SECRET OF ORANGE CATS FINALLY UNCOVERED AFTER 60-YEAR SEARCH

In 2024, after six decades of searching, geneticists finally pinpointed the gene responsible for the marmalade coloring in domestic cats.

Two independent research teams discovered that those vibrant orange coats are likely caused by a missing segment of DNA—found not in a protein-coding region, but in a non-coding part of the feline genome.

“It’s been a genetic mystery, a conundrum,” Stanford University geneticist Greg Barsh told Science reporter Sara Reardon.

Barsh and his team discovered that skin cells from orange-coated cats produce 13 times more RNA from a gene called Arhgap36 compared to cells from non-orange cats. Initially, they expected a mutation in the gene’s protein-coding region—but the surprise twist came when they found the real culprit was a missing stretch of DNA just before the gene itself.

This 5-kilobase deletion appears to ramp up the gene’s activity and was found in every orange cat examined in their study. The team analyzed a sample of 188 cats, which included 145 orange cats, 6 calico/tortoiseshells, and 37 non-orange cats.

One part of the puzzle that wasn’t surprising? The gene is located on the X chromosome—just as long suspected. This explains why most orange cats are male, while females typically display a mix of colors, such as in calicos and tortoiseshells, due to their two X chromosomes.

“Together, these findings offer strong genetic and genomic evidence that the 5 kb deletion is responsible for sex-linked orange coloration,” Barsh and his team wrote in their paper.

Since humans began living alongside cats nearly 10,000 years ago, it’s long been a fascinating mystery how a black cat and an orange cat can produce such a wide variety of kitten colors.

Male kittens from this pairing typically end up either orange or black, just as genetics would suggest. But female kittens often surprise with more complex patterns—like the patchwork of black, orange, and white seen in calicos, or the marbled blend of orange and black characteristic of tortoiseshells.

Both teams confirmed the mutation responsible for orange fur is on the X chromosome, which is why such clear differences in colored patterning can appear between the sexes.

Unlike males, who inherit just one copy of the mutation on their single X chromosome, females receive two copies—one on each X chromosome from their parents.

To avoid an overload of X chromosome products, mammals randomly inactivate one of the two X chromosomes in each of their cells. This results in female orange cats having some skin cells where the orange mutation is active, while adjacent cells have the mutated X chromosome deactivated.

In rare cases, when both X chromosomes carry the mutation, the female cat will develop a coat as ginger as any male.

Orange cats happen to have a hilarious reputation for not being the brightest of their species. Anecdotes aside, such links between kitty coloration and cognition are scientifically unsupported, with no obvious negative consequences from this mutation in health or mental wellbeing.

Arhgap36 is known to cause developmental issues in other animals when it is either overactive or underactive. However, in orange cats, the gene seems to be overexpressed only in the developing and mature pigment cells, known as melanocytes.

“The key difference between tortoiseshell and calico cats is the presence of an additional white spotting mutation in calicos, which affects the survival of developing melanocytes as they migrate from the neural crest. This allows surviving melanocyte clones to expand into larger areas of the body,” Barsh and his team explain.

A second study, led by Kyushu University geneticist Hidehiro Toh, also pinpointed Arhgap36 as the gene responsible for orange fur in cats. The researchers discovered that increased expression of this gene suppresses the color pigment genes, shifting eumelanin pigments (responsible for dark brown to black fur) toward pheomelanin pigments, which create the reddish to yellow tones typical of orange fur.