Sequence Tells Mouse, Human Genome Secrets

[编者的话]

来自science的小短文。

Sequencing a genome is a little like opening a present. Researchers have been tantalized for 3 years as they've unwrapped mouse DNA. Now, they're examining the contents and finding them even more exciting. This week, researchers from around the world describe what they have found so far: discoveries about the mouse genome that are providing insights into our own genetic code and making mice an even better biomedical research tool. "The data are turning out to be as valuable as we hoped," notes Karen Artzt, a geneticist at the University of Texas, Austin.

The mouse genome is only the second mammalian one sequenced to date. The ability to compare it to the closely related human genome "makes the [work] most meaningful," says Maja Bucan, a geneticist at the University of Pennsylvania in Philadelphia. An analysis of the sequence, published in the 5 December issue of Nature, is accompanied by five papers delving into the mouse's genetic characteristics and comparing them to those of humans. Some genes and other bits of sequence are similar across the board; elsewhere, there are intriguing differences.

Humans and mice have about 30,000 genes each--about 80% of which match up, reports a team led by geneticists Robert Waterston of the Washington University Genome Sequencing Center in St. Louis, Missouri, and Kerstin Lindblad-Toh of the Whitehead Institute/MIT Center for Genome Research in Cambridge, Massachusetts. But the human genome is longer--with about 3 billion bases, compared to the mouse's 2.5 billion. And the types of genes vary: The mouse has many more genes involved in reproduction, immunity, and olfaction, for example, and the genes in the first two categories have evolved much faster in mice than in humans.

Researchers have taken advantage of the similarities between human and mouse DNA to study where in the body genes are active. "Knowing when and where a gene is expressed facilitates enormously further functional analysis," explains Marie-Laure Yaspo of the Max Planck Institute for Molecular Genetics in Berlin. A team led by Andrea Ballabio of the Telethon Institute of Genetics and Medicine in Naples, Italy, matched mouse sequence against the known genes along human chromosome 21. The researchers tracked the expression of each of these mouse genes--about 160 in all--at several stages of development, viewing expression in three dimensions in whole embryos. They also monitored which of these genes were active in 11 types of adult tissue, such as brain, muscle, and heart. In this way, they identified genes of interest, including one called Adarb1 that's involved in heart development and might play a role in Down syndrome.

Yaspo and her colleagues took a similar tack in studying genes from chromosome 21, the shortest human chromosome, but they concentrated on brain development shortly after birth. They found that about half the mouse genes were active throughout the brain and half were expressed in specific regions.

Such studies can help researchers determine the functions of normal genes. But the data can also be used to home in on genes that cause disease, says Bucan. Once they find a few candidates, knowing where each candidate is active "will make getting the [right] gene easier," she points out.

Another study took a broad view of human chromosome 21, comparing its DNA and that of the mouse genome. Stylianos Antonarakis and Emmanouil Dermitzakis of the University of Geneva, Switzerland, and their colleagues report that only about half of the more than 3000 conserved sequences turned out to be genes. That other stretches of DNA are maintained through evolution means they must be important, possibly as regulators of gene activity, and could also play a role in human disorders, says Antonarakis. Indeed, notes Lindblad-Toh, "one of the highlights [of this week's reports] is that such a large fraction of the genome is conserved."

Other mouse-centered DNA studies should make the rodent even better suited for genetic studies, says Joseph Nadeau of Case Western Reserve University in Cleveland, Ohio. In one, Claire Wade of the Whitehead genome center compared the draft sequence, which comes from the B6 strain, with DNA from another mouse strain, cataloging the differences between individual bases. She and her colleagues found 80,000 of these single-nucleotide polymorphisms (SNPs), many of them clumped together in SNP-rich regions. These landmarks and their distribution should help researchers locate disease genes, Nadeau notes.

Adding to the genetic wealth, a team from Japan's Institute of Physical and Chemical Research (RIKEN) has released almost 61,000 sequences, called full-length cDNAs, derived from mouse RNA. Many of these sequences represent proteins made by the mouse genome. Surprisingly, the total number of cDNAs proved to be larger than the number of genes, indicating that some genes are put together in different ways as they are expressed. "This is a very important point," says project leader Yoshihide Hayashizaki.

While the mouse genome sequencers celebrate their accomplishments, the U.S. team sequencing the rat genome also has cause to cheer. Last week, Richard Gibbs, director of the genome center at Baylor College of Medicine in Houston, Texas, and his colleagues announced that they had completed a high-quality draft of the rat genome. "Mouse and man are fairly far apart," Artzt explains. Having two rodent genomes "will be particularly useful" in interpreting sequences from all three mammalian species--another gift waiting to be pulled out of its box.