A menagerie of mammals
If you stand in the lobby of the Broad Institute, it’s hard not to notice the movement of mammals above your head. A 17-foot wide mobile that hangs from the lobby’s ceiling includes the silhouettes of a chimpanzee, two-toed sloth, alpaca, little brown bat, elephant, dolphin, and more. Each of the depicted mammals gently swaying from the mobile’s branches has had its genome sequenced at the Broad Institute, the Genome Institute at Washington University, or the Baylor College of Medicine Human Genome Sequencing Center.
Broad researchers recently compared all 29 of these genomes in an effort to understand our own genomic mysteries. By looking across species, they have cast new light on the molecular components of all life and have taken an important step toward decrypting the information locked in our own DNA.
The human genome – written in the four-letter, chemical alphabet of A, C, T, and G – is like a book written in a language we cannot read. Since the completion of the Human Genome Project in 2003, researchers have had an entire copy of the text (compiled from the genomes of several people), but it’s unclear which sentences are critical to life and which are gibberish. That’s where other mammalian genomes can help: scientists are using them to help crack the code and figure out what sections contain instructions essential for life. These critical sentences, researchers theorize, will remain similar from book to book – or mammal to mammal. Researchers refer to these essential elements of the genome as being “conserved” across species. Consulting some of the other volumes in the vast library of genomes may help us understand the language of the genome and the story of our own.
“Evolution is teaching us something about biology,” says Evan Mauceli, a computational biologist in the Broad’s Vertebrate Genome Biology group. “If it’s conserved across the mammalian lineage, that doesn’t happen by accident. At this level of resolution, there’s something functional going on.”
Kerstin Lindblad-Toh leads the Vertebrate Genome Biology group and has been analyzing and comparing genomes since the first two mammalian genomes – human and mouse – were available.
“One of the greatest findings to come out of sequencing the mouse was the discovery that at least five percent of the human genome is functional,” said Kerstin. “That really laid the foundation for the mammalian sequencing we’ve been doing since.”
When Kerstin and Evan use the term “functional,” they mean that these sections of the genome are doing something critical – something that has an impact on an organism. Only a fraction of these elements actually contain the instructions for proteins, but the rest may still influence when and where proteins are put together, and therefore, the overall health of an individual. But with only the mouse and human genomes in hand, researchers had a very rough map of the landscape of functional elements.
“With only two mammals, and even with four, we could only detect things that were large, such as genes,” says Kerstin. “With the analysis of the 29 mammal genomes complete, we now have a map with greater resolution, allowing us to see where some of the regulatory proteins bind the DNA. The power of this resource is that it continues to improve with the inclusion of more species. It’s a very systematic and unbiased approach that will only become more powerful with the inclusion of additional genomes.”
The researchers plan to sequence 150 to 200 mammals, which would allow them to see the non-protein-coding parts of the genome at an even finer scale. In the mean time, the 29 mammals that have been sequenced are already helping scientists understand how the many mutations in these regions of the genome are influencing human health and disease susceptibility; with additional genomes, their understanding will continue to increase.