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The cat could serve as a model for more than 200 human inborn genetic errors.
What makes the feline genome so important is that "the cat's genome is clearly the closest to the human of any mammalian genus other than primates," notes Stephen J. O'Brien, chief of the LGD. Our furry feline friends have "maybe 75 percent homology to humans in terms of [genetic] content," O'Brien says.
The domestic cat, Felis catus, has 19 pairs of chromosomes (18 pairs of autosomes and one pair of sex chromosomes), while the human has 23 pairs (22 pairs of autosomes and one pair of sex chromosomes). Dogs, on the other hand, have "39 pairs of little, tiny chromosomes that you can barely tell apart," remarks O'Brien. Various comparative chromosomal mapping techniques show that there are many areas of regional syntenies (known marker genes that lie on the same chromosome) between the human and cat chromosomes.1
In both the feline and human genomes, there has been little rearrangement over the course of evolution, since about 90 million years ago when the carnivores and the primates diverged. Looking at the mapped human and feline chromosomes side by side, you can see that large regions--in some cases, nearly entire chromosomes, such as human chromosome 5 and feline chromosome A1--are homologous. It would take little to rearrange the feline chromosomes so that they almost entirely match the human chromosomes. O'Brien remarks that even with inversions or flips, in which areas of the chromosome from one species run in the opposite direction in the other, and with translocations, where segments found on one chromosome in one species are on another in the second species, "it only takes 10 scissor cuts to reorganize the human chromosome[s] into a cat or vice versa." He adds that it would take about 30 cuts to reorganize the cow's chromosomes to fit the order in the human.
O'Brien notes that the genomes of the cat and the human are highly conserved. This, according to William J. Murphy, also of the LGD, makes the cat "a better tool for looking at genome structure and evolution" than the dog. He explains, "The dog happens to be highly rearranged," and it is difficult to find extended conserved areas of DNA in the dog. Other animals with rearranged chromosomes include the mouse, most of the bears, the rat, and the gibbon. "Those are examples of species where the ancestral genome organization has been reshuffled pretty much beyond recognition," Murphy says. The cat genome, says O'Brien, is "going to tell you what the primitive mammal looked like."
A 20-Year Quest
O'Brien, who originally was a Drosophila population geneticist, began studying the feline genome by a back door route. "It wasn't like I loved cats since I was a little boy," he says. "I liked dogs and hated cats." He became interested in cats because of the science. When he first started at the National Institutes of Health, he was interested in studying the genetic relationship between retroviruses and their hosts. Chickens, mice, primates, and cats were known retroviral hosts. O'Brien decided to look at cats. He "realized there wasn't a gene map, [and] I figured we'd build one" in short order. That was more than 20 years ago. He developed the first cat gene map in 1982, which was published in a cover article in Science,2 and he published the first framework map of the domestic cat about seven or eight years ago. "It had about 150 genes," says O'Brien. "Where genes were linked together in cats, were they linked together in other species?" he asks rhetorically. "The answer is, 'Yes.'"
Menotti-Raymond first mapped type I loci in the cat (evolutionarily conserved coding genes that are known markers in the human genome). She now is filling in the feline map with type II loci (microsatellites that are abundant, short tandem repeating segments with a high mutation rate). She began her career studying the evolutionary genetics of Drosophila, but she ended up studying cats at the LGD because "Steve's so charismatic."
But the ongoing study of the feline genome is more related to Drosophila than to charisma. "All the Drosophila mutations we find, we don't find in humans," states Menotti-Raymond. "They help us understand basic biology." And researchers hope that knowledge of the feline genome will aid in understanding basic biological processes, too. Some coat color genes, for example, which control not only color but also spotting and striping, may be unique to the cat. "Some of these, like spotting, haven't been mapped in anything and have to be mapped in the cat," says Menotti-Raymond. Such genes may be "related to neurological and developmental processes."
More Than Just Pretty DNA
Reasons for mapping the feline genome extend beyond basic biological and evolutionary interest. Such maps will aid in identifying animal models of human hereditary diseases. O'Brien notes that the cat could serve as a model for more than 200 human inborn errors. Urs Giger, chief in the section of medical genetics at the School of Veterinary Medicine, University of Pennsylvania, noted during a recent short course on feline genetics for cat breeders held at the department of animal science, Cornell University, that there are about 189 recognized genetic diseases in cats.
And what makes the cats so useful, notes O'Brien, is that because of high levels of veterinary care, there is extensive medical surveillance and a vast extensive literature on feline diseases. "The level of scrutiny associated with the house cat is greater than [that for] other species except humans and dogs," says O'Brien. "You have a [nonscientific] literature that worships cats; anecdotes are endless," and, adds O'Brien, you can look at feline relatives by going to the zoo.
