Orange cats are not rare in themselves: it is the tortoiseshell females who are. About 80% of orange cats are males, with 20% females, i.e., four males for every female. The explanation lies in a gene carried on the X chromosome, identified in May 2025 by two independent research teams.
A single copy of the gene is sufficient for a male, the female requiring two copies.
Un chromosome X, deux règles du jeu
Like cats and humans alike, the male carries an X and a Y chromosome, while the female carries two X chromosomes. The orange coloration gene, called the O gene, is located only on the X chromosome. A male who receives an X carrying the mutation from his mother will therefore be entirely orange, without a second X to compensate.
For a female, the equation becomes more complex. She must have the mutation on both of her X chromosomes, which requires an orange father (who transmits his sole mutated X) and a mother who is orange or tortoiseshell, able to also pass on a mutated X. An orange male, by contrast, can be born as soon as his mother transmits the correct X. This parental combination is statistically less frequent than the maternal inheritance that a male must rely on.
Breeding crosses illustrate this clearly. An orange male paired with a non-orange female yields no orange kittens: half the offspring are tortoiseshell females, the other half are black males.
ARHGAP36, le gène resté introuvable pendant des décennies
It has long been known that orange coloration depends on the X chromosome. The exact gene, however, remained unknown until May 15, 2025, when two studies were published simultaneously in Current Biology. One study came from Kyushu University (Japan), led by Hiroyuki Sasaki, the other from Stanford Medicine (United States), with Christopher Kaelin, and both point to the same gene: ARHGAP36.
The two teams took different approaches. At Stanford, researchers first identified 51 variants of the X chromosome common to orange males, ruled out 48 because they also appeared in non-orange cats, and among the remaining three selected a small deletion that increased the activity of a neighboring gene. In Kyushu, sequencing ten orange cats and eight non-orange cats revealed a 5.1 kilobase deletion in a non-coding region of the gene, present in the ten orange cats and in none of the eight others. It was subsequently confirmed by PCR on 40 additional samples.
Until then, ARHGAP36 had no known link to pigmentation.
This gene is normally not active in pigment-producing cells of mice, humans or non-orange cats. The deletion removes a regulatory region, causing the gene to be erroneously expressed in melanocytes, with roughly thirteen times more RNA produced than in cats of other colors. Stanford’s work shows that the protein produced in this way lowers the amount of PKA, an enzyme downstream of the Mc1r receptor, thereby diverting pigment production from eumelanin (black and brown) toward pheomelanin, responsible for the orange hues.
Pourquoi les femelles affichent des taches
In a female carrying the mutation on only one X, each cell randomly inactivates one of its two X chromosomes, a phenomenon known as X inactivation. Depending on the X that remains active, the hair region will produce orange or black color, hence tortoiseshell coats and, with white, calico patterns.
The Japanese researchers verified that this inactivation mechanism applies to ARHGAP36 in mice, cats, and humans. This validates the longstanding hypothesis used to explain color mosaics. Fully orange females carry the mutation on both X chromosomes, thus lacking any black area.
The occurrence of tortoiseshell or calico males is exceedingly rare, and the same study provides the explanation. The calico male analyzed was heterozygous for the deletion, corresponding to the presence of an extra X chromosome (XXY configuration). In the literature, other possible causes include chimerism and mosaicism, or a mutation that arose in only some cells.
Une mutation qui semble propre au chat domestique
According to the Stanford team, this mutation has not been observed in any other mammal. The ARHGAP36 gene, highly conserved across mammals, had previously been studied in oncology and developmental biology: it is normally expressed in neuroendocrine tissues, where its overexpression can promote tumors. The researchers thus measured its activity in the kidney, heart, brain, and adrenal gland, finding no differences between orange and non-orange cats.
No health problems related to the mutation have been observed at this stage.
Because the gene is active in certain brain areas and in hormone-secreting glands, the Kyushu team does not rule out effects beyond coat color, but nothing supports such effects. Stanford researchers, for their part, did not observe any difference in brain expression, leaving the question of behavior open. The reputed temperament of orange cats therefore remains, for now, outside the realm of genetic evidence.
In practice, the deletion can now be searched for by PCR, the technique used in Kyushu to confirm the link with the orange color. As for the 80% male ratio, this is a commonly cited order of magnitude, which can vary depending on the cat populations studied.
Sources : nature.com | sciencedirect.com | pmc.ncbi.nlm.nih.gov
