Sometimes it seems as if genome projects are cropping up everywhere.1 But until costs come down, limited resources are being largely concentrated into what Joseph Nadeau, professor of genetics at Case Western Reserve University School of Medicine, calls "the genome seven," an apples-and-oranges list of viruses, bacteria, fungi, Arabidopsis thaliana, Drosophila melanogaster, Caenorhabditis elegans, and mouse, with Homo sapiens in its own category.2
Researchers widely acknowledge that in the rodent arena, the mouse leads the pack in terms of critical mass and amenability to genetic manipulation. Yet the recent publication of a preliminary genome map of Rattus norvegicus and meetings at the National Institutes of Health have refocused attention on the rat.
The NIH Rat Model Priority Meeting held May 3 wasn't a call for genome sequencing, but an analysis of how the animal--long a staple of biomedical research--can best be used in light of the coming completions of various genome projects. "The National Heart, Lung, and Blood Institute (NHLBI), in conjunction with 13 NIH Institutes and Centers, organized a broad-based meeting of distinguished scientists to identify needs and opportunities, establish priorities, and recommend costs," says Susan Old, health scientist administrator in the division of heart and vascular diseases at the NHLBI. A workshop held in August 1998
assessed the tools and resources necessary to support rat genome sequencing and expressed sequence tag projects, plus set up a database. A report on the May meeting was to be available by now, but for this article, P. Michael Conn, associate director of the Oregon Regional Primate Research Center in Beaverton, sums it up: "The big question is, is a rat just a big mouse? The overwhelming conclusion at the meeting was, 'No.'" He gave a presentation on the advantages of using the rat as a model organism.
Also in May, a large team assembled a radiation hybrid map of the rat genome3; team members were from the Wellcome Trust Center for Human Genetics; Otsuka GEN Research Institute in Tokushima, Japan; the University of Cambridge; Research Genetics in Huntsville, Ala.; and the University of Tokyo. They blasted the genome into fragments, typed 5,255 markers among the pieces, and then assembled them, creating a physical map. They also put together a comparative map including rat versions of 145 human genes and 48 mouse genes.
The rat map effort illustrates several trends in the still-new field of genomics, such as a punctuated-equilibrium time course, with lengthy background work spawning spurts of frenetic activity. "The actual radiation hybrid mapping began about two years ago, but Linda McCarthy in Cambridge had taken at least one year before that to construct the set of rat cell lines," says Michael James, one of the principal investigators on the project, from Wellcome. The second trend is the sharing of technology among projects. The team used a high-throughput radiation hybrid mapping system that James' lab had developed for part of the world consortium Human Genome Project. "Almost all of the actual mapping was done on this system, and most of it was done in intensive bursts. Two Otsuka people, for example, did the 600 genes for the comparative map project in a two-week visit to Oxford," he adds.
Mice and rats are neck-and-neck in their popularity as lab animals, according to MedLine. A search from 1996 to April 1999 using "mouse" and "rat" as keywords turned up 58,606 entries for the former, and 64,395 for the latter, according to rat fan Conn. "The rat, in many ways, is a much better model than a mouse. The genetic distance between a rat and a mouse is greater than that between a rat and a human. And in terms of physiology, a rat is more similar to a human too," he says. Rats have proven useful models in studies of endocrinology, reproduction, toxicology, physiology, nutrition, cancer, and parasitology, he adds. "Most pharmaceutical industry work is done on rats," adds James.4
The rat is also easier to work with, mostly due to its larger size. Researchers can bleed the same rat several times, making it possible to monitor drug metabolism over a time course. It's also easier to obtain tissues for culture from rats, and to maintain a constant anesthesia level and body temperature during surgery. And as anyone who has had both types of rodents as pets can attest, rats are more responsive to handling and adapt more quickly to new environments, making them more suited for behavioral studies than skittish mice. On the reproductive front, rat litters tend to be of a more consistent size than mouse litters, and they reproduce more frequently. Their brains demonstrate sexual dimorphism earlier, making drug tests where gender is important more meaningful. And the rat's resemblance to humans has made it a leading contender in replacing the fetal pig in the biology classroom.5
Rats may reign in physiology, pharmacology, and behavioral studies, but mice rule genetics. Of the abstracts for papers and posters presented at the 1998 annual meeting of the American Society of Human Genetics, held in Denver in October, eight titles had the word "rat," whereas 69 had "mouse."
The rat varieties that have played a large role in biomedical research--such as models of arthritis, hypertension, and certain metabolic disorders--are the products of traditional breeding. Mice too have a long history of providing useful natural variants, but they have charged far ahead in the realm of genetic engineering.6 "One factor that has greatly impeded rat research is the general inability to genetically engineer or modify rat genes, as has been done so successfully in the mouse. It is now completely routine to make mouse transgenics, mouse knockouts, knock-ins, and conditional promoters. Little if any of this is currently possible in the rat. The impact of the ability to genetically manipulate the organism can't be overestimated," says Nadeau. James adds that transgenic rat technology exists, but the embryonic stem cell-based homologous recombination step critical to creating knockouts is not yet possible. Plus, the fact that mice have been cloned opens up new avenues in developmental biology research.7
Many members of both rodent camps agree that the current state of affairs suggests that full-scale rat genome sequencing be tabled until the genome seven, plus the human genome, have been completed. "Few of us in the field believe either that (sequencing the rat genome) will happen, or that it is really justified, at least until sequencing technology, and thus costs, improve enormously," says James.
Meanwhile, researchers can concentrate on genes that rats share with the species whose genomes are receiving priority in the sequencing stakes. "With the mouse and the human genomes certain to be fully sequenced in the next few years, one major reason for us constructing the comparative map is to exploit those sequences. The mouse and human will be a surrogate and will provide most, but not quite all, the needs of the rat community," James adds. Researchers can also continue to concentrate on known high-interest areas among the rat's 21 pairs of chromosomes. The 10th-largest chromosome, for example, harbors many genes involved in determining quantitative traits and in autoimmune disorders.
So rather than a battle of the rodents, it looks like both models will continue to guide biomedical research. "It is short-sighted to imagine that one rodent is the ideal model for all things; a greater variety of species means a greater chance to find a disease model," says Conn. Adds Nadeau, "Parts of a rat's biology are inherently more like humans, but at the same time, parts of mouse biology are inherently more like humans. No amount of genetic engineering will change these features that are the products of evolutionary adaptations. Instead, we have to learn which happens to be more similar for particular systems."
Ricki Lewis (firstname.lastname@example.org) is a contributing editor for The Scientist.