Developmental Biology, Genetics
Pfizer-University of Granada-Junta de AndalucÌa Center for Genomics and Oncological Research
Dr. García Pérez is an assistant professor in the Department of Human DNA Variability at the Pfizer-University of Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain.
Biology of Human LINE-1 Retrotransposons
Growing up in Granada, Spain, José García Pérez would wake up early and find his father, an M.D./Ph.D. oncologist, reading scientific journals. “I remember I used to ask him, ‘Why are you studying when you have a job?,’” he recalls. His father would explain what he was trying to learn, and it struck García Pérez that one’s education never ends.
But when he began studying chemistry as an undergraduate at the University of Granada, the hours García Pérez spent watching solutions drip through a column as he synthesized a hormone-like molecule didn’t feel educational. They felt boring. One day, however, García Pérez dropped the chemical off at a research lab at the nearby medical school and stayed to watch some experiments. When he saw his compound excite the nerves in the brain of a rat, he was converted to a biologist on the spot.
He began his doctoral studies at the Spanish Research Council investigating Trypanosoma cruzi, the tropical parasite that causes Chagas disease—but his career took another unexpected turn. While searching for genes to use in developing a vaccine against the parasite, García Pérez helped to characterize a retrotransposon, a mobile piece of DNA that copies itself and inserts the copy into a new site in the genome. “That really shook me, to see that there was a fluidity of the genome,” he says.
Bits of mobile DNA, known as transposable elements (TEs), make up about 42 percent of the human genome. For years, they were thought to be merely junk DNA. While most TEs have quieted down during evolution, a small percentage still manage to hop around inside the genome. If they insert themselves into inopportune places in cells that go on to divide—such as stem cells in an adult or the rapidly dividing cells of an embryo—they can cause dysfunction and disease.
The idea that mobile pieces of DNA could cause trouble grabbed García Pérez’s attention. As a postdoc in the lab of John Moran, an HHMI investigator at the University of Michigan, he focused on one of the most abundant TEs in the human genome, the LINE-1 (L1) retrotransposon.
More than half a million copies of this segment of DNA have scattered themselves about the human genome. Most are inactive, but a few go on to cause problems. “We’re trying to figure out in what types of cells and when in development an insertion takes place and why it matters,” García Pérez says. “It’s important to know where they move, which kinds of cells can accommodate movement, and how important they are for the function of a human tissue.”
To answer those questions, Moran and García Pérez adapted an assay to determine how often a particular copy of a retrotransposon moves. Since then, García Pérez has found that the L1 retrotransposon is more active in some cell types than in others and that a number of other factors influence just how animated they are.
Human embryonic stem cells—in which insertion of mobile DNA is particularly likely to cause damage—have abundant L1 activity, García Pérez has found. In 2009, he and his collaborators showed that L1 is also active in human neuronal stem cells, the progenitors of brain cells.
Now, García Pérez wants a better understanding of the genetic outcome of the movements of mobile DNA. “We don’t know much about the impact of having a mobile piece of DNA in our genome,” he acknowledges. “How is the host genome reacting to the transposition or the generation of a mutation?”
García Pérez’s laboratory has already discovered that embryonic stem cells can silence newly inserted mobile DNA. García Pérez hypothesizes that this limits damage by reducing the numbers of active L1 elements and preventing too many changes during development. He is eager to find the factor that recognizes the mobile DNA insertion and stamps nearby DNA with a mark that keeps the region safely off limits.
TEs challenge the ideas that the genome is mostly stable and that changes to its makeup are slow, and that keeps García Pérez interested. Discoveries in his lab suggest that “the genome is much more dynamic than we think,” he says. He’s content to continue adding to that evidence, even if it goes against conventional thinking. “Any scientist has to be a little bit of a rebel at heart,” he says.