The mystery of orange cats solved: a gene explains why almost all of them are male.

From Garfield to Nurang, a feline who recently went viral after stealing the hearts of thousands of tourists at Bangkok International Airport (Thailand), orange cats have left their mark on popular culture. Their image, already immortalized in Renaissance paintings, is associated with a reputation for being mischievous, sociable, playful, and chaos-loving. Beyond their unique behavior, these vibrant redheads have sparked scientific curiosity: behind the origin of their color lies a genetic mystery that now has an explanation. Two independent studies conducted by American and Japanese scientists have analyzed the genetic origin of these cats' color.

Working separately, both teams reached the same conclusion, published this Thursday in the journal Current Biology : the orange fur of cats is the result of genetic variations on the X chromosome, one of the two sex chromosomes. What's unique is that this trait is sex-linked, which is not the case in any other mammal.

Gregory Barsh of Stanford University (USA) and Hiroyuki Sasaki of Kyushu University (Japan) and colleagues studied feline genomes to determine which protein, encoded by a cat's genes, enhanced the orange hue. Although this genetic exception was discovered 100 years ago, the molecular identity of the mutation was unknown. Mutations usually turn off a gene or reduce its expression. In this case, it's the other way around, so it's a DNA abnormality.

ARHGAP36 is an X-chromosome gene that encodes the protein behind the orange effect in cats. “The color is due to the loss of a fragment of DNA, which causes ARHGAP36 to be abnormally expressed in pigment cells, or melanocytes,” Barsh explained. The gene is not deleted, but it is located near the deletion site, which can alter the reading of the DNA sequence. This is a harmless mutation, in a place—such as the fur—where it is not expected to have a negative effect.

In mammals such as orangutans, dogs of the breed Whether you're a golden retriever , a tiger, or a human, this shade of red is often found, but only in domestic cats is the color sex-linked, appearing more frequently in males. "We believe these types of regulatory mutations are the primary drivers of species differences and constitute one of the great forces of evolution," adds geneticist Christopher Kaelin , co-author of one of the two studies with Barsh.

The predominance of males among orange tabby cats had long led to the suspicion that the redhead gene was located on the X chromosome, but until now no one had identified it. After a century, that hypothesis has been confirmed. Males, with only one X sex chromosome (the other is Y), will have orange coats as long as they inherit a copy of the ARHGAP36 gene from one of their parents. Females, which have two X chromosomes, need to inherit both copies of the gene to have a completely orange tabby coat. This is why they are much less common.

Cats that inherit only one copy of the orange gene—and the other copy is black—show partial color in their coat, or a mottled pattern, known as tortoiseshell. or with orange, black, and white markings, typical of calico fur. This occurs through a genetic phenomenon called random X-chromosome inactivation, in which one of the two copies is deactivated in each cell. The result is a mosaic of pigment cells: some express the orange color and others do not.

Sasaki's team analyzed the DNA of 18 cats—10 redheads and eight non-redheads—and found that all the orange cats shared a specific deletion in the gene. Meanwhile, the US scientists performed a functional analysis using cells and tissues from orange and tortoiseshell cats. “One of the key experiments in our study used fetal tissue from cats obtained at spay/neuter clinics, which helped us trace how the mutation works at the cellular level,” Kaelin explains.

This is because cats are not experimental models—like laboratory mice—points out Priscila Ramos, a senior scientist at the National Institute of Agricultural and Food Research and Technology . “The studies are based on samples obtained in clinics or from animals that have died of natural causes, which makes it more difficult to conduct research that involves direct manipulation of their DNA,” adds the genetics expert.

A genetic puzzle

The ARHGAP36 gene was being investigated by scientists in the fields of cancer and developmental biology. It is normally expressed in neuroendocrine tissues, where it can cause tumors. Its effect on pigment cells was unknown. “In human studies, [the gene] had been associated with developmental problems or cancer. In cats, it has not been seen to be expressed in these tissues, and when this mutation occurs, it only influences melanin production: that's why the orange color of fur appears,” Ramos says.

Efforts to understand how domestic cats acquired different colors and patterns, scientists say, are a gateway to understanding the emergence of other physical traits, from the spots of cheetahs to the physiognomy of dolphins.

The discovery was facilitated, in part, by the development of genomic resources for cats, which have only recently become available. Christopher Kaelin points out that much of the genetic research of the last 30 years has focused on identifying mutations in one gene. "In our case, the mutations are present in 98% of the genome," he concludes.