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A new study may have uncovered exactly what makes orange cats special — though it might not be for the reason you think.
Ginger kitties are known among cat owners for being particularly friendly and feisty. To geneticists, however, the uniqueness of these house cats comes from the unusual way they get their color. Now, scientists say they have unraveled a longstanding mystery by identifying the specific DNA mutation responsible for that golden hue — and the variant has not been found in any other animal.
The genetic variant is described for the first time in a paper published May 15 in the journal Current Biology.
“This is a really unusual type of mutation,” said lead study author Christopher Kaelin, a senior scientist in genetics at Stanford University in California.
The vast majority of fully orange cats are male, which led scientists to reason decades ago that the genetic code for orange color is carried on the X chromosome. As with other mammals, female cats have two X chromosomes, while males have one X and one Y. Any male cat carrying the orange trait on its one X chromosome will be entirely orange. A female would need to inherit the trait on both X chromosomes (one from each of her parents) to be completely orange, which makes it less likely. Instead, most female cats with orange fur have patchy patterns — calico or tortoiseshell — that may include black and white.
But where the mutation exists on the X chromosome, and how it gives rise to orange coloration, has been an enigma until now. Typically, mutations that lead to yellow or orange fur in animals (and red hair in humans) occur within genes that control for color. And those genes aren’t carried on the X chromosome. “That suggested to us that by identifying the molecular cause, we might learn something new and interesting, which turned out to be the case,” said senior study author Greg Barsh, a professor emeritus of genetics and pediatrics at Stanford.
The findings not only elucidated the peculiar origins of some cats’ charismatic coloration, but also revealed new insights about a familiar gene.
Genetic glitch behind orange cats
Step one was to identify genetic mutations that are unique to orange cats and might give rise to their color. For a decade, Kaelin has frequented cat shows, asking owners of ginger-colored cats if he could take samples of the animals’ DNA with a cheek swab. (He’s also interested in patterns that are similar to those found in wild cats such as leopards and ocelots, which are common in popular breeds like Bengal cats and Toygers.)
Comparing his collection of DNA with feline genomes that have been sequenced in the past five to 10 years, he and his research team found 51 genetic variations on the X chromosome that were shared by orange males. But 48 were also found in non-orange cats, which left three likely candidates for the elusive mutation.
One was a small, 5,076-base pair deletion that removed about 0.005% of the X chromosome in a region that didn’t appear to code for a particular protein. The deletion wasn’t located within a gene, where mutations usually are found. However, the mutation lay between two sites associated with a nearby gene called Arhgap36, which regulates an important hormone signaling pathway used by nearly all mammalian cells and tissues. There was no known connection to pigmentation. The gene isn’t even turned on in pigment-producing cells.
To find out how the gene affects color, Kaelin studied its actions in live tissues collected at spay and neuter clinics that otherwise would have been discarded. The experiments showed that, somehow, the deletion activates Arhgap36 in pigment cells, where it blocks production of black pigment so the cells produce orange instead.
The variant has not been found in other animals, including the wild cats that gave rise to domestic cats.
“It’s a genetic exception that was noticed over a hundred years ago,” Kaelin said in a news release by Stanford University. “It’s really that comparative genetic puzzle that motivated our interest in sex-linked orange.”
That singularity suggests the mutation probably occurred once during domestication and then was selectively bred for, Kaelin said. “We see the same mutation in all orange cats that we’ve looked at over a wide geographic area, so there’s a single mutation that occurred,” he said. “And we know that mutation is quite old because there are depictions of calico cats in Chinese art that dates to the 12th century.” He added that specialists in prehistoric DNA might be able to use the new findings to pinpoint when and where the mutation originally arose.
“The variants identified could serve as valuable tools in population genetics to trace domestic feline evolutionary history,” said Hannes Lohi, a professor of veterinary biosciences and genetics at the University of Helsinki in Finland. Lohi was not involved in the study.
In the meantime, Kaelin and his collaborators want to figure out how a small deletion that’s not itself within a gene can change the activity of a nearby gene.
“The goal is, sure, that we’ll learn about the mutation,” Barsh noted, “but we also want to learn more about mutational mechanisms in general: Why is this so unusual and might the same mechanism occur in other genes that cause other phenotypes in other animals?” He pointed out that there are many conditions in humans that are thought to be genetic, but for which no genetic mutation has been identified. Maybe, he posits, the problem isn’t just that we haven’t located the mutations, but that we don’t understand all the ways that mutations can cause disease traits in the first place.
And could orange cats’ unusual genetics possibly explain their particular personalities? So far, Kaelin says he and his colleagues have no reason to think so, though other researchers could make use of the new study’s findings to look for associations between behavior and coat color. “I think orange cats have really convinced their owners that they’re different, but they’ve yet to convince us,” he said.
Amanda Schupak is a science and health journalist in New York City.
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