What actually makes us who we are?

That is the question that two Penn State researchers have been asking for over 10 years, working towards unraveling the genomic sequence of the Norway rat in an attempt to unlock the secrets of the human genome.

Ross Hardison, professor of biochemistry and director of the Penn State Center for Comparative Genomics and Bioinformatics, and Webb Miller, professor of biology and computer science and engineering, have been in collaboration on various genomic projects since the late 1980s.

Through the more than 12 years of discovering sequences and attempting to develop way to align these sequences, exceptional collaborators have joined the team and a great deal of new discoveries have been made and new techniques have been developed, Miller said.

Through a partnership with researchers here at Penn State and across the country, Hardison, Miller and their collaborators have successfully completed the genomic sequence of the Norway rat.

Now that this rat genome has been sequenced and is understood more clearly, it can be compared to both the mouse genome and the human genome. Much of Hardison and Miller's current and future work will focus on how to compare the sequences and find relationships in the data.

Miller said he is confident that having three sets of genomes will allow the team to address a completely different set of questions than used to be asked with only the mouse and human genomes.

With two sets of sequences, one can see that they are both different; but with three sequences, one can study exactly how they changed to be different, Miller said.

As more genomes are being examined and mapped, each produces a new set of challenges, explained Miller, who often adjusts current software and develops new techniques to reach meaningful comparisons between the genomes.

"My rule for each new genome is to look at different questions than the last genome," Miller said. "That's the really fun part, getting to see something exciting that I never saw before."

Hardison explained that their interest in the alignments of the genomes is important because the comparison can lead to finding out which sequences are important and which are not.

Hardison and Miller explained that it is estimated that only 5 percent of the human genome is actually doing something to improve the biological fitness of the individual; possibly through the comparison with the mouse and rat genomes, this 5 percent can be isolated.

About a third of the human genome matches with the rat and mouse genetic sequence. It is in these similar sequence regions that the 5 percent is believed to reside, Hardison said.

Through this comparison, probabilities of a specific part of the sequence being important are calculated.

Miller also added that upon closer examination, they have also discovered that in most cases, it is the regions that are changing more slowly in the genome that have the highest probability of being functional.

While bioinformatics and comparative genomics may be a fairly new science, the advances in both computing software and scientific maturity and acceptance towards certain genomic theories have helped it progress to its current point over the last 10 to 15 years, Miller said.

Before they began sequencing the rat genome, Miller had no idea that the project would be so encompassing or where the data would take them, but through more than a decade of study, it become more apparent.

Hardison explained that this science is now becoming more prominent, and its purpose has been concretely established.

"The more we understand gene evolution, the better we can infer their biological function and assign it," he said. "You find out things you never expected to learn about evolution."

Miller suspects that dozens of genomic sequences will be mapped in the next few years but not with the same depth as the mouse and rat genomes. Once a fairly good number of genomes are established, researchers will be able to determine with high accuracy which parts are important.

Once the human genome can be mapped and labeled effectively, it will lead to a great deal of medical advancements.

Miller said he believes deciphering the human genome will lead to more beneficial improvements in the next century and even within his lifetime.

"Cancer has had a large impact on my personal life, and that's part of what gets me up every day," he said. "I want cancer researchers to have the best information to study, but it's not just cancer; it can be used for diabetes or heart disease, too."

Hardison added that it is not only health care that is helped by genomic research.

"We emphasize health care, but similar approaches can be used in plant genomics and can be of great agricultural importance; there is a good chance we can improve the food supply through plant and animal disease resistance," he said.

However, Hardison said he agreed that the greatest benefits of his research involve human health and well-being.

"What I think about the most is what we can learn from genetically inherited diseases and that some of the stuff we are doing that cancer biologists are using," he said. "With cancer, things go wrong, the biological regulation falls apart, and we need to understand what makes that happen; that's where we are contributing valuable information."