Erasing Life’s Letters

Erasing Life’s Letters

Search for a Smaller Mouse

RNA model
Ribose sugars and phosphate backbones combine with base pairs in the familiar helix.
Credit: Darryl Leja/Access Excellence.

Can you lose scores of pages from a novel and still follow the story line?

In the case of the mouse’s genome, or "book of life" — and perhaps even our own — the answer appears to be, astonishingly, "yes." Researchers from the U.S. Department of Energy Joint Genome Institute (JGI) and Lawrence Berkeley National Laboratory demonstrated that, after deleting large swaths of DNA sequence shared by mice and humans, they were still able to generate mice that suffered no apparent ills from their genomes being millions of letters lighter.

The research findings are published in the October 21 edition of the journal Nature. After completing the sequencing of the human genome, a question still lingers: is all the non-coding DNA (sometimes called "junk DNA")–which makes up nearly 98 percent of the genome–required, or is some of it potentially disposable?

"In these studies, we were looking particularly for sequences that might not be essential," said Eddy Rubin, Director of the JGI, where the work was conducted. "Nonetheless we were surprised, given the magnitude of the information being deleted from the genome, by the complete lack of impact noted. From our results, it would seem that some non-coding sequences may indeed have minimal if any function."

To see what these non-coding sequences were doing, the investigators took a brute-force approach. "To use an architectural analogy, we asked which walls in the room actually support the ceiling above," said Marcelo N?brega, lead author on the Nature paper. "Remove the walls and you will know."

Removing letters is equivalent to biochemical editing

Through molecular techniques, a total of 2.3 million letters of DNA code from the 2.7-billion-base-pair mouse genome were deleted. To do this, embryonic cells were genetically engineered to contain the newly compact mouse genome. Mice were subsequently generated from these stem cells. The research team then compared the resulting mice with the abridged genome to mice with the full-length version.

A variety of features were analyzed, ranging from viability, growth, and longevity to numerous other biochemical and molecular features. Despite the researchers’ efforts to detect differences in the mice with the abridged genome, none were found. "By and large, these deletions were tolerated and didn’t result in any noticeable changes," said N?brega.

"An important caveat, however, is that no matter how detailed our analyses, our ability to test for a particular characteristic in mice is limited. All we know is that, in the time frame examined, there were no detectable changes in the specific features that we studied."

The negligible impact of removing these sequences suggests that the mammalian genome may not be densely encoded. Similar-sized regions have previously been removed from the mouse genome, invariably resulting in mice that did not survive, because the missing sequences contained important genes and their deletion had severe consequences for the animal.

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