Just as you shouldn’t judge a book by its cover, it’s unfair to judge a cat by its coat color. Still, people seem to have a sweet spot for orange cats. Videos of their antics are filling the internet, and gingers are also getting starring roles in TV and movies (think Garfield, Heathcliff and Puss in Boots). A 2012 survey found that people are more likely to view orange cats as friendly than other cats. But despite their popularity, the genetic basis of their striking coat color has puzzled scientists for decades.
In humans, reddish-orange hair is associated with certain traits variants of the melanocortin-1 receptor gene (MC1R).. This gene controls the production of melanin, the pigment that gives hair, skin and eyes their color, by cells called melanocytes. These cells can make one of two forms of melanin: the red/yellow pheomelanin and the black/brown eumelanin. In certain variants of the MC1R gene, melanocytes mainly produce pheomelanin, leading to red hair and fair skin.
It would be easy to assume that the MC1R gene is also responsible for the orange coat in cats, but this is not the case. Scientists have noticed that most cats with multi-colored coats, such as calicos or tortoiseshells, are female. This led them to believe that the genes for orange and black fur are located on the X chromosome. Because females have two X chromosomes, they can inherit different coat color genes from their parents, creating mixed colors. Males, with only one X chromosome, usually have fur that is all one color, orange or black, based on the gene they get from their mother. Since the MC1R is not located on the X chromosome in catsit can’t be the gene that causes orange fur.
To find out what causes orange fur in cats, geneticist Greg Barsh and his team at Stanford University studied the DNA on the X chromosome of orange male cats. They found that they all had a specific stretch of DNA, about 1.28 million base pairs long, that was the same. Within this region, they identified 51 unique DNA variants that orange cats have, but non-orange cats do not. However, 48 of these variants also occur in some breeds that do not have orange or calico fur, so they cannot be linked to the orange coat color. This allowed Barsh’s team to narrow it down to three DNA variants. Two of these were in parts of the DNA that don’t seem to affect the way genes work, but the third – a deletion of about 5,000 base pairs – was near the Arhgap36 gene. The proximity of this deletion to a functioning gene made it more likely that it was the cause of orange fur.
Barsh and his colleagues saw that all 145 orange cats they studied, as well as 6 calico and tortoiseshell cats (which also have orange spots), had the same piece of missing DNA near the Arhgap36 gene, while 37 non-orange cats did not .
They then analyzed skin samples from orange and non-orange cat fetuses and found that the Arhgap36 gene was much more active and produced 13 times more RNA protein in the melanocytes of orange cats compared to those of non-orange cats. So the removal of nearby DNA should make the Arhgap36 gene more active.
But how is this gene linked to orange fur?
Further experiments showed that when Arhgap36 is more active, it weakens the effects of the MC1R gene, which normally controls melanin production, and instructs melanocytes to produce red/yellow pheomelanin instead of black/brown eumelanin, the researchers reported in a preprint op bioRxiv in November 2024.
Surprisingly, there will be another research group led by a developmental biologist Hiroyuki Sasaki at Kyushu University in Japan, simultaneously independently discovered the same genetic trait associated with orange fur. They also published their findings on bioXriv. Both studies will now have to undergo peer review to verify the findings.
“The fact that two groups independently identified the same gene suggests this is probably correct.” Jonathan Losossays an evolutionary biologist at Washington University in St. Louis Popular science.
This finding could provide important research into when the orange coat color first appeared, Losos says. “Now that we know the gene for orange, we can look for it in ancient DNA studies of cat specimens from archaeological sites.”
“More generally, we can explore the evolutionary significance of orange color,” he adds.
Scientists have known since 1961 that the multicolored fur coats seen on calico and tortoiseshell cats is caused by a phenomenon in female mammals called X chromosome inactivation, in which one of the two X chromosomes in each cell becomes randomly inactivated. In cats that carry two different color genes, one black and one orange, X-inactivation causes different colors to be expressed in different parts of the body. “We’ve known this was happening for a long time, but now that we know the actual gene, we can get a much more detailed explanation of how the variation is actually produced,” says Losos.
At the very least, this discovery probably confirms that orange cats really do have something that sets them apart from other cats. And, as Losos notes, “it’s a major breakthrough that opens the door to a lot of interesting research.”
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