Nine thousand years ago, humans began domesticating cats. Nine hundred years ago, before the advent of intentional cat breeding, a genetic mutation gave rise to the first orange cat. Days ago, Stanford Medicine researchers revealed exactly which gene created the fuzzy fodders for Garfield, Puss In Boots and Toulouse from The Aristocats, to name just a few.

Unlike any other “ginger” mammals, orange cats’ coloration owes to a sex-linked gene, which is why 80% of orange felines are fellas.

The unique sex-linked orange genetic mutation remained enigmatic for years while scientists tried to figure out what induced cats’ pigment cells to produce yellow, orange or red coloration instead of the usual brown and black.

Researchers from Brown University, the Frederick National Laboratory for Cancer Research and Auburn University also contributed to the study. A team at Kyushu University in Japan published similar findings by studying the DNA of cats in Asia, furthering the understanding that the reason for orange cats is consistent worldwide.

The only exception is the Norwegian forest cat, which manifests as orange because of the same genetic trait that causes red hair in humans.

Stanford Medicine’s Christopher Kaelin, a senior scientist in genetics, Greg Barsh, an emeritus professor of genetics and pediatrics, and genetics researcher Kelly McGowan shared cat DNA samples with these groups to get a strong global sample.

The team also attended dozens of cat shows from California to Brazil, approaching hundreds of orange cat owners for help collecting cat DNA.

Kaelin found breeders and owners to be deeply supportive of cat research even if the collection process was challenging. At one large, three-day show in Cleveland, Ohio, Kaelin and crew swabbed 100 cats on-site by sticking a cotton swab into their mouths to collect a small bit of DNA from the inside of their cheeks.

Spay-and-neuter clinics also contributed tissue after surgically sterilizing feral cats.

The scientists sequenced the genomes from 200 out of 3,000 collected samples of orange cat DNA with non-orange DNA to extrapolate the differences. They found 51 possible variants on the X chromosomes of male orange cats and eliminated 48 of them after finding the genomes in some non-orange cats as well.

Of the three remaining variants, a gene called Arhgap36 came into focus. Researchers in cancer and developmental biology were already studying this gene because its over-expression in neuroendocrine tissues led to tumors in various mammals. No one previously had made any connection to pigment cells.

The mechanism they found, Kaelin said, “is not located on a gene — it’s located near a gene.”

In cats only, a small deletion of information on the X chromosome activates Arhgap36 in pigment cells where it is normally not active, triggering orange fur.

Males have XY sex chromosomes and females have XX. Male cats with an orange X chromosome will be orange, whereas females need to inherit this trait on both of their chromosomes to be completely orange.

Females with just one orange X chromosome can present as tortoiseshell or calico. These mottled and patchy coats are a visual manifestation of the genetic phenomenon of “random X inactivation” in all female mammals. In each cell of a female organism, one of the X chromosomes is “turned off.” In female cats, coat color shows whether the sex-linked orange is the chromosome that’s “on” or “off” in the underlying pigment cells.

“Our ability to do this has been enabled by the development of genomic resources for the cat that have become available in just the last five or 10 years,” Kaelin said.

He has received a flurry of congratulatory texts from orange cat owners, breeders and fans whose cats participated in the study.

“It’s an interesting mutation and unlikely to happen twice,” said Kaelin, explaining why cat lovers and researchers want to know more. McGowan said that about 10% of cats in Northern California today are orange.

The research publication cites the appearance of orange cats in 12th-century Chinese paintings and Renaissance paintings. Kaelin said scientists who examine ancient cat DNA continue seeking the origin of the first orange cats. The biobank of cat genes remaining from his team’s orange cat research could aid in this pursuit, as well as further research about adaptation and evolution on the molecular scale in other mammals, including humans.

Laura Birdsall, director of behavior and medical services at Pets in Need in Redwood City, said the shelter is having an unusual wave of orange cats during this spring’s delayed “kitten season,” when a new generation of feral cats blooms.

Birdsall said that prospective cat adopters go by color and size preference when choosing kittens, and consider personality more when evaluating full-grown cats. She said orange cats found homes quickly for reasons of both standout appearance and personality.

“I’m partial to orange cats,” she shared. “I grew up with an orange cat — that was my baby. This is just my opinion, but they seem to be more outgoing and friendly.”

Kaelin, Barsh and McGowan haven’t found any other physical or behavioral quirks linked to Arghap36 other than coat color so far. For now, Kaelin hypothesizes that orange cats’ reputation as “friendly agents of chaos” might have something to do with their being mostly male.

But who knows — Kaelin pointed out that there haven’t been too many scientific studies about orange cats’ personalities, but that citizen studies often surveyed the public for commentary on their perceived quirks.