Genetics, Molecular Biology
University of Michigan
Dr. Moran is also the Gilbert S. Omenn Collegiate Professor of Human Genetics and a professor of internal medicine at the University of Michigan Medical School.
Studies of a Human Transposable Element
As an information storage device, the human genome appears to be strangely inefficient. Genes constitute only a few percent of our DNA. The rest—consisting largely of repeated sequences, broken-down genes, and miscellaneous evolutionary debris—seems to have so little purpose that it sometimes is called junk DNA.
University of Michigan geneticist John Moran has found treasure in that junk. He studies a genetic sequence known as long interspersed element-1 (LINE-1) whose many copies make up 17 percent of the human genome. Long thought to be a genetic parasite intent only on maintaining its presence in our DNA, LINE-1 now appears to play a more active role in shaping the genome. In fact, some have suggested that LINE-1 is responsible for many of the structural differences that separate different species of primates. "You can see evolution in action through the movements of LINE-1s," Moran says.
Moran was a relative latecomer to genetics. After studying chemistry at the Rochester Institute of Technology in New York, he entered a graduate biochemistry program at the Ohio State University. Soon after, he was required to take a molecular genetics course, and Moran says he went "kicking and screaming" all the way to his first class.
But his attitude quickly changed. "I was overwhelmed by the power of molecular genetics," he says. He stopped his biochemistry program and transferred to the Ohio State molecular genetics department as a graduate student.
Moran delved deeper into molecular genetics at the University of Texas Southwestern Medical Center at Dallas, where he completed his Ph.D.—ironically, in biochemistry—in the lab of Philip Perlman, who is now a senior scientific officer at HHMI. There, he studied mobile bits of DNA in the yeast mitochondrial genome.
He was introduced to LINE-1 during a postdoctoral fellowship at the University of Pennsylvania Medical School. "What turned me on is the idea that genomes are not static, they're fluid," Moran says. "I wanted to apply that knowledge to the human genome."
LINE-1 sequences encode proteins that can copy their own DNA sequence and reinsert it elsewhere in the genome. More than 500,000 copies are sprinkled throughout the human genome. The vast majority of these are truncated or otherwise mutated and can no longer colonize other parts of our DNA. But about 100 LINE-1 sequences in the average human genome retain the ability to copy and insert themselves elsewhere.
Sometimes these insertions are disastrous. Haig Kazazian, Moran's postdoctoral adviser at Penn, first discovered that LINE-1 sequences are still active when he found two cases in which a LINE-1 had jumped into a blood-clotting gene and caused hemophilia. LINE-1 insertions also have led to cases of muscular dystrophy, colon cancer, and other diseases.
While in Kazazian's lab, Moran made his first major contribution to the field. He created a system to track the movement of LINE-1 sequences in the genomes of cultured human cells. Since then, he has been using a rapidly expanding set of tools to study where, when, and why LINE-1 sequences jump, what effects they have on the human genome, and how host cells control their proliferation.
Sometimes LINE-1 sequences carry additional DNA segments with them when they hop into a new location, and on occasion LINE-1 insertions can benefit the organism. For example, an inserted segment of DNA may change the regulation of a gene in a useful way. "Any mutation can be neutral, deleterious, or beneficial," says Moran. "Sometimes new sequence added to a genome can be co-opted by the genome for useful purposes."
Moran's research took another step forward when he began using human embryonic stem cells to study the movement of LINE-1. Although most existing stem cell lines are difficult to work with, they have many advantages over the cell cultures he was using previously. "It's still early, but stem cells provide us with a unique resource to do this research." One of the great advantages of being an HHMI investigator, he says, is that his lab will be able to use stem cell lines that cannot be studied with federal funds.
In the future, Moran and his colleagues at the University of Michigan plan to examine the effects of LINE-1 insertion events on the activity of genes. Researchers have suggested that LINE-1 may fine-tune gene expression as organisms evolve. Being able to control and observe the movements of LINE-1 sequences makes it possible to "accelerate the evolution of the genome," Moran says.
Some biologists have speculated that genomes have retained LINE-1 sequences because of their usefulness in evolution. Moran is not willing to go that far, but he acknowledges that evolution takes advantage of whatever is available. "Are these events purposeful?" Moran asks. "Not necessarily. But they need not be purposeful to have a major impact on the genome."