Among the genetic diseases that are similar in humans and cats are hemophilia A and B. The former is a defect in clotting factor VIII, while the latter is an abnormality in factor IX. Marjory Brooks, associate director of the comparative coagulation section in the diagnostic laboratory of the Cornell University College of Veterinary Medicine, notes that hemophilia is one of the most common hereditary coagulation defects in cats. In the last five years, Cornell has identified 20 cases of feline hemophilia A and six cases of hemophilia B. Like the human genetic defect, feline hemophilia A and B are sex-linked traits. Therefore, we know that the genes responsible for both forms of hemophilia are carried on the X chromosome. Hemophilia A and B are both single-gene defects. Clotting factor VIII and factor IX proteins are each the product of one gene. The feline genome map will not be the only important key in finding the cause of feline hemophilia. "We know which genes are involved," says Brooks, "but we do not know how mutations cause the gene product to malfunction." With knowledge of the human genome map to find the feline homologues of factor VIII and factor IX, researchers can then go back and look for the sequence of these genes on the feline X chromosome. "With the human map, you have a tool. You don't have to go back to square one," states Brooks. "You have a framework to look for the location of your disease gene."
Locating the hemophilia A and B genes on the feline genome map will be beneficial for cats and for humans. Brooks points out that although hemophilia is passed down with the X chromosome, it is likely that different mutations cause hemophilia in "different affected families and breeds.... We think each case in unrelated cats results from a distinct or de novo mutation. [T]here are many new mutations," remarks Brooks. "Are they the same mutations as in people? Are they the same in dogs? That could give insight into how and where genes mutate." At the same time, identifying the specific mutations could result in highly accurate diagnostic tests for detecting carrier cats--tests that will pinpoint which mutation the particular breed or family has.
In humans, polycystic kidney disease (PKD), according to Stephen P. DiBartola of the department of veterinary clinical sciences, College of Veterinary Medicine, Ohio State University, is an autosomal dominant defect and is the most common human genetic disease, affecting between 1:500 and 1:1,000 live births. It results from a defect in one of two genes, PKD1 on chromosome 16p13.3 or PKD2 on chromosome 4q21-23. The PKD1-mediated form is the most common. Both diseases cause abnormality in the protein, polycystin, which has a role "in the development of tissue that has a branching structure," DiBartola told the Cornell feline genetics class. Affected individuals form cysts within the kidney, but they also can form cysts in the liver and pancreas and have other defects as well, including cerebral aneurysms, mitral valve defects, and hypertension. They eventually die of the disease.
PKD also occurs in long-haired cats. It, too, according to DiBartola, is an autosomal dominant disease and, as in human PKD, homozygotes are nonviable. DiBartola is working with Menotti-Raymond and O'Brien, using primers from human PKD1 to identify the gene or genes responsible for this defect in cats.
Hypertrophic cardiomyopathy is another example of a genetic defect that cats and humans share. Mark Kittleson, associate director of the Veterinary Medical Teaching Hospital, University of California, Davis, explained to the Cornell genetics class that this disease results from a point mutation in the ß-myosin heavy chain within heart cells. More than 125 different mutations in nine separate genes have been identified in human females with this disease. In humans, it is inherited as an autosomal dominant. It also has been identified in Maine coon cats and some American shorthair cats. In affected individuals, there is a marked thickening of the left ventricular wall. Researchers currently have nine candidate genes for the site of this mutation in Maine coon cats and are searching for other genetic markers of the disease. Once the genes have been identified, it will be possible to devise a genetic test to identify the defect in this breed.
Genetic testing is of increasing concern to people who want to know if they carry a particular, usually harmful, genetic trait. But it can be important for cat breeders, too. The University of Pennsylvania's Genetic Testing Laboratory offers feline testing for inborn errors of metabolism, such as ornithine aminotransferase deficiency, liver disease, taurine deficiency, decreased levels of felinine, lactic acidosis, isovaleric aciduria, excessive oxalate, diabetes mellitus, mucopolysaccharidoses, alpha-mannosidosis, and numerous other tests, including blood typing. Most of these tests are valuable for cat breeders so that they know if any animal they are planning to breed or any kitten that is born carries a specific trait. It also can aid a veterinarian's diagnosis for a sick cat.
The NCI cat genome group, from left, William J. Murphy, Victor David, Marilyn Menotti-Raymond, Joan Menninger, Stephen J. O'Brien, Eduardo Eizirik, and Naoya Yuhki.
Model for Viral Diseases
The reason O'Brien first became interested in cats remains important. Cats are host to numerous viruses: feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), the endogenous retrovirus RD-114, feline coronaviruses, feline panleukopenia virus, etc. FeLV and FIV, both of which result in severe immunodeficiency, have served as models for human immunodeficiency virus (HIV) infection.
