Mice Thrive Despite Massive Genetic Makeover

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 Nóbrega, lead author on the Nature paper. "Remove the walls and you will know."

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 Nóbrega.

"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.

The other authors of the study include Yiwen Zhu, Ingrid Plajzer-Frick, and Veena Afzal.

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This research was made possible by the National Institutes of Health Programs for Genomic Application along with support from the DOE Office of Biological and Environmental Research.

The Joint Genome Institute

(http://www.jgi.doe.gov) was established in 1997 as part of the Human Genome Project by combining the DNA sequencing resources from the three DOE national laboratories managed by the University of California: Lawrence Berkeley and Lawrence Livermore national laboratories in California, and Los Alamos National Laboratory in New Mexico. JGI has since extended the scope of its sequencing to whole-genome projects devoted to microbes and microbial communities, model system vertebrates, aquatic organisms, and plants. Funding for the JGI is predominantly from the Office of Biological and Environmental Research in the DOE Office of Science.