“To knock out 2 megabases and not have an effectâ€â€that’s remarkable,†says Jim Hudson, a geneticist at Open Biosystems in Huntsville, Alabama. “It can’t be true,†says a skeptical Arend Sidow of Stanford University.
Arend Sidow is not a dumb or unqualified guy. He’s the principal researcher at Stanford University’s Sidow Lab. In fact this is his lab’s primary area of investigation: Much of our work rests on a simple, fundamental, principle of evolution: functionally or structurally important sites in the genome are subject to selective constraints;
So why can’t it be true? Because if evolutionary theory (natural selection) is true then it MUST BE TRUE that conserved (constrained) regions of DNA have biological activity. Arend won’t entertain natural selection at the DNA sequence level not being true. The knockout experiment, if there is no mistake, overturns his faith in evolutionary theory. So the experiment must be flawed. “It just can’t be true.” Arend is having a crisis of faith. Isn’t that just precious?
THE BIOLOGY OF GENOMES MEETING: Disposable DNA Puzzles Researchers
Elizabeth Pennisi
11 JUNE 2004 VOL 304 SCIENCE
For a long time, any DNA that didn’t make up genes was considered junk, even though it constituted the bulk of the human genome.
Gradually, though, genome biologists have found gems among this non–protein-coding sequence, suggesting that “junk†was a serious misnomer. But new research suggests that vast tracts of this sequence may be disposable after all: Marcelo Nóbrega, a geneticist at Lawrence Berkeley National Laboratory (LBNL) in Berkeley, California, finds that mice can do just fine with millions of these bases deleted from their genomes.
About 2 years ago, Edward Rubin, director of the Department of Energy Joint Genome Institute in nearby Walnut Creek, and his colleagues discovered that some DNA sequence in human gene desertsâ€â€long stretches of DNA between genesâ€â€was almost the same as the sequence in comparable mouse deserts (Science, 31 May 2002, p. 1601). This conservation across species that shared a common ancestor more than 80 million years ago seemed highly unlikelyâ€â€unless those regions served a purpose. Since then, “we’ve had the assumption that all these regions are doing something,†says Michael Zody, a computational biologist at the Broad Institute in Cambridge, Massachusetts; that something is probably gene regulation, he says.
Nóbrega and his colleagues found support for this idea when they compared desert regions conserved between fish and humans, quite distant relations. “Most sequences conserved between fish and humans are not only functional, but they help regulate genes,†Nóbrega reported. But their mouse-human comparison told a different story. They analyzed 15 comparable desert sequences and found that only one was a regulatory region in both species.
Puzzled, Nóbrega, Rubin, and their colleagues decided to delete deserts from mouse genomes, hoping to learn what other function these regions might serve. His LBNL colleague, geneticist Yiwen Zhu, knocked out two regions, one about 2 million bases long and the other about 1 million, both of which were conserved in humans and mice but not fish. After inserting the altered genome into embryonic mouse stem cells, Zhu added the cells to mouse embryos and looked for abnormalities in their descendents. “There was no sign of any difference in survival†between the genetically altered and normal mice, Nóbrega reported at the meeting. “There’s no sign of overt pathology.â€Â
Other researchers are dumbfounded. “To knock out 2 megabases and not have an effectâ€â€that’s remarkable,†says Jim Hudson, a geneticist at Open Biosystems in Huntsville, Alabama. “It can’t be true,†says a skeptical Arend Sidow of Stanford University. Both Hudson and Sidow wonder whether these noncoding regions have a function that just doesn’t show up in the tests Nóbrega did. So the question remains open, says Rubin: “Is the genome like a trash novel, from which you can remove 100 pages and it doesn’t matter, or is it like a Hemingway, where if you remove a page, the story line is lost?â€Â