Scientists discover ‘meow-tation’ gives ginger cats their distinct color

By Stephen Beech

The "meow-tation" that gives ginger cats their distinct fur has been discovered.

A small deletion in a gene on the X-chromosome lies behind the fiery coats of ginger tabbies and the splotchy orange patches of calicos and tortoiseshell cats, say scientists.

Ginger cats - such as lasagne-loving Garfield - are both cultural icons and popular pets.

But their distinctive color comes with a genetic twist - most orange tabbies are male, while calicos and tortoiseshells are nearly always female.

The pattern suggested it was down to an unknown “orange gene” on the X chromosome, but identifying that gene had eluded scientists until now.

Researchers at Kyushu University in Japan have pinpointed the X-linked mutation behind orange fur in house cats.

They say the "deletion mutation" - a type of mutation where a section of DNA is missing - not only explains the peculiarity of ginger genetics, but also reveals an entirely new mechanism for promoting orange coloring in animals.

The findings have been confirmed in a second independent study by researchers at Stanford University, with both papers publishing simultaneously in the journal Current Biology.

Lead author Professor Hiroyuki Sasaki, a self-proclaimed cat-lover, said: “Identifying the gene has been a long-time dream, so it’s a joy to have finally cracked it.”

Scientists had suspected that the orange gene was located on the X chromosome.

Sasaki explained that male cats, with only one X chromosome, will have orange coats if they inherit the orange gene.

But females, with two X chromosomes, need two copies of the gene to be fully orange, making them less common.

If females inherit one orange and one black gene, they develop the patchy or mottled coats seen in calicos and tortoiseshells.

Sasaki said: “These ginger and black patches form because, early in development, one X chromosome in each cell is randomly switched off.

“As cells divide, this creates areas with different active coat color genes, resulting in distinct patches.

"The effect is so visual that it has become the textbook example of X-chromosome inactivation, even though the responsible gene was unknown.”

His team analysed DNA from 18 cats - 10 with orange fur and eight without- and found that all orange cats shared a specific deletion in the Arhgap36 gene, while the non-orange cats did not.

The pattern held true in 49 additional cats, including samples from an international cat genome database.

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The team also found that in mice, cats, and humans, the Arhgap36 gene is chemically marked for silencing during X chromosome inactivation, aligning perfectly with the long-standing hypothesis.

Sasaki said, “This was such strong evidence that even at this stage, we were confident that Arhgap36 was the orange gene."

Looking closer at the mutation, he found that the deletion lies in a non-coding region of Arhgap36, so the protein itself remains unchanged.

Sasaki said, “This is key.

“Arhgap36 is essential for development, with many other roles in the body, so I had never imagined it could be the orange gene.

"Mutations to the protein structure would likely be harmful to the cat.”

With help from local vets, the researchers examined skin tissue from four calico cats and found that Arhgap36 was much more active in melanocytes - the pigment-producing cells found in skin - in tissue taken from orange patches compared to tissue from black or white patches.

Sasaki said, “This suggests that when present, this section of DNA normally suppresses Arhgap36 activity.

“When missing, Arhgap36 stays active.”

Since Arhgap36 is active in many areas of the body, including in areas of the brain and hormonal glands, the researchers say it’s possible that the orange variant may cause shifts in gene activity elsewhere, influencing more than just coat colour.

Sasaki said: “For example, many cat owners swear by the idea that different coat colours and patterns are linked with different personalities.

“There’s no scientific evidence for this yet, but it’s an intriguing idea and one I’d love to explore further.”

Dr. Christopher Kaelin, of Stanford University, said: “Arghap36 is not expressed in mouse pigment cells, in human pigment cells or in cat pigment cells from non-orange cats.

“The mutation in orange cats seems to turn on Arghap36 expression in a cell type, the pigment cell, where it’s not normally expressed.”

He believes that, hundreds of years ago, the rare orange, calico or tortoiseshell cat may have caught the attention of humans, who encouraged their proliferation.

Dr. Kaelin added: “This is something that arose in the domestic cat, probably early on in the domestication process.

“We know that because there are paintings that date to the 12th Century where you see clear images of calico cats. So, the mutation is quite old.”

Sasaki is also curious about the orange gene’s origins.

He said: “One idea is to study ancient Egyptian cat paintings - or even to test DNA from mummified cats - to see if any cats back then were orange."

He added: “It’s ambitious, but I’m excited to try.”