Volume 5, Issue 39 November 2008
The Instruction Manual of the Genome
Michael Eisen is also a cofounder of the Public Library of Science (PLoS), a publisher of peer-reviewed science journals freely available on the internet, and was named a Howard Hughes Medical Institute investigator this spring. Photo credit: Noah Berger/AP, copyright Howard Hughes Medical Institute.
A squirrel, a squid and a spider appear as different as animals can be. Yet the building materials for each—a vast array of protein molecules—are by and large the same. So how can a squid have ultra-flexible tentacles while a spider has stiff, jointed limbs? It boils down to how those proteins are assembled. And the instruction manual for each body, like the code for each protein, is written within an organism's DNA.
"Many of the interesting and important differences between species and individuals arise from differences in the way genes are turned on and off," says Michael Eisen, a Berkeley professor of genetics, genomics and development. "Yet we remain largely ignorant of how such regulatory changes are encoded in DNA."
Eisen is learning to decipher the instruction manual of the genome. He combines bench-top experiments with computational biology to link genetic sequence variations with functional differences. "By characterizing the molecular machinery of gene regulation in detail, and coupling that with analyses of the genome sequences they're reading, we'll ultimately be able to understand what they do," he says.
Eisen is particularly interested in a platoon of proteins called transcription factors that control how DNA is read. Each transcription factor binds to a specific DNA sequence to influence when nearby genes are turned on and off.
Proteins called transcription factors influence how DNA is read. With the help of a special fluorescent marker, Eisen can see where certain transcription factors are active in fruit fly embryos. Image credit: courtesy Michael Eisen
Scientists are still deciphering how transcription factors work. Among the outstanding questions are why transcription factors alight on only a small fraction of possible regulatory sequences. This is partly because much of the genome is coiled around special packaging proteins. These affect how readily transcription factors bind. To complicate matters further, transcription factors may enhance or inhibit each other's binding affinity.
Eisen employs a transgenic system to reveal gene regulation in fruit flies at a glance. He inserts small chunks of DNA that activate genes in specific cell sets within developing fly embryos. Eisen joins these regulatory elements to a gene that tints cells blue when switched on. With this tool, he can identify every cell where the regulatory element is active.
Other species of Drosophila contain similar regulatory genes. Even though the specific sequences are different from those in D. melanogaster, they perform the same function.
Eisen is particularly interested in a platoon of proteins called transcription factors that control how DNA is read. Each transcription factor binds to a specific DNA sequence to influence when nearby genes are turned on and off.
Eisen hopes to use these gene segments in the same way that archeologists used the Rosetta Stone-to translate an unknown language. "It's like the same paragraph was written in all of these different languages," he says. "If we can gather different versions of these enhancers from different species, each of which has the same function but is written in a different way, we'll be able to figure out what they all have in common. We'll glean from that the heretofore elusive understanding of what actually creates these patterns of expression."
Eisen is identifying differences in transcription factor binding patterns among Drosophila fruit fly species. The study will demonstrate how gene regulation affects evolution. Image credit: courtesy Michael Eisen
Eisen will soon have plenty of enhancers to compare. He and other scientists plan to sequence the genomes of all 4,000 or so species in the Drosophila genus within the next five years.
Eisen will undertake a similar comparison among hundreds of D. melanogaster fly lineages, whose genomes are also being sequenced. For each transcription factor, he is likely to find groups of flies with different binding patterns. "We'll be able to identify what's different about the genomes of these groups, and deduce their functional effects. This is where we'll see the role that gene regulation really plays in evolution-by learning how these flies actually differ," Eisen says.
His work has major implications for the future of health care. Within the next ten years, most Americans will be able to afford to have their own personal genomes sequenced. The information could help doctors select better medications for their patients and avert potentially serious diseases. But between now and then, science has to figure out what the individual variations in each person's sequence mean.
"What limits our ability to utilize the genome sequences is figuring out what the genome says," Eisen says. "Our hope is that we'll be able to use what we learn from Drosophila and apply it broadly to the consequences of genetic variation in humans."