Garfield, the star of the comic strip of the same name created by Jim Davis in 1978, is orange like many of the cats that roam our homes. He is orange in the same way that some people are red-haired, some horses are brown, or some dogs are Irish setters, but there is an important difference.
For all other animals, including red-haired humans, we know what causes this distinctive color, but surprisingly, we did not know what causes it in cats – and cats in general – until now.
Two papers have recently been published on bioRxiv – one of the most popular pre-publication repositories of unreviewed articles – that explain the genetics behind orange cats. One comes from Greg Barsh’s lab at Stanford University, California. The other is from Hiroyuki Sasaki’s lab at Kyushu University in Japan.
Eumelanin and Pheomelanin: Two Mammalian Pigments
Mammals have only two pigments, which are two colors of melanin: eumelanin (dark brown, black) and pheomelanin (yellow, red or orange). People with red hair produce only pheomelanin, while dark-skinned people have mainly eumelanin deposits. All other skin and hair colors fall somewhere in between, thanks to the more than 700 genes that control pigmentation in animals.
In primates, horses, rodents, dogs, cows and many other animals, melanin production and the decision to produce eumelanin or pheomelanin is in the hands of a membrane protein called MC1R.
It controls skin cells called melanocytes that release melanin. If melanocyte-stimulating hormone (alpha-MSH) is released, the melanocytes start producing eumelanin. If an antagonist, such as agouti-signaling protein or beta-defensin in dogs, is activated, production of the dark-colored eumelanin stops, and the melanocytes produce orange-colored phaeomelanin instead.
Cats, however, are a different matter altogether. Anyone who has a cat around the house knows that they are very strange animals, very special in every way, and this extends to their pigmentation.
In cats, eumelanin or phaeomelanin production is not controlled by the MC1R receptor. Instead, it is in the hands of a locus (whose gene was unknown until now) called “orange.” A locus is a physical location in the genome whose effects are known (such as a black or orange coat), but not the details of the exact DNA sequence it contains, nor the gene to which it belongs.
For this reason, we usually identify the locus first and then, over time, we discover and describe the corresponding genes in detail. The orange color locus in cats can come in two forms: an ‘O’ type that supports the production of phaeomelanin (orange), and an ‘o’ type that is responsible for the production of eumelanin (black).
One detail worth noting is that the orange color locus is on the X chromosome. Female cats are XX and male cats are XY, just like all other mammals. And just like all female mammals, all cells will randomly inactivate one of the two copies of the X chromosome during development. Oo female cats – carrying the O type on one X chromosome and the o type on the other – will generate areas of their bodies that are orange (in areas where they have inactivated the ‘o’ allele) and others that are black (upon inactivating the ‘O’ allele).
This means that when we see a dichromatic (black/orange) or trichromatic (black/orange/white) cat, or one of its more dilute versions, we know it must be a female, and its pigmentation pattern will be completely unique.
Male cats are either orange or black (they only have one X chromosome), but they cannot be bichromatic or trichromatic, unless they have a chromosomal change equivalent to Klinefelter syndrome in humans (where males are born with an extra X chromosome).
Calico cats
Females can therefore have unique mosaic patterns, much coveted by cat lovers. When combined with another mutation affecting the proliferation and differentiation of melanocytes (producing white spots, with no pigmentation), this produces a trichromatic cat, commonly known as a calico.
Each calico is unique because the inactivation of one of the X chromosomes in each pigment cell occurs at random during development. The earlier this inactivation occurs during development, the larger the resulting spots. The later it occurs, the smaller the spots.