Why are there tortoiseshell cats?

By Yuchen Lin

Cats are lovely pets, and usually, they have simple fur colours. However, there is a class of cats named tortoiseshell cats with a mixture of two colours: red, orange, yellow, or cream combined with black, tabby, chocolate, grey, or blue. The colours are mixed closely in large patches or small brindles all over their bodies. Tortoiseshell cats tend to be hot-tempered and independent, but their unique traits of fur colours make them attractive. So, how do tortoiseshell cats become beautifully parti-coloured? 

Tortoiseshell cats do not belong to a specific breed. Instead, they are produced from either purebreds or mixed-breeds of various cat breeds, named after their multi-color fur. There are two kinds of fur colour styles. Mosaic pattern, with two colours mixed at random, is the most common type (Judith Singer-Sam, 2010). The other is the chimaera that each colour is on one side of the body. This pattern can be limited to the face but may also happen on the entire body. 

X-inactivation is the direct cause for the colouring of tortoiseshell cats. X-inactivation, a classic example of epigenetic modifications, randomly switches off the gene expression in one of the two X chromosomes in female mammals (Judith Singer-Sam, 2010). It occurs because females have two copies of X chromosomes, one maternal and one paternal, while males only have one maternal X chromosome. If a female offspring expresses both X chromosomes, there will be twice as many X chromosome gene products as in males. Thus, dosage compensation is required to avoid overexpression. That is why tortoiseshell cats are usually females. The silencing of gene expression generally occurs during the foetal growth around gastrulation after the initial cell division (Good Horse, 2019). Either of the X chromosomes can be inactivated in different individual cells and tissues, leading to the characteristic appearance. 

Such epigenetic changes do not affect the DNA sequence, but they influence how cells read genes. X-inactivation alters the physical structure of DNA through histone methylation (Leland H. Hartwell et al., 2011). A gene named Xist, a long non-coding RNA (lncRNA), is responsible for the inactivation. lncRNA, combined with transcription factors (TFs), targets numerous aspects of the gene transcription mechanism. Here, Xist induces H3K27M3 compaction on the inactivated X chromosome. Xist coats the inactive X chromosome in cis, so the expression of Xist determines which X chromosome to silence. In the six repeats of Xist transcript, Repeat A (RepA) is essential for the silencing (Leland H. Hartwell et al., 2011). RepA acts in cis by forming a secondary structure to allow the histone methyltransferase complex Polycomb Repressive Complex 2 (PRC2) to bind. PRC2 carries out H3K27me, laying down the histone methylation, and there is a specific sequence on Xist to guide PRC2 along the X chromosome (Leland H. Hartwell et al., 2011). H3K27me makes the DNA sequence densely packaged in the form of heterochromatin. Inactivated X chromosome curls itself up into a tight mass, Barr body (Leland H. Hartwell et al., 2011). Therefore, this high packing density prevents TFs from binding to the genome and blocks the gene transcription and translation.  

Tortoiseshell cats start with a zygote that contains full genetic information, half maternal and half paternal. When the zygote divides, the same complete copy of the genome is still preserved. After X-inactivation, some melanocytes (skin cells that produce pigment) retain the partner X, while others keep the maternal X (Good Horse, 2019). Sex-linked orange locus O is a co-dominant gene that decides the pigments produced in melanocytes. Gene O masks the primary fur colour gene B (Centerwall & Benirschke, 1973). The orange allele O and non-orange allele o of O cause cats to synthesise orange pheomelanin or black eumelanin pigments respectively. Only the heterozygous pattern Oo results in tortoiseshell cats (Centerwall & Benirschke, 1973). When the X chromosome carrying allele O is silenced, gene B determines cells to express allele o. Otherwise, activated allele O will replace black with reddish pigment. When melanocytes migrate from neural crest to skin surface, different pigment alleles spread apart in females. In contrast, as male cats only have one X chromosome, its gene O is active in all melanocytes, and there is no equivalence on the Y chromosome to switch it off. Thus, their fur colours are typically orange or black. 

The time of X-inactivation occurrence decides whether the cats have colour patches or brindles. If the silencing occurs early, melanocytes will multiply into more cells with the same colour to form large patches. Each patch represents cells derived from one original cell in the early embryo stage(Sarah Hartwell, 2016). Oppositely, if it happens late, cells produce the same pigment gathered in a brindled pattern only. Depending on melanocyte migration speeds, the size of patches and intermingle levels of cells with orange or black alleles vary (Sarah Hartwell, 2016). Further modification on gene B and O by recessive dilute gene dd softens fur colours to cream or grey, generating more tortoiseshells combinations. 

Very rarely, tortoiseshell is found in males due to abnormalities in chromosome karyotype. Roughly one in every 3000 tortoiseshell cats is male with an extra X chromosome as XXY instead of XY (A S Pedersen et al., 2013). Those cells in males undergo X-inactivation like females. The aberration of XXY karyotype is similar to the Klinefelter syndrome in man (Good Horse, 2019). There are two situations for male tortoiseshell cats to occur. Firstly, the male tortoiseshell cats might have derived from two zygotes as two embryos with different colour genotypes fuse in the early developmental stage. Or it arises after conception, and male tortoiseshell cats will have a mixture of cells with various numbers of X chromosomes (A S Pedersen et al., 2013). Despite having such abnormalities in chromosomal composition, some of them are still fertile. 

Calico cat is a subcategory of tortoiseshell cats with similar causes. Apart from gene O, an additional spotting gene that produces white fur is needed. If melanocytes fail to migrate to a specific position before the skin is fully formed, such as chest and belly which take a longer time for cells to reach from backbone, that place will lack the colour pigments and stay white (Sarah Hartwell, 2016). Therefore, calico cats have primarily white fur with tortoiseshell colour patches throughout the bodies.

Most tortoiseshell cats are females, with their distinct appearance having arisen from random X-inactivation. The specific colour pattern is unique to each cat, and can arise from a number of causes, the mechanisms of this meaning that you can never find two identical tortoiseshell cats.

References:

Centerwall, W.R. & Benirschke, K. (1973) Male Tortoiseshell and Calico (T-C) Cats: Animal models of sex chromosome mosaics, aneuploids, polyploids, and chimerics. Journal of Heredity. 64(5): 272-278. Available from: doi:10.1093/oxfordjournals.jhered.a108410

Good Horse. (2019) Introduction to Genetics, Case Study 1: Tortoiseshell cat colour. Available from: https://good-horse.com/genetics-evolution/introduction-genetics-case-study-1-tortoiseshell-cat-colour/ [Accessed 25th Feb 2021]

Hartwell, L.H., et al. (2011) Genetics: From Genes to Genomes. 4th ed. New York. McGraw-Hill. 

Hartwell, S. (2016) Tortoiseshell and Tri-colour Cats. MessyBeast. Available from: http://messybeast.com/tricolours.htm [Accessed 21st Feb 2021]

Pedersen, A.S., Berg, L.C., Almstrup, A. & Thomsen, P.D. (2013) A tortoiseshell male cat: chromosome analysis and histologic examination of the testis. Cytogenet and Genome Research. 142(2):107-11. Available from: doi: 10.1159/000356466.

Singer-Sam, J. (2010) Monoallelic Expression. Nature Education. 3(3):1. Available from: https://www.nature.com/scitable/topicpage/monoallelic-expression-8813275/ [Accessd 21st Feb 2021]

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