, Benner says.

As an example of how this approach may benefit the search for therapies, Benner cites the cautionary tale of leptin, the so-called “obesity gene.” Rockefeller University scientists discovered this gene in mice in 1994. When they deleted it, mice became obese, creating widespread excitement that the parallel gene in humans would perform the same function, opening the door to genetic therapy or cure for obesity.

That goal has proved elusive, however, with researchers so far able to conclude only that leptin plays some role in obesity in some people in some cases.

Benner says examining the evolutionary history of the leptin gene family reveals that it evolved quickly between 40 million and 50 million years ago – after the divergence of rodents and primates in the lineage leading to human-like apes. That suggests its function in the body changed quickly as well, just as apes were moving to the top of the food chain.

“Different biochemistry in humans and mice reflects their different strategies for survival,” Benner says. “Correlating events in the genetic record with events in the fossil record suggested that leptin in humans may not play the same role as leptin in mice.”

This approach may prove useful for many other diseases, including Alzheimer’s and osteoporosis, Benner says. Scientists seeking to identify and extract genes and proteins implicated in these and other diseases today make an educated guess about what they might be, and then perform experiments to confirm or reject their hypotheses. This process is long and expensive given the dizzying number of possible interactions between all human genes.

In the paper, Benner and his colleagues suggest history can help point researchers in the right direction by narrowing the number of hypotheses that need testing.

The paper also for the first time correlates the contemporaneous evolution of different proteins, suggesting this approach could be used to find functional connections between different genes and proteins. These connections are important from the biomedical standpoint because they can open another door for scientists to control a disease, Benner says. For example, scientists may identify a protein key to Alzheimer’s disease, but they may not be able to inactivate it because it also is key to essential life processes. Finding how it is triggered could reveal a way to turn off the part of the protein tied to Alzheimer’s but leave the rest functional.

Benner is the main author of the paper. The other authors are M. Daniel Caraco, a postdoctoral researcher at the Foundation for Applied Molecular Evolution; J. Michael Thomson, a UF graduate student; and Eric Gaucher, a postdoctoral associate of the National Research Council/NASA Astrobiology Institute who works at the Foundation of Molecular Evolution.