Why are mice (Mus musculus) the hands-down favorite animal model of biomedical researchers (Homo sapiens)? Their two genomes split apart some 90 million to 100 million years ago.

"I think the most important reason to me," opined mouse geneticist Neal Copeland, director of mouse cancer genetics at the National Cancer Institute in Frederick, Md., "is just how similar mice and humans are to each other. That bodes very well for using model organisms like mice for exploring the function of the human genome and human genes. We don't have any idea how half of the human genes function," he went on. "So we use model organisms like the mouse because we can make mutations in its genome and see how they affect the animal."

Copeland is first author of a "Perspective" in today's Science, dated May 31, 2002. His commentary reviews a paper by Celera Genomics Group, of Rockville, Md., in the same issue of Science. Its title: "A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome." It took 177 co-authors, from four centers - in the U.S., Australia and Israel - to produce that report.

"The reason Celera picked mouse chromosome 16," Copeland observed, "is because a lot of that murine chromosome was homologous to human chromosome 21, which has been well sequenced. I think what sets this paper apart from other papers," he told BioWorld Today, "is that this is the first time we've had almost full sequences of two mammalian genomes to compare against each other. The ideal would be complete, error-free mouse and human genomes. But we don't have that; they're both draft sequences, with holes and mistakes because they're not finished. Nonetheless, I think Science published Celera's paper now so one can infer from this single chromosome what's likely to be happening when you look at the whole genome."

Public Consortium May Outstrip Celera

That outcome may come not from Celera but from the International Public Genome Consortium, Celera's competitor. Copeland explained: "The public effort is also racing to finish their mouse genome. Their goal is a complete sequence, essentially error-free. They have just released into the public domain a new assembly of the mouse genome, which is much better than what they had before. Probably as good, if not now better, than the Celera sequence.

"The consortium is a few months behind because they're doing a lot of genomics," Copeland remarked. "I imagine soon they'll be ahead of Celera, because that company is not doing any more sequencing. J. Craig Venter [senior author of the Science paper] has left the company. They want to change Celera's whole direction from sequencing - proteomics, bioinformatics - into a pharmaceutical firm that's doing drug development.

"Indirectly," he pointed out, "the mouse 16 chromosome has relevance to drug development. A lot of mouse geneticists, including ourselves, are trying to make animal models for human diseases, so we can use those human-like mice to test drugs before they go into the clinic. Half of my research involves leukemia and lymphoma mouse models, so we can test drugs in these animals."

Copeland cited the salient mouse-human similarities that emerged from Celera's paper:

"They were able to identify 731 mouse genes, and all but 14 of those they could find in what they think is the same gene, or a related gene in the human genome. Out of those 731 murine genes they could probably say with a fair degree of accuracy that they could identify identical genes in the human genome for 509. And the 222 differences, minus those 14, are related.

"They also identified what's called syntenic anchors," he continued. "These are little pieces of DNA - 300 base pairs or a bit smaller. There's a stretch of that DNA very similar in sequence to human and mouse. They identified almost 1,200 of these syntenic anchors on mouse chromosome 16, where you can find the same little bits in human chromosome 21. These sequences are conserved if they are parts of genes because genes are conserved in evolution. They could represent exons from known or unknown genes, and a lot of those are - so it's a way of finding new genes. One reason for comparing species like human and mouse is to look for sequences that are conserved but aren't genes.

"The Celera co-authors found these syntenic anchors to be just as frequent in gene-rich regions as in desert regions where there are very few genes. And they reported these syntenic anchors as frequent in gene deserts as in gene-rich regions. They are probably conserved because they are important to the existence of the species. Another striking finding," Copeland remarked, "was that a large number of these syntenic anchors were located in runs of 128 or so in a row - the same order and orientation as in humans."

Celera Strategy Is Bullish On SNPs

Celera's project sequenced four distinct mouse strains, whereas the public consortium confined its program to one prototypic murine variety. Copeland explained, "Celera chose to do the four other strains because they were looking for SNPs - single nucleotide polymorphisms - which are very useful gene markers. They sequenced those four discrete strains and compared them against each other. They sequenced each region about five times and also incorporated the public prototype, looking for its SNPs as well. They were hoping when they did the full mouse sequence they could get a whole bunch of SNPs, and sell that information to mouse geneticists.

"But there's one drawback to that plan. It complicates the assembly if you have differing strains that aren't identical in their gene content - but at the same time you do get SNPs. It will be easier for the public consortium to assemble theirs ultimately because they're doing only one strain - but they won't get any SNPs.

"A lot of mouse geneticists are eager to acquire SNPs, but the problem is that mouse people are so few. Celera never really developed this murine source of SNPs into a database where they could commercialize it. They did it with the human genome because there were so many people who wanted it and were willing to pay for it, so it was worth their while."