Mining the mouse: a rodent's DNA sheds light on the human genome.In 1906, a descendant of Paul Revere Revere, city (1990 pop. 42,786), Suffolk co., E Mass., a residential suburb of Boston, on Massachusetts Bay; settled c.1630, set off from Chelsea and named for Paul Revere 1871, inc. as a city 1914. named Clarence Cook Little was pursuing studies in the new discipline of genetics while attending Harvard University Harvard University, mainly at Cambridge, Mass., including Harvard College, the oldest American college. Harvard College
Harvard College, originally for men, was founded in 1636 with a grant from the General Court of the Massachusetts Bay Colony. . One of his professors challenged him to do a project on the inheritance of coat color coat color
the overall or main color of the animal. If the points are distinctively colored that is also noted, e.g. black with white points.
cat coat color in mice. As part of the effort, Little mated brothers to sisters and created the very first inbred strains of mice. This reduced the variation among the mouse genes and made it easier for scientists to study inheritance.
Little rode his pioneering mouse work to prominence, becoming the president of the University of Maine "UMO" redirects here, but this abbreviation is also used informally to mean the Mozilla Add-ons website, formerly Mozilla Update
Should not be confused with Université du Maine, in Le Mans, France
The University of Maine and later of the University of Michigan (body, education) University of Michigan - A large cosmopolitan university in the Midwest USA. Over 50000 students are enrolled at the University of Michigan's three campuses. The students come from 50 states and over 100 foreign countries. . In 1929, he founded a facility in Bar Harbor, Maine Bar Harbor, Maine, may refer to:
Later that year, however, the stock market collapsed, and funds for research dried up. Little and his colleagues at the Maine center raised money by selling inbred strains of mice to other scientists. That tradition continues today. The center, now known as Jackson Laboratory The Jackson Laboratory was founded in Bar Harbor, Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B. Jackson Memorial Laboratory. , houses and sells thousands of unusual strains of mice, such as abnormally obese or cancer-prone ones.
Little, who died in 1971, would be surprised to see the current scale of Jackson Laboratory. However, the geneticist ge·net·i·cist
A specialist in genetics.
a specialist in genetics.
geneticist would be even more stunned by the progress in mouse genetics over the past few years. Using an inbred strain that Little originally created, one known as C57BL, an international consortium of scientists has deciphered nearly the entire DNA sequence DNA sequence Genetics The precise order of bases–A,T,G,C–in a segment of DNA, gene, chromosome, or an entire genome. See Base pair, Base sequence analysis, Chromosome, Gene, Genome. of the mouse. This makes the rodent only the second mammal, after people, to have its full DNA sequence, or genome, revealed.
Two months ago, the fruits of that accomplishment started to become clear. In a series of reports in the Dec. 5, 2002 Nature, biologists disclosed the results of their initial studies of the mouse genome and its comparison with the human genome The human genome is the genome of Homo sapiens, which is composed of 24 distinct pairs of chromosomes (22 autosomal + X + Y) with a total of approximately 3 billion DNA base pairs containing an estimated 20,000–25,000 genes. . The mouse seems to have almost the exact same set of protein-coding genes that people do. And when the scientists compared mouse and human DNA sequences that don't encode proteins, they found many more shared sequences than they had expected.
Researchers contend that insights gleaned from the mouse genome will ultimately have a profound impact on biomedical research Biomedical research (or experimental medicine), in general simply known as medical research, is the basic research or applied research conducted to aid the body of knowledge in the field of medicine. . "It's clear that the mouse is a Rosetta stone Rosetta Stone: see under Rosetta.
Inscribed stone slab, now in the British Museum, that provided an important key to the decipherment of Egyptian hieroglyphs. for understanding human biology Human biology is an interdisciplinary academic field of biology, biological anthropology, and medicine which focuses on humans; it is closely related to primate biology, and a number of other fields. " says Robert Waterston of Washington University School of Medicine Washington University School of Medicine, located in St. Louis, Missouri, is one of the most competitive and highly regarded medical schools and biomedical research institutes in the United States. in St. Louis.
