The genome of a mouse is structurally a chaotic place. At some point in its evolutionary past, the mouse mixed up its ancestral genome like a game of cards, corrupting the architecture that makes most other mammalian genomes look like a mammal. “I always think it’s the biggest outlier,” said Bill Murphy, a geneticist at Texas A&M University. “It is about as different from any other genome of placental mammals as the moon is compared to anything else on earth.”
Mouse genomes are still incredibly useful. Years of painstaking tinkering, meticulous mapping, and insane breeding have allowed researchers to decipher the mouse’s genetic code so thoroughly that they can age the animals up or down or change their susceptibility to cancer – findings that have a major impact on humans. But the mouse’s genomic disorder makes it less suitable for research that might help us understand how our own genetic codes are packaged and stored. Because of this, some researchers have turned to other subjects of study, just one step up the food chain.
It turns out that cats harbor genomes that are similar to how we look and behave. “Aside from primates, the cat-human comparison is one of the best you can get,” said Leslie Lyons, a feline genetics expert at the University of Missouri, on genome organization.
Lyons and Murphy, two of the world’s foremost experts in cat genetics, have long been on a mission to make a name for themselves in their small area of research. In addition to genetic architecture, cats share our homes, diets, behavior, many of our microscopic pests, and some of the chronic diseases – including diabetes and heart problems – that permeate western life. “If we could figure out why these things happen to some cats and not to others,” Lyons told me, maybe humans and cats could have a few more health benefits as well.
Cat genomes are now essentially mapped end-to-end, “with near-perfect sequence,” said Lyons, an achievement researchers recently achieved with humans. Complete genomes create references – flawlessly transcribed texts that scientists can sift through with no blank pages or deletions to block. Cats cannot tell us when they are sick. But more investment in cat genomics could pave the way for precision medicine in cats, where veterinarians assess the genetic risk for various diseases and intervene as early as possible to give them “a leap into diagnostics,” Elinor Karlsson, expert on Vertebrate genomics at the institute told me. Since humans and cats are plagued by some of the same diseases, identifying their genetic calling cards might be good for us too. For example, cats can develop a neurological disorder similar to Tay-Sachs disease, “a life-threatening disease for children,” said Emily Graff, a veterinary pathologist and geneticist at Auburn University. But gene therapy appears to work wonders for the disease in cats, and Graff’s colleagues plan to adapt treatment for their analogues in children.
The cat genome could also fuel more fundamental scientific endeavors, Lyons told me. Essentially all cells in our body contain identical genomes, but have extremely different developmental fates. Researchers have spent decades trying to unravel the mechanics of this process by which cells have to force some of their genes to dormant while others are used extensively. One of the most dramatic examples of this phenomenon is the muting of one of the two X chromosomes in female cells. “We still don’t have a good sense of how genes are turned on and off,” said Sud Pinglay, a geneticist at New York University. “That’s a whole chromosome.”
X inactivation is what stains the coats of calico. These cats are almost exclusively female and must be genetic mutts: one of their X chromosomes carries an orange gene, the other a black one. Only one chromosome remains awake in each cell. This decision is made early in a cat’s development, and the cells that split off from these lineages stay true to the color chosen by their parent cells and create large patches of color. “That helped us summarize that the inactivated X chromosome was relatively stable and remained stable over many rounds of cell division,” said Sundeep Kalantry, an X inactivation expert at the University of Michigan. “This is why the calico cat has such a prominent place in X-inactivation.”
Genomes can be so persistent in inactivating X that they can hold their own after being moved to other cells. The first cloned cat named Carbon Copy, or CC for short, was genetically identical to a classically colored calico named Rainbow. But CC was only born in shades of brown and white: it had apparently been created from a cell that had turned off its orange X and refused to go back.
Many of the vagaries of gene and chromosome silencing – their relative persistence or impermanence in different contexts, for example – are still studied in different types of researchers, including Kalantry, whose lab website has an engaging photo of a calico. But they have long known that the shape and structure of a genome and the arrangement of the genes in it determine how its content is expressed. Most of our genome is believed to be made up of annotations and embellishments that shape the reading of the rest; DNA snippets can even twist, bend and cover great distances to underline each other. This is a big area that cats can help us in, Lyons told me: If their genes are organized like ours, maybe they are regulated like ours too. “Maybe this is where the cats come in,” she said.
Some people may feel uncomfortable with the idea of testing cats in the laboratory. Murphy notes, however, that a lot of genetic work can be done very gently. His team has gotten very good at extracting clumps of DNA from cat cheek cells by using small wire brushes that they wave into the animals’ mouths.
Working with popular pets also has great benefits: people in the community are often eager to contribute either directly or through their veterinarians. When cats get sick, researchers can give them a try and, in many cases, help them get better. “I’d say about 90 percent of the studies in cats are done on naturally occurring disease models,” Murphy told me. And the cats that go through Lyons’ lab in Missouri, she told me, will be adopted after they finish their science careers.
Mice are easy and cheap to breed and keep in laboratories, and they already have a hell of a head start in scientific research. Cats are unlikely to outperform them; they may not even outperform dogs, who are particularly fond of working with people, and they have done that extensively, told me Gita Gnanadesikan, a canine researcher at the University of Arizona. As research volunteers, cats tend to be grumpier and more reserved. (Dogs also have disadvantages. We know a lot about their genomes, but dog breeds have been so genetically isolated that their populations “aren’t diverse, so they’re not that good of a model for humans,” Karlsson told me.)
But cats have their place, experts told me – as members of a whole menagerie of animals that humans would understand better. “In genetics, there is this tension: are you trying to learn all about a small number of organisms, or do you branch out and try to learn a little about a larger number of species?” Gnanadesikan told me. “I think one of the answers to that is just … yes.”