Virologist Colin Parrish of the James A. Baker Institute for Animal Health at Cornell's College of Veterinary Medicine has been studying how the feline panleukopenia virus underwent mutation some time during the 1970s and acquired the ability to infect canines. That mutated virus, canine parvovirus, was first identified in dogs in 1978. This mutated virus has since given rise to several slightly variant strains of canine parvovirus. Parrish is studying "how mutations in the virus can alter the host animal that it can infect. One host range is the ability to infect cats, the other is the ability to infect dogs." For the latter to occur, the virus mutated so that it could take advantage of the specific properties of the canine cells. Parrish explains that he is now trying to define how dogs differ from cats in control of their viral susceptibility to this particular disease.
Parrish's laboratory has identified a gene from the cat that controls infection of cat cells. When transferred to dog cells, this gene makes them susceptible to feline panleukopenia virus. The gene was mapped to feline chromosome C2 using hybrid cell and radiation hybrid mapping in collaboration with O'Brien's laboratory at NCI.
Not only will the results of the research lead to new ways to increase resistance to the virus in dogs, but also at the level of basic biology, it will explain what allows a virus to become infectious for a new host and what causes the host's cells to succumb to virus infection.
Knowledge of the cat genome also will help in understanding the evolution of the Felidae, the cat family, which includes 37 species. About 12 million years ago, the South American feline lineage, which is basically the ocelot lineage, split off from the common ancestor of all the cats. Two million years later, the smaller cats, including the domestic cat lineage, evolved. The house cat is the domesticated version of the African wild cat, Felis silvestris, notes O'Brien. Understanding the evolution of the feline genome will help scientists better understand both the natural history of the wild cat and the process of domestication that led to the companion animal of today. In fact, Murphy, from O'Brien's lab, has "just finished up a study that revises traditional views of mammalian taxonomy," using his work on the feline genome. This paper is about to be published.
Suggested ReadingM.D. Kittleson et al., "Familial hypertrophic cardiomyopathy in Maine coon cats: an animal model of human disease," Circulation, 99:3172-80, 1999.
M. Menotti-Raymond et al., "A genetic linkage map of microsatellites in the domestic cat (Felis catus)," Genomics, 57:9-23, 1999.
W.J. Murphy et al., "Extensive conservation of sex chromosome organization between cat and human revealed by parallel radiation hybrid mapping," Genome Research, 9:1223-30, 1999.
C.R. Parrish, "Host range relationships and the evolution of canine parvovirus," Veterinary Microbiology, 69:29-40, 1999.
Web Sites and Other Contacts The Laboratory of Genomic Diversity (LGD), including the most current maps of the feline genome, may be accessed at rex.nci.nih.gov/lgd/Cat/cat_genome.htm.
The School of Veterinary Medicine, University of Pennsylvania, section of medical genetics Web page may be accessed at www.vet.upenn.edu/penngen/view.html. This site also includes abstracts from the First International Feline Genetic Disease Conference, held June 25-28, 1998, at the University of Pennsylvania.
Cornell's Feline Genetics Symposium, which is a distance learning course, will be available via the Internet. For information, contact Susan Hunter Herbert: email@example.com.
Perhaps one of the most unique uses of feline genomic data is in forensics. It began in 1996 when the Royal Canadian Mounted Police contacted the LGD. The laboratory "utilized genetic markers developed in the cat genome project to conduct forensic analysis of a single cat hair deposited at a ghastly murder scene," recalls Menotti-Raymond. She served as a witness in the murder trial at which a man was convicted of murdering his estranged wife based on genetic identification of his cat Snowball's hair.3
"The work established an important legal precedent for introduction of an animal DNA fingerprint identification in capital crimes," states Menotti-Raymond. Carrying this one step farther, the U.S. Department of Justice has recently provided funding to the LGD "to develop a genetic database for forensic analysis in the cat," she says. The lab is asking cat owners to participate in the project by donating blood or cheek swab samples from their unrelated cats to the laboratory. (For information on how to participate, E-mail her at firstname.lastname@example.org.)
Feline Genome Almost Complete
Thus, although little known, the feline genome research continues at a rapid clip. Menotti-Raymond expects that the feline genome map including type I and type II markers will be available within the next 18 months. O'Brien expects the full feline genome map to be somewhere between the third and fifth mammalian one to be made public, after the human and mouse genomes.
O'Brien says a meeting that will include both the canine and feline genome researchers is in the works for next year.
"Once you discover everything there is to know about the cats, you can't understand why anyone works on anything " says O'Brien. "Everything I needed to know about genetics I learned from my cat," he quips. S
Myrna E. Watanabe is editor of Cornell University College of Veterinary Medicine's newsletters for pet owners, CatWatch and DogWatch.
1. W.J. Murphy et al., "A radiation hybrid map of the cat genome: implications for comparative mapping," Genome Research, 10:691-702, May 2000.
2. S.J. O'Brien, W.G. Nash, "Genetic mapping in mammals: chromosome map of the domestic cat," Science, 216:257-65, 1982.
3. M. Menotti-Raymond et al., "Pet cat hair implicates murder suspect," Nature, 386: 774, 1997.