The genetics of the calico cat

In an earlier post, I detailed the life and work of Nettie Maria Stevens, the namesake of our new calico cat. Nettie Stevens is known for her discovery of the X and Y chromosomes as the basis for sex determination. While researching the post, I found myself in another internet rabbit hole and I wanted to share some of the things I learned about cat genetics because, it turns out, calico cats are an excellent lesson in genetics.

The genetics of cat fur color (like the genetics of human hair color) are rather complex. There are many different genes that create the spectrum of coat colors and patterns found in domestic cats. In other mammals, white fur color alone has been linked to at least six genes (MITF, EDN3, EDNRB, PAX3, SOX10, and SNAI2). For this discussion, I will focus only on the gene loci that create the calico pattern: agouti (A), orange (O), and spotted (S). Based on the combined expression of these genes, some cats are tortoiseshell, a mix of black and orange and some cats are calico, a mix of black, orange, and white. Because the Orange gene is on the X chromosome, most torties and calico cats are female. There are rare cases of male cats with Klinefelter syndrome (XXY) that can have these fur color variants.

Figure 1 Schmidt-Kuntzel, et al., 2009

Agouti (gene name ASIP) encodes a protein that inactivates the melanocortin receptor and thus controls the distribution and amount of pigment cells (melanocytes) in the hair. The Orange gene has not yet been identified, but its position on the X chromosome has been mapped. Interestingly, the MC1R gene, which has been linked to red hair in humans and other mammals, is not involved in the coloring of calico cats because it isn't on the X chromosome. A recent study of the Syrian hamster, which shows sex-linked inheritance of yellow fur color, described the sex-linked yellow gene (Sly) as being independent of MC1R function and not likely homologous to the Orange gene in cats. However, recessive versions of the MC1R allele create orange/amber fur color in Norwegian forest cats. The gene for white spotting (S) has been linked to the KIT locus; more recent publications have shown that a retroviral insertion in the KIT oncogene caused white spotting, with a full insertion leading to the recessive all white mutation.

The genetics of the tortoiseshell/calico cat

If fur color followed the rules of Mendelian genetics, you would expect cats to be only black and white or orange and white, not two or three colors at once. The patterns observed in calico and tortoiseshell cats can be explained by a phenomenon called X chromosome inactivation. Somatic chromosomes come in even pairs, but the sex chromosomes are not created equal. The Y chromosome is rather small and does not encode many genes. In contrast, the X chromosome contains lots of protein-encoding genes. If an XX individual expressed all the genes on both X chromosomes, they would have a huge imbalance in protein expression in comparison with someone with XY. Organisms have different ways to level the compensate for these differences. In mammals, this involves silencing one of the X chromosomes in each cell with the XX genotype. In organisms like the fruit fly, the XY males just double the expression of the genes on the X chromosome.

The specifics of how this happens is actually pretty amazing. (For further details of the process, check out my post on Nessa Carey's book Junk DNA.) In short, a long non-coding RNA known as Xist (X-inactive specific transcript) turns off one copy of the X chromosome in each cell; on the opposite strand of DNA, a gene called Tsix is found. Xist and Tsix have mutually exclusive expression, which ensures that only one X chromosome is inactivated in each cell. X chromosome inactivation occurs at the 8 cell stage of the embryo. Different cells inactivate different copies of the X chromosome, which means some cells express alleles for orange and white and other cells express black and white alleles. These 8 cells then divide and produce the millions of cells that make up a cat. This random pattern of gene inactivation leads to the pattern observed in Nettie and other calicos.

Carbon copy (left) is a clone of Rainbow (right)

Importantly, because these traits are not strictly inherited by classic Mendelian patterns, it makes cloning cats a bit trickier than other animals. As highlighted in the book Frankenstein's Cat, scientists were disappointed when the cloned cat Carbon Copy ended up looking quite different from its clone mother. Had they thought more carefully about the genetics of calico cats, they might have picked a different breed for their experiment!

maneki-neko calico cat figurines are
thought to bring good luck

Calico cats like our Nettie offer excellent lessons in genetics as they higlight X-linked genes and dosage compensation. After all this reading, I think I will take advantage of cat genome sequencing to discover the specific mutations in our cat. I learned more than expected about cat genetics and hope to share these lessons with you soon. For now, if you want to learn more about the genetics of cats, you should check out Herding Hemingway's Cats by Kat Arney.