Orange Cats Have Long Been a Genetic Mystery. Scientists Have Finally Solved It

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5 days ago

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Here's what you'll learn when you read this story:
The gene that causes orange coloration in cats had been pondered for years, but never actually found—until now.
Cats with orange coats get them from a deletion (meaning a missing segment) mutation in the noncoding region of a gene associated with both neuroendocrine tissues and pigmentation.
There are more male orange cats than females because this gene is located on the X-chromosome, which males only have one copy of. Females are more likely to be tortoiseshell or calico because they have two X chromosomes, and therefore have more genetic coat color options to 'choose' from.
Garfield might be the most iconic orange tabby around, but Hollywood has seen quite a few leading cats of the same color—Heathcliff, Oliver, Hiyao Miyazaki's adorably terrifying Catbus from My Neighbor Totoro, and Morris from those retro cat food commercials all come to mind. Like most celebrities, they have so far refused to give up their most guarded beauty secret—how did they get those fabulous golden auburn coats?
Hiroyuki Sasaki—a cat enthusiast and geneticist at Kyushu University in Japan—was determined to identify the elusive gene that carries the orange mutation in Felis silvestris catus (the domesticated cat). He and his research team analyzed DNA in skin tissue from cats with and without orange fur, and found a mutation to the ARHGAP36 gene. This was a type of deletion mutation, meaning that a segment of a gene is missing. In orange cats, the missing segment is located on an intron, or noncoding region, of the ARHGAP36 gene, which is also in neuroendocrine tissues (especially the hypothalamus), adrenal glands, and pituitary glands.
The location of the mutation on this particular gene also explains why there are so many more male orange cats than female ones. ARHGAP36 is known as X-linked, meaning that it is located on the X chromosome. In female cats (and all female mammals), one of the two X chromosomes in each cell is randomly switched off in a process known as X chromosome inactivation, so even if the mutation is present, it is unlikely that it will be expressed by every cell and appear as an even (or even semi-even) orange coat. To be orange, a female cat must have the orange gene on both X chromosomes, so no matter which one is deleted, the orange gene still dominates.
Male cats, on the other hand, only have one X chromosome, and are therefore much more likely to evenly express that mutation.
Whether orange or not, all fur pigmentation genes are X-linked. Calico and tortoiseshell coats also come from different combinations of activated X chromosomes—both with and without the deletion that results in orange—which explains why most of them are female. For this to happen to a male cat, there would have to be two X chromosomes present next to the Y chromosome in order for random inactivation to result in mottled fur.
Sasaki and his team found that ARHGAP36 was most active in melanocytes (cells in the skin which produce pigment) found in the orange patches of calicos and tortoiseshells. Genes promoting melanogenesis, or the production of melanin in melanocytes, suppress ARHGAP36 and are upregulated in brown, black, and gray patches. These colors are associated with the black or brown pigment known as eumelanin, which is also the most common form of melanin.
Sasaki believes that when a mutated ARHGAP36 is expressed as orange fur in cats, the missing part of the gene would have suppressed orange coloration had it been present. In cats, mutated ARHGAP36 was shown to suppress other genes involved in the production of eumelanin so that it could instead produce a different type of melanin called pheomelanin, which is the reddish-yellow pigment in orange fur. Found only in mammals and birds, pheomelanin is also behind red hair in humans and flashy red feathers in some bird species.
It seems that high ARHGAP36 activity is, in general, associated with reduced activity in genes involved with the production of eumelanin. Sasaki is convinced that this gene's takeover may somehow shift pigment production to pheomelanin instead—though, how exactly it pulls this off is still unknown. And because ARHGAP36 also has significant importance in the brain, there is even speculation as to whether there are true associations between fur color and personality (the confirmation of which could either prove or silence all the orange cat memes out there).
'Although it is not fully understood how the identified deletion switches the pigment species, the variation likely dominates the cat population with orange coat color,' the researchers wrote.
Somewhere, Garfield is smugly beaming next to a tray of lasagna.
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