Why are some cats orange? Stanford scientists solve century-old mystery
Orange cats are special — and not just because of notoriety for silly behavior. They have also been a longtime genetic enigma.
Scientists have now cracked the cat color code. Two studies, published in tandem Thursday, pinpointed the gene responsible for orange cat fur. One study was led by Stanford University's School of Medicine and scientists based in the United States; the second was led by researchers in Japan.
'Over the past hundred years or so, it was recognized that orange cats kind of fall outside of the genetic rules for how coat color in mammals is determined,' said author Christopher Kaelin, a geneticist at Stanford University's School of Medicine. The investigation of felines' orange coat color addresses broader questions about animal evolution and how gene regulation is encoded in the genome, Kaelin said.
Past studies pointed to the orange mutation as being on the X chromosome. By analyzing sequencing data, the American scientists further mapped the mutation to a DNA deletion near a gene called Arhgap36. In humans, increased expression of this gene has been implicated in brain tumors and endocrine cancer, according to the study.
The researchers found cats with the orange mutation expressed higher levels of RNA from the Arhgap36 gene, specifically in pigment cells. They propose that the protein produced by this gene limits a step in the middle of the biological pathway behind coat color.
In male cats, who typically have one X chromosome, the orange mutation means more Arhgap36 protein in pigment cells and activation of a pathway to produce reddish yellow pigment. By contrast, in male cats without the mutation, and less Arhgap36, pigment cells produce a different pigment that's black or brown.
This switch recapitulates a molecular pathway in humans, in cells that make pigment that causes red hair, said author Gregory Barsh, a geneticist at Stanford University's School of Medicine and HudsonAlpha Institute for Biotechnology.
Coat color is more complicated with female cats, who have two X chromosomes. A random process, known as X-chromosome inactivation, turns off one X chromosome in each cell. If a female cat has the orange mutation on just one X chromosome, this random inactivation results in a mixed tortoiseshell or calico pattern.
Like the American team, the Japanese researchers identified Arhgap36 as the reason for orange cats' coat color. They additionally confirmed that the gene experiences chemical modifications that indicate it undergoes X-chromosome inactivation.
'The orange gene was a long-standing mystery for scientists,' said study author Hiroyuki Sasaki, a geneticist at Kyushu University's Institute of Bioregulation and Institute for Advanced Study, by email. 'It is a great joy for me to have finally cracked it with my colleagues.'
The two studies were originally posted as preprints last year. The Japanese results were posted on Nov. 21, 2024; the American results were posted on Nov. 22, 2024.
'It's fantastic that not only one group, but two groups have published on this,' said Leslie Lyons, a feline geneticist at the University of Missouri College of Veterinary Medicine, who wasn't involved with the new studies.
Lyons still wants to know more about how the genetic findings translate into the ginger hues of orange cats. One step could be quantifying how much reddish yellow pigment is produced, compared with other pigments. Another could be probing how much pigment is put into feline hairs.
The U.S.-based researchers found the orange mutation specifically affected pigment cells, suggesting Arhgap36 isn't involved in orange cats' reputation for goofy behavior. Potentially, their friendly demeanors could just be a byproduct of orange cats typically being male. But there also could be linkage with some other genes, Lyons said.
Scientists say orange cats' personalities could be an area for future study.
'There's a lot of anecdotal stories about orange cats and behavior, or orange cats and appetite, but those aren't well-documented in the scientific literature,' Kaelin said. 'I do think there's opportunities using citizen science approaches to make those types of associations.'
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