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Humans and Mice Together at Last
Scientists compare mouse chromosome 16 to the human genome
  
By
Edward R. Winstead



Featured article.

The first head-to-head comparison of draft human and mouse genome sequences can be summarized in one word—fourteen. Fourteen genes on mouse chromosome 16 are not found in humans. All the others—more than 700 mouse genes—have counterparts in the human genome, most of which are grouped together and in the same order as in the mouse genome.


In short, the human and mouse genomes are remarkably similar not only in the structure of their chromosomes but also at the level of DNA sequence. Scientists have reported similarities between the two species for decades but never with the detail that is possible by lining up two genome sequences.

The new findings, by researchers at Celera Genomics in Rockville, Maryland, provide the strongest evidence yet that the mouse is a useful model for understanding human health and disease. Almost any gene in humans is going to be present in mice and vice versa, the team concludes.

"The study confirms what we mouse geneticists have all hoped would be true," says Neal G. Copeland of the Mouse Cancer Genetics Program at the National Cancer Institute in Frederick, Maryland. "And that is important because we're using the mouse as a model organism to study functions of genes in the human genome."

The Celera team compared mouse chromosome 16 with its corresponding regions of the human genome. Much of this chromosome corresponds to human chromosome 21, which contains genes involved in Down syndrome and similar disorders. The draft of chromosome 21 is also among the most refined publicly available human chromosome sequences.

The human counterpart genes reside in genomic blocks on six chromosomes (3, 8, 12, 16, 21, and 22). Of the genes in these blocks, only twenty-one have no obvious counterparts in mice.

The findings, which appear in today's issue of Science, have a colorful if somewhat unusual publication history. A paper was submitted to Science some months ago, received excellent reviews, but was then withdrawn by Celera officials. Eventually, the company changed its mind.

"We are just glad to see the paper published," says Mark D. Adams, who heads the genome sequencing programs at Celera.

The sequence data on mouse chromosome 16 have been deposited in the public database called GenBank. The rest of the mouse genome is available to researchers who have a subscription to the company's database. Celera's draft mouse sequence was completed a year ago.

In the eighties, researchers estimated that the human and mouse genomes consist of about 200 genomic blocks that are rearranged between the species but contain similar complements of genes. The new study confirms this notion but also shows that small stretches of DNA within these blocks are strikingly similar.

The Celera team, led by Richard J. Mural, identified 11,822 short segments of mouse DNA that correspond to just one region of the human genome. The order and orientation of DNA in these segments is nearly identical in both genomes for 99 percent of the segments. The segments are about 200 base pairs long and are called 'syntenic anchors.'

"The anchor concept is fairly new," says Mural. "The actual distribution of short highly-similar DNA matches in the genome has not been generally known."

Mural's team found these short segments throughout the genome; more than 40 percent occurred in regions that lack genes. The vast majority of segments in regions outside genes have no known functions.

Having a third mammalian genome sequence would help researchers figure out what these sequences are doing. DNA sequences that have been conserved during evolution in diverse species are likely to have similar functional roles. Researchers can test the functions of these sequences in mice by knocking them out, for example.


Detail of figure showing pairs of orthologous genes identified in the study. View full

Celera has done preliminary sequencing of the cow, pig, chicken, and dog; the chicken is on a list of species that may be sequenced by the publicly funded Human Genome Project. The rat is being sequenced, but it is probably too closely related to the mouse to be useful in this comparison.

"Nothing in this study was singularly surprising," says Mural. "The important point is that there are now complete drafts of the mouse and human genomes, and they do a lot to inform our understanding of both as well as other mammalian genomes."

Another finding is that the mouse genome is ten percent smaller than the human genome because it has fewer repetitive sequences. The size difference is consistent throughout the mouse genome, not just in certain regions. Again, earlier studies have suggested that this was the case but there has been no proof until now.

"There's a lot of data out there to suggest this degree of similarity, but this is the first time anyone has been able to compare a whole-genome assembly of two mammalian species," says Copeland, who co-authored an accompanying commentary in Science. "You couldn't have known this result without doing the study."

If there are very few mouse-specific and human-specific genes, why are the species so different? "Unfortunately, it is not possible to answer that question now," says Adams. The answer, he adds, will likely involve functional differences in related genes, in how they are regulated, and in their protein structures.

The Celera mouse sequence includes DNA from three mouse strains, and the publicly funded mouse genome project is sequencing a fourth strain. It is only a matter of time before researchers can routinely look at genetic variation within genes to understand how differences like single nucleotide polymorphisms affect the health of mice.

Because the mouse is so critical in research, the Celera team has found equal or greater interest in the mouse genome compared to the human genome. "Even researchers who are not mouse geneticists will find tremendous value from examining the sequence," says Adams.

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Copeland, N.G. et al. Mmu16—Comparative genomic highlights. Science 296, 1617-1618 (May 31, 2002).
 
Mural, R.J. et al. A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome. Science 296, 1661-1671(May 31, 2002).
 

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