Mouse map marks genetic milestone

In a milestone expected to escalate the transition to an era of gene-based medicine, researchers said Wednesday they have sketched a map detailing the genetic structure of the most important animal model in biomedical research and completed the first analysis and comparison of the genomes of mice and men.

In a climax to a tale as gripping as John Steinbeck's 1937 novel that draws a fateful parallel between the two species, scientists described and analyzed the achievement in 20 articles in the British journal Nature and at news conferences in Tokyo, Washington, London and Rome.

Unlike the protagonists in Steinbeck's "Of Mice and Men," whose "best-laid schemes" go awry, the more than 1,200 players from 12 countries in the real-life science drama have scored a bull's-eye with their plans.

They have nearly completed sequencing the genome of the Mus musculus, the house mouse, a laborious task which involved placing in proper order the 2.5 billion subunits of DNA that make up the rodent's complete set of genes. The on-schedule feat holds even greater promise than the decoding of the 2.9 billion chemical "letters" of humans' genetic code, an achievement many regarded as heralding a biomedical revolution.

The deciphering of the human genetic blueprint, published last year after an 11-year effort, gave rise to the greater challenge of determining the functions of all the newly revealed genes. The mouse work, an offshoot of the Human Genome Project, should facilitate greatly the search for the all-important genetic identities and roles.

As the premier research tool in investigations of mammalian disease and biology, the mouse stands to shed unique, detailed insights into the human condition -- and ways to optimize it, scientists told United Press International.

"Publishing the sequence in 2001 of the first mammalian genome -- our own -- was a remarkable and historical achievement," said Dr. Francis Collins, director of the National Human Genome Research Institute in Bethesda, Md.

"To sequence another mammalian genome in less than two years and to discover the treasure trove of information one can derive from a comparison of the two is beyond nearly anyone's dreams. It constitutes a tremendously exciting and defining moment for biomedical research."

Although not identical, the biology and pathology of mouse and human bear pragmatically useful similarities. For nearly every gene in the human genome, a counterpart can be identified readily in the mouse. Thanks to today's cutting-edge techniques and technologies, the rodent can be genetically manipulated with extraordinary precision to reveal the secrets of a wide range of human ailments -- from heart disease, diabetes and obesity to schizophrenia, learning abnormalities and memory disorders, scientists said.

At present, an estimated 25 million mice worldwide are helping researchers study and devise treatments for such disorders as cancer, AIDS and malaria. The new elucidation and analysis of a version of Mus musculus -- which one key paper reveals shares some 80 percent of its genes with humans -- should prove a boon to investigators searching for new treatments and cures.

It will be decades, however, scientists cautioned, before the full potential of the research can be transferred from the laboratory to the doctor's office.

"Having the sequence of the most important model organism for humans is critical," Gregor Eichele of the Max Planck Institute of Experimental Endocrinology in Hanover, Germany, who co-authored one of the comparative studies, told UPI. "Nonetheless, mice are not humans and thus extrapolating from one to the other needs some caution."

Even so, the advances portend a permanent shift in biomedical research, scientists asserted.

"The mouse genome sequence will change the way research is done in this important experimental animal, just as genome sequences have opened new avenues of study for yeast, worms and flies," said Dr. Robert Waterston, director of the Genome Sequencing Center at Washington University School of Medicine in St. Louis.

Many researchers who have worked with other organisms might now switch to the mouse as their model of choice, predicted Mark Boguski of the Fred Hutchinson Cancer Research Center in Seattle, who analyzed the main paper.

"The implications are huge," Dr. Kerstin Lindblad-Toh of the Whitehead Institute-MIT Center for Genome Research in Cambridge, Mass., and lead author of the lead report, told UPI. "It will cut 10 years off some projects where disease genes have to be identified."

The emerging molecular picture of mouse biology sets the stage for devising more effective therapies, Waterston added.

"The mouse genome sequence ... has already made a huge impact on the research community," Allan Bradley, director of the Wellcome Trust Sanger Institute in Cambridge, England, pointed out. "It is a huge asset to researchers, and its significance matches that of the human genome."

In the past six months, for example, the institute -- which offers data on the World Wide Web -- has received 2.6 million online requests for detailed information about the mouse genome and 3.2 million about the human blueprint.

Scientists at Sanger, Whitehead, Washington University and the European Bioinformatics Institute in Hinxton, England, make up the Mouse Genome Sequencing Consortium. The group has opted for as-they-happen worldwide release of results from the $130 million sequencing project funded by government and private charities.

"This superb resource has been given freely to all researchers to speed the discoveries that will transform human healthcare," said Dr. Mike Dexter, director of the Wellcome Trust, which financed the Sanger research. "The medical and scientific benefits are already beginning to flow."

The data can be viewed at ensembl.org or ncbi.nih.gov/genome/guide/mouse or genome.ucsc.edu.

"The availability of the mouse genome sequence is a real leap forward in making everyday lab work simpler, quicker and more effective," said Azim Surani, professor at the Wellcome Trust/Cancer Research UK Institute in Cambridge.

The consortium's open-door policy made possible the comparative studies reported alongside the main 42-page paper. Half of these targeted the mouse counterpart to the smallest and best-understood human chromosome, which has been linked to at least 30 genetic diseases, including Down syndrome.

The congenital disorder characterized by mild-to-severe mental retardation, slow physical development and such features as low muscle tone, a flattish nose and upwardly slanted eyes occurs in some one-in-700 live births. The syndrome, which also is marked by heart abnormalities, results from an extra chromosome attached to the 21st of the 23 pairs normally present in the human genome.

