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Calico Cuties: Why These Colorful Cats Are (Almost) Always Female
Calico cats are not just ordinary felines. They are legendary and revered in many cultures as symbols of luck and good fortune. In Japan, the Maneki-Neko (or “beckoning-cat”) figures, adorned with the white orange and black calico colors, are believed to bring prosperity to their owners. In the US, they are affectionately known as “money cats.” Even the German word for calico, “Glückskatze,” translates to lucky cat! But their charm doesn’t end there. The fascinating fact is that almost all calico cats are female, a peculiarity attributed to the very nature of their sex chromosomes.
X Marks the Spot
Like humans, the biological sex of a cat is determined by the sex chromosomes X and Y. Female cats have two X chromosomes (XX), while male cats have one X and one Y chromosome (XY). The X chromosome is substantially larger and contains many more genes than the Y chromosome. You might imagine, then, that having two X chromosomes means that females have an increased gene dosage or the number of copies of a gene present in the cell of an organism [1]. If this were the case, it would lead to many cellular complications, resulting in inviability, meaning the cells wouldn’t survive. To avoid this, cells from female mammals across all species undergo a form of gene-dosage compensation by silencing one of the two X chromosomes, leaving only one active, similar to that of biological males (XY). This process of chromosome silencing, initially proposed by scientist Mary Frances Lyon in 1961 [2-3], is called X chromosome inactivation.
Back to calicos: two essential genes for coat color are found on the X chromosome of cats, encoding the information necessary to produce black and orange fur. During development, each cell in the cat embryo randomly silences one of the two X chromosomes, a process called lyonization in tribute to Dr. Lyon, leaving the other available for expression. For example, let’s say the X chromosome with the orange fur allele (or version of the gene) is silent, and the one for black fur is left active: this embryonic cell, and eventually all of its daughter cells, will continue to silence that same chromosome, producing a patch of black fur.
So that explains two of the three calico’s fur colors, but what about the third? The white fur results from an entirely separate genetic mechanism unrelated to the sex chromosomes. White spots in calicos can be caused by many different genes [4-5] affecting pigmentation found on autosomes or non-sex chromosomes. One example is Piebald spotting, caused by the presence of the white spotting allele of the MITF gene [4]. This allele prevents pigmentation entirely, overriding the gene for black or orange fur color from the X chromosome, resulting in a white patch.
How does X-Chromosome Inactive Work?
A unique class of molecule is needed to inactivate an X chromosome: long noncoding RNAs. Rather than directly contributing to protein production like traditional messenger RNAs, long noncoding RNAs regulate the amount and type of protein produced in a cell. The specialized long noncoding RNA involved in X-chromosome inactivation is called X-inactive specific transcript or XIST [6]. XIST is the master regulator of X-chromosome inactivation, and it works by spreading out along the surface of the entire chromosome, silencing genes, recruiting other molecules to modify the chromosome’s structure, and completely reorganizing it into an inactive state called a Barr body [7]. In the image to the left, you can see the Barr body as a small black dot at the edge of the nucleus of a cell grown in a tissue culture dish from a female donor.
The Elusive Male Calico
You are likely wondering… is it possible for a calico cat to be male? And the answer is yes – but they are scarce. For a male cat to be calico, he must have a rare chromosomal abnormality: an extra X chromosome (XXY), a condition called Klinefelter syndrome [8]. The extra chromosome comes from an error during cell division, typically when producing eggs or sperm. During division, the chromosomes are divided unevenly between the two daughter cells, with one of them having an extra X and the other no X. If the cell with the additional X is fertilized and develops into a fully formed kitten, he will contain the extra X chromosome in each cell of his body. He can, therefore, have X chromosome inactivation and calico spotting as described in females.
Klinefelter syndrome can occur in humans, too! Take a look at the karyotype (a diagram showing each chromosome from an individual) to the right, showing the presence of two X and one Y chromosome at the bottom right corner.
X Inactivation in Humans
Calico cats are not the only animals affected by this mosaic expression of genes from the X chromosome; it happens in all female mammals, including humans. It is interesting to note that the inactivation of the X chromosome is not perfect. Biological mechanisms are seldom black and white, and it’s not as clean as one chromosome that is entirely silenced and one that is entirely active. There is some escape from inactivation, where genes on the inactivated X are still expressed, even 12-20% of them [6]. X chromosome inactivation is a fascinating mechanism of diversity in cells across the female body and is also related to various diseases. For instance, autoimmune diseases such as Systemic Lupus Erythematosus and psychiatric conditions such as Bipolar and Major Depressive Disorder are associated with X-inactivation escape in females [9]. There are many more rabbit holes to chase about the implications of X-inactivation for human health. Still, we can thank our calico friends for pointing the way to this body of research and being the cutest go-to example in genetics class.
References:
- https://www.ncbi.nlm.nih.gov/meshDb=mesh&Cmd=DetailsSearch&Term=%22Gene+Dosage%22%5BMeSH+Terms%5D
- https://www.nature.com/articles/518036a
- https://www.nature.com/articles/190372a0
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130573/
- https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2052.2005.01389.x
- https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008333
- https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/barr-body
- https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-20353949
- https://onlinelibrary.wiley.com/doi/10.1155/2022/1391807#:~:text=X%2Dchromosome%20inactivation%20(XCI),on%20the%20status%20of%20XCI.
- https://www.nature.com/articles/s41594-023-01086-5
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