With two genomes, we can begin to pick out what matters," adds Eric S. Lander of the Whitehead Institute of Biomedical Research in Cambridge, Mass. "We've been missing much of the story."
SHUFFLING AROUND About 75 million years ago, a ratlike animal, the last common ancestor of mice and people, roamed the planet alongside dinosaurs. Since that period, evolution has scrambled that creature's genetic code enough to produce two extraordinarily different species: Homo sapiens and Mus musculus, the common laboratory mouse.
A superficial look at the human and mouse genome reflects the huge gulf between the mouse and humankind. People have 23 pairs of chromosomes, while mice have only 20, for example. One measure of genome size--the number of base pairs, or subunits of DNA--displays a similar gap. The mouse genome has about 2.5 billion base pairs, significantly less than the 2.9 billion base pairs that make up the human genetic code, according to Lander, Waterston, and their dozens of colleagues. That team sequenced the mouse genome over the past few years, as has Celera, a biotech firm in Rockville, Md. However, Celera supplies its data only to paying customers and has published just one report on one mouse chromosome.
The number of chromosomes or base pairs by itself doesn't offer much insight into an animal's biology. For instance, closely related species can pack the same amount of DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. into very different numbers of chromosomes. And the mouse's smaller number of base pairs may simply stem from that animal's ridding its genome more effectively of so-called junk DNA junk DNA
DNA that does not code for proteins or their regulation but is thought to be involved in the evolution of new genes and in gene repair, and constitutes approximately 95 percent of the human genome. sequences than humans did.
Indeed, a close look at the two genomes reveals striking similarities. The order of genes on each species' chromosomes has been so well preserved that researchers can line up some 350 blocks of mouse genes--representing more than 90 percent of the genome--with areas in the human genome.
Evolution may have shuffled those segments quite a bit, but the correspondence holds. "If you know where you are in the human genome, you know where you are in the mouse genome, and vice versa VICE VERSA. On the contrary; on opposite sides. ," says Lander. It's like two books that have the same chapters but in different orders, he notes. Imagine if three sections of human chromosome 11 showed up as two areas on mouse chromosome 3 and one on mouse chromosome 5. From such data, geneticists This is a list of people who have made notable contributions to genetics. The growth and development of genetics represents the work of many people. This list of geneticists is therefore by no means complete. Contributors of great distinction to genetics are not yet on the list. can reconstruct the blocks of genes that probably existed in the chromosomes of the two species' common ancestor.
Mice and people also possess a similar complement of genes, say the researchers. The total number of genes used by people has been debated ever since the initial analyses of the human genome sequence 2 years ago indicated that people have just 30,000 to 40,000 genes, rather than the 75,000 to 100,000 genes that many scientists had predicted. Much of the debate centers on the definition of a gene, a surprisingly complicated issue because a cell may read the same DNA sequence in different ways to produce distinct proteins.
Today, the scientists analyzing the mouse genome estimate that the animal, like a person, has about 30,000 genes. The mouse genome has already helped scientists find more than 1,000 new human genes. Francis Collins, director of the National Human Genome Research Institute in Bethesda, Md., points to the recent discovery of a gene involved in fat metabolism that may have a role in heart disease. This gene was found in the human genome only after investigators detected its mouse version, he says.
In other cases, scientists have used the mouse data to determine that a given human DNA sequence isn't a gene. "The mouse genome is helping us clean up a lot of noise," Lander says.
He and the other investigators who sequenced the mouse genome report that some 80 percent of mouse genes have a single counterpart in the human genome, while about 20 percent have multiple versions in people. "Essentially, every mouse gene has a human [version]," says Lander.