"Down syndrome is the most complicated genetic insult that's compatible with extended survival beyond birth," said Dr. Roger Reeves, professor of biophysics at the Johns Hopkins University School of Medicine in Baltimore, who analyzed the work.

"It's a very, very hard problem," he said in a telephone interview. "What we do know is that some or all of the 250-odd genes on the chromosome are present in three copies instead of two."

The mouse provides the critical tool for determining what went wrong where during development, Reeves said. It also reflects what went right.

"For the first time we have an opportunity to see ourselves in an evolutionary mirror," said Whitehead Director Eric Lander. "The mouse genome represents a very important chapter in evolution's lab notebook. Being able to read this notebook and compare genomic information across species allows us to glean important information about ourselves."

Since mouse and man diverged from their common ancestor around 75 million years ago, the rodent has retained certain common genetic features that have turned it into the lab researcher's best friend.

The house mouse, which first appeared as a distinct species on Earth after the last Ice Age some 10,000 years ago, underwent a number of incarnations before being called to service in science. Along the way, mutants -- displaying unusual colors, sizes or behaviors -- caught the eye of Chinese and Japanese emperors who began selectively breeding "fancy" pet mice.

In 1909, Harvard University biologist Clarence Little had a more practical idea, creating the first inbred strain that has been used in genetics laboratories to this day. In 1921, Little developed another lab variety called C57BL, which became a research staple and whose genetic secrets now are being told.

In the sequence and analysis of 96 percent of the mouse genome, 9,000 previously unknown rodent genes popped up. Comparisons with the human genome revealed 1,200 new human genes, a significant number of which likely are involved in cancers and other diseases. These may point to targets for diagnosis and treatment, researchers said.

Both species have some 30,000 protein-producing genes, with only 300 unique to either, the studies showed. Some 90 percent of genes associated with disease are identical in human and mouse. This highlights the value of the mouse as a biomedical research tool, scientists said.

"We have learned a huge amount about human medical problems by studying mouse genetics," said Robert Winston, professor and director of NHS Research and Development at Imperial College, Hammersmith Hospital, in London. "This new landmark announcement is of immense importance and will undoubtedly further our understanding of the molecular basis for human diseases and the treatment of the widest range of human disorders."

Genetic commonalities between mouse and men are so great, humans even have genes that could make a tail, observed Dr. Jane Rogers, head of sequencing at Sanger.

The research also uncovered some differences, including a far greater number of genes involved in smell and mating behavior in mice than in humans.

The mouse genome is 14 percent smaller than the human version, one of the key papers revealed, mostly because the human genome has a great deal of repetitive sequences, once called "junk DNA" but more recently showing themselves to be anything but. Even these previously discarded regions could be critical for controlling gene activity, a separate study found.

Scientists came upon another surprise in comparing the mouse and human counterparts of chromosome 21. They found much of the genetic material common to both species is not genes but some unknown element that might play a part in regulating the function of genes or ensuring that chromosomes work properly.

"The results are important in selecting candidate genes for symptoms of Down syndrome, such as heart defects, mental retardation and dysmorphic features," study leader Dr. Stylianos Antonarakis, professor and director of medical genetics at the University of Geneva Medical School in Switzerland, told UPI.

In additional projects, researchers mapped mouse counterparts to chromosome 21 onto a three-dimensional "atlas" of a growing mouse embryo. The results should simplify deducing exactly what these genes do, they explained.

The study provides significant information on which genes of chromosome 21 could be important for the proper development of various organs, lead author Dr. Andrea Ballabio of the Telethon Institute of Genetics and Medicine in Naples, Italy, told UPI.

Using the mouse as a model, another group produced the first "expression" map of chromosome 21, showing when and where genes turn on and off.

"(The map) offers a pool of candidates for genetic diseases, and especially for Down syndrome," lead author Dr. Marie-Laure Yaspo of Max Planck told UPI. "DS is a complex disease affecting many tissues, but for which no candidate genes were identified so far."

Another international group collected the world's most complete library of gene-like segments making up the so-called mouse transcriptome -- a set of gene transcripts, or copies of instructions. The transcripts are passed on from the DNA blueprint to the RNA messenger molecule, which then translates them into proteins, complex compounds found in all living cells. The team found nearly a third of these units never are converted into proteins. Instead, their job could be to switch other genes on and off at specific times and places during growth.

"The largest-scale gene mouse transcriptome data in the world will result in rapid progress of discoveries of gene function," Dr. Yoshihide Hayashizaki, project director of the Riken Genome Exploration Research Group and chief scientist at the Genome Science Laboratory in Yokohama, Japan, told UPI. "Genetic material previously thought to be useless has now been found to have function."

Even before the mouse consortium reaches its goal to produce a completely "finished" mouse map -- with no gaps and 99.99 percent accuracy -- within the next three years, other groups are lining up with sequencing proposals.

High on the list of candidates are the chimpanzee, chicken, cow, dog, honey bee, sea urchin, several species of fungi and two simple organisms commonly used in laboratory studies, Oxytricha trifallax and Tetrahymena thermophila, according to Boguski, who sits on the panel that reviews such proposals.

"We are in a remarkable period in biology," said geneticist Bob Weiss of the University of Utah in Salt Lake City, who participated in the mouse sequencing. "In April 2003, we will have the 50th anniversary of the discovery of the double helical structure of DNA, which was just about 50 years from the rediscovery of Mendel's laws" of heredity.

"Now, we have human and mouse genomes, and other genomes across a vast expanse of living things," Weiss told UPI. "By looking at this genomic information, we realize simultaneously how far we have come, and how long we have to go -- to truly understand life."