Rats get a bum rap. To be sure, rats desert sinking ships, and spreaddiseases, but the rodents have also served science for well over acentury as laboratory models of the human condition.
In fact, Rattus norvegicus was the first mammalian speciesdomesticated for laboratory research in the mid-1800s. It is today themost widely studied experimental model for biomedical research,says a paper in the January Nature Genetics.
Now the value of rats to humankind has taken a quantum jump withpublication in that journal of "the first complete genetic linkagemap" of R. norvegicus. The paper sets forth 432 DNA segments _simple sequence length polymorphisms _ between two rat strains,ordered in a single second-generation intercross along the animal's21 pairs of chromosomes.
"Because 99.5 percent of the markers fall into one of the 21 largelinkage groups," the article says, "the maps appear to cover the vastmajority of the rat genome." By comparison, linkage maps of Musmusculus, the common lab mouse, currently contain over 5,000simple sequence length polymorphisms, and more than 1,000restriction fragment length polymorphisms in genes.
Five U.S. and five European centers collaborated in the four-yearundertaking, led by the Massachusetts Institute of Technology'sWhitehead Institute for Biomedical Research. The paper's principalauthors are molecular geneticist Howard Jacobs and Eric Lander,director of Whitehead.
"Because the markers show an average polymorphism rate of about50 percent among common inbred strains," the article observes, "themap makes it possible to scan the genome in most rat crosses, andshould thus facilitate the study of many complex disease models inthe rat."
"What we're using the map for," said molecular geneticist DonnaBrown, a co-author, "is to dissect rat models of human disease. Suchanalyses are more difficult in diseases caused by multiple genes,such as hypertension or diabetes," Brown told BioWorld Today, "asopposed to single-gene disorders, such as cystic fibrosis, which youcan sometimes dissect in humans."
To illustrate the linkage map's actual use in elucidating multigenedisorders, Brown cited "the field of hypertension, which is where wedo most of our work." She explained: "You would take a rat strainthat is inbred to reliably develop this disease, cross it with a strainthat doesn't, and look for differences."
Extrapolating From Rats To Folks: Not So Far-Fetched
Variations in second-generation animals can then be mapped back totheir specific loci on the genome, depending on which rats have thehighest degree of hypertension, and which ones always share certainmarkers. "Then you know," Brown said, "that your gene of interestwould be fairly close to the marker with which you are mapping."
Rats and people have a lot in common. "There are some fair amountsof genomic conservation between mammalian species," Brownobserved. "Various parts of the rat and human chromosomes can becorrelated as to synteny conservation _ their gene order. You canbring this rodent synteny information into human studies, whichgives you new candidate genes to look for, and test in humanpopulations that are having problems." She added: "I would say thatin general there are large blocks of DNA where the order of thegenes is conserved between mammals."
Once that gene is located, she continued, "you can find out moreabout its function, and develop therapies more directed toward theactual lesion, as opposed to general therapies current at present."
She and her co-authors have been working on several crosses inhypertension, renal failure and diabetes. "We're using the map tolocate these loci, working toward their physical mapping, and seeingwhether they play a role in the human disease also."
Gene-mapping data are eminently patentable, but "Ours has not beenpatented," Brown said. "It's in the public domain, freely available onthe World Wide Web/Mosaic through the Whitehead electronicserver." The polymerase chain reaction primers, for users who don'twish to synthesize them themselves, she continued, can be obtainedcommercially from Research Genetics Inc., of Huntsville, Ala.
In an editorial accompanying the paper, mouse geneticist WayneFrankel of the Jackson Laboratory in Bar Harbor, Maine, observed:"The new rat genetic map will benefit all of mammalian genetics,although the rat clearly has the most to gain, as it is a poor cousin ofthe mouse when it comes to genetic linkage analysis."
NIH Offers $11 Million For Rat Genetic Map
Just one month ago, in the NIH Guide to Grants and Contracts datedDec. 6, 1994, the National Institutes of Health's MammalianGenomics Branch invited applications from "domestic for-profit andnon-profit organizations [to] construct a genetic map of the ratgenome with a resolution of 0.43 centiMorgans or better."
"This would be an extension of the work that we've begun,"observed the Whitehead's Brown, "and would bring the map toabout 6,000 markers."
The five-year NIH research grant amounts to "a maximum of about$11.06 million," to be awarded on or about September 30, 1995.Deadline for applications is March 15, 1995.
"For many years," the NIH announcement reads, "the rat has been animportant experimental model for studying human diseases such ashypertension, cancer, behavioral disorders, and obesity, amongothers. . . . The usefulness of the rat as a model system is hampered,however, by the lack of high-resolution genetic and physical maps ofthe rat genome."
The initiator and coordinator of the NIH rat-map project is StephenMockrin at the Heart, Lung and Blood Institute. He told BioWorldToday: "The key difference between our effort and Whitehead's map_ which was a great first step _ is that we need a heck of a lotmore signposts. We're interested in 6,000 markers. Plus choice ofstrains that are of the widest possible utility to all biomedicalresearch."
Mockrin said that 12 NIH institutes and centers bought into the $11million kitty. "Each institute contributes a certain amount," he said,"and each one benefits as if it had funded the whole thing."
Editor's Note: Readers interested in more information concerningthis NIH grant proposal may address inquires to Dr. Mockrin at(301) 496-1613. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.