That's not to say researchers haven't found significant differences between the two genomes. Of the mouse genes identified so far, there are 300 that don't have a recognizable human copy. Moreover, mice have many more copies of certain genes involved in reproduction, immunity, and olfaction, for example. The greater number of working genes devoted to the proteins that detect scents may reflect that rodents have a greater dependence on their sense of smell than people do (SN: 5/6/00, p. 298).
SHARE AND SHARE ALIKE The biggest surprise emerging from the ongoing comparison of the mouse and human genomes is that they share many DNA sequences that don't encode proteins. Slightly less than half of the shared DNA sequences don't seem to encode proteins, and their function remains largely a mystery.
"What do they do? We don't know Don't know (DK, DKed)
"Don't know the trade." A Street expression used whenever one party lacks knowledge of a trade or receives conflicting instructions from the other party. . That's what's exciting," says Lander, who jokes that he and other geneticists are "extending our ignorance" with their studies of the mouse genome.
Evolution is the great experimentalist, notes Landers, and it doesn't preserve DNA sequences unless they provide vital functions for an animal. "Evolution's job is to knock things out and see how it works," he says.
Scientists suspect that most of this unexplained conserved DNA somehow regulates the activity of protein-coding genes. Dramatic differences in gene regulation probably explain how a similar set of genes can produce either a mouse or a person, they say.
Some of the shared DNA, however, appears to encode RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic strands rather than proteins as its end product. Just within the past few years, biologists have begun to realize that RNA strands of varying sizes may have unexpected roles in cells (SN: 1/12/02, p. 24). In its year-end issue, the journal Science called the growing appreciation of so-called RNA genes the most important scientific breakthrough of 2002.
Another mystery emerging from the mouse genome centers on the speed with which its DNA mutates Mutates
Undergoes a spontaneous change in the make-up of genes or chromosomes.
Mentioned in: Antiretroviral Drugs . The mouse has "a rapidly changing genome, changing under forces we understand only poorly," says Waterston.
Over the 75 million years since human and mouse ancestors diverged, the mouse genome has by some measures accumulated mutations at twice the rate of the human genome. More recently, says Waterston, the mutation rate of mice seems to have sped up to five times as fast as that of the human genome, he says. Moreover, the mutations seem to accumulate at different rates in various parts of a mouse chromosome.
BETTING ON 21 Several of the reports in the Dec. 5, 2002 Nature illustrate how the marriage of the mouse and human genomes may illuminate aspects of human health. For example, two research groups tallied the list of genes on a person's chromosome 21 and examined when and where in developing mouse embryos the rodent versions of the genes are active.
There's a practical reason why both teams focused on chromosome 21. About 1 in 700 newborns has three instead of two copies of this chromosome and so develops Down syndrome Down syndrome, congenital disorder characterized by mild to severe mental retardation, slow physical development, and characteristic physical features. Down syndrome affects about 1 in every 730 live births and occurs in all populations equally. , the most common form of mental retardation mental retardation, below average level of intellectual functioning, usually defined by an IQ of below 70 to 75, combined with limitations in the skills necessary for daily living. . Because the disorder seems to involve many genes, scientists have struggled to determine which ones are responsible for the physical and mental features of the disorder.
"Finding out when and where each chromosome 21 gene is expressed during development is a crucial step toward understanding the syndrome," notes Roger H. Reeves of Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine, located in Baltimore, Maryland, USA, is a highly regarded medical school and biomedical research institute in the United States. in Baltimore.
Investigators at the Sanger Institute in Hinxton, England, have even more ambitious plans. They intend to document the pattern of activity of every mouse gene.
And researchers there and elsewhere have proposed creating so-called knockout mice--rodents in which a single gene has been deactivated--for all 30,000 rodent genes. The mutant mice should reveal which genes are crucial to mammalian development and to the health of the adult animal.
Appropriately, the laboratory that Clarence Cook Little created is among the groups entertaining the idea of such a massive project. "It's not unrealistic," says Rick Woychik, director of Jackson Laboratory. "It's a resource that would be extremely valuable."