Mystery of Orange Cats Finally Solved—They’re Mutants

This Strange Mutation Explains the Mystifying Color of Orange Cats

By Gayoung Lee edited by Lauren J. Young

Cats are arguably perfect. At least, evidence suggests that felines, which have evolved with minimal variation and maximal efficiency, have reached the “perfect” genetic form.

“Everything you need to know about genetics, you can learn from your cat,” says Leslie Lyons, a veterinary scientist specializing in cat genetics at the University of Missouri. Studying cats’ coat colors, for instance, has informed various aspects of modern genetics, she says. But one cat fur hue has stumped scientists for decades: orange. In house cats, orangeness appears to be sex-linked; it almost always occurs in males because of a mutation on the sex-determining X chromosome. Scientists have long been unable to pinpoint any specific gene responsible for pumpkin-colored cats, however.

Now two papers, published concurrently on Thursday in Current Biology, reveal a remarkably unique genetic pathway that has never been seen in other felines—or any other mammals. With their colleagues, two separate groups at Stanford University and Kyushu University in Japan independently arrived at the same surprising conclusion: a tiny deletion in a cat’s X chromosome increased the activity of a gene called Arhgap36, which scientists had never previously associated with pigmentation. In this case, it appeared to be coaxing the cat’s melanin-producing cells to shift orange.

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These findings close decades’ worth of investigations surrounding house cats with a ginger hue—a coat coloration that had “been recognized for more than a century [as] kind of an exception to the genetic rules that explain coloration in most mammals,” says Christopher Kaelin, a geneticist and lead author of the Stanford study.

That’s partly because what seemed to be causing orange fur in cats wasn’t so much an “orange gene” as it was an “orange mutation” in an unknown gene, Kaelin says. The term mutation refers to changes to the original DNA, notes geneticist Greg Barsh, senior author of the Stanford study. “So how do you know that a visible trait [like orange fur] is caused by a change in DNA sequence?” Barsh adds. “The answer is pretty simple: you see it inherited from parent to child.”

The marked abundance of male orange cats had long led scientists to suspect the trait is sex-linked—more specifically, tied to a variation in the X chromosome. British geneticist Mary Lyon confirmed this theory in 1961 through the discovery of X-inactivation, wherein female mammals’ cells randomly switch off one of the two X chromosomes they inherited from their parents. For most mammals, including humans and cats, this helps prevent genetic complications that might arise from having an additional X chromosome.

Male kittens, also like most other male mammals, have one X chromosome and one Y chromosome. Male cats with orange-colored parents only get one copy of the orange mutation and thus end up with entirely orange fur. Female cats, however, have two X chromosomes. If one of these happens to have the orange mutation, the process of X-inactivation will produce orange, brown or black patches depending on which X chromosome—orange or nonorange—is activated in that part of their skin. This will give the kitten an overall coat pattern that is either mottled orange and black (tortoiseshell) or a patchwork of orange, black and white (calico).

Over the years, scientists had incrementally closed in on the key mutation’s general location on the cat genome. “The candidate region had more than 10 genes, none of which was known for pigment regulation,” says Hiroyuki Sasaki, a geneticist and senior author of the Kyushu University study. Sasaki and his team decided to sequence the whole genomes of cats with different coat colors to single out any variations on the X chromosome. Similarly, the Stanford team collected a variety of data from a wide assortment of cats, directly comparing the DNA sequences of orange and nonorange ones.

Both teams identified the small mutation, which was not in the Arhgap36 gene “but close to it,” Kaelin explains. That meant that the mutation didn’t disrupt the gene’s expression in the cat’s genome but that it was close enough to affect the gene’s activity, specifically in cells that produce melanin. “That’s a very unusual kind of mutation,” Barsh says.

“The [mutation’s] pathway is interesting because it adds to the knowledge about this gene and how it functions,” says Lyons, who was thanked for contributing to cat genomic resources in the Stanford paper but wasn’t involved in either study. “This tells us that health is a complex interaction of genes and occurrences during the developmental process.”

Orange and tortoiseshell cats’ tendency toward amusing, friendly and sometimes mischievous behavior is a running joke among cat owners, but there’s no scientific evidence linking coat colors and behavioral differences, Barsh says. Researchers aren’t yet sure if the mutation could play a role in this—it’s a question they’d like to ask next, however. “Because Arhgap36 is expressed not only in pigment cells but also in the brain and hormonal glands, an interesting possibility is that its altered expression causes changes in neuronal activity and even behavior,” Sasaki suggests.

“We think that there is no advantage—or really, disadvantage—to having an orange mutation in a cat,” Barsh says. “It’s just something that happened [because] they’re attractive; people like them, and so people saved it.”