Gene Behind orange fur in cats found at last

 Scientists have spend more than 60 years unsuccessfully trying to find the gene that causes orange fur and the patchwork of colors in calicos and tortoiseshells. Two different studies found finally the mutation and discovered the protein that influence this mutation. Tortoiseshell and calico cats are the offspring of a black cat and an orange cat. The multicolored cats are mostly female suggesting that chromosomes X is the responsible. Female cats inherit a X chromosome from each parents but during embryonic formation cells would need only an X chromosome and will choose randomly which one to express. The other X chromosome will inactivate. So tortoiseshell fur depends on which chromosome was inactivated in difference part of the skin. Calico adds to this already particular situation the withe fur which through another genetic mechanism shut down pigment production. 

In most mammals red hair is cause by a mutation of the surface protein Mc1r that determines if melanocytes needs to produce a dark pigment or the lighter red-yellow pigment for skin and/or hair. If the protein Mc1r is less active the red or blonde hair will occur. Unfortunately this mutation didn’t seem to explain why cats had orange fur since the protein and the mutation are not located on the X chromosome. A team led from Greg Barsh, collected samples of red fur from cats fetuses and measured how the skin cells express the gene and the color by measuring the amount of RNA that each melanocyte produced. Turned out that the melanocytes from the orange cats produced 13 times more RNA from a gene called Arhgap36. The gene is located on the X chromosome which led to think that this was the responsible. The DNA sequence of the Arhgap36 protein shown not a mutation on the gene but a deletion of part of DNA that doesn’t affect directly the protein but that is involved in regulating how much it produced. Searches on genetic databases have shown that every single orange, calico and tortoiseshell cat have this particular mutation. The discovery was preprint on the server bioRxiv.

 A separate study from Japan confirmed this theory. 24 feral japan cats and 258 cat genome around the world revealed the same genetic deletion. Moreover, researchers also found that calico cats have more Arhgap36 in the orange regions compared to the black and brown ones. It has also discovered that the gene is subject to X inactivation since it silences one of the two X chromosome in females. The two team respectively found out that the increase level of Arhgap36 in melanocytes activate another way for  the cell  to produce the red pigment regardless if the MC1r is active or not. This discovery is very interesting because it is  unusual that a deletion instead of a mutation makes a gene more active rather than less. Moreover, the discovery of a new molecular pathways for hair color it was unheard and unexpected but shine a light on how complex is gene expression. This discovery also prove once again how RNA have a crucial role in controlling gene regulation and expression of different phenotypes.  

The Genetic Rarity of Male Calico Cats

     The article, 'Why Are Male Calico Cats So Rare', discusses the uncommon genetic abnormality of male calico or male tortoiseshell cats. So much so that the chances of a calico cat being a male is estimated to be one in three thousand. Calico cats do not describe the cat breed, but rather the feline's coat; typically a calico has a tricolor coat, white, cream, and gray or white, orange, and black, and a tortoiseshell coat has two colors black and orange marbled.  It has been found that coat color is coded in specific chromosomes referred to as a sex-linked trait. For example, both male and female felines could have an orange coat (the X chromosome carrying the black gene becomes inactivated creating orange fur) or a black coat (vice versa if the chromosome carrying the orange gene on the X chromosome becomes inactivated creating black fur) because the gene that controls both of these color patterns is found on the X chromosome. Biologically, females have two X chromosomes, while males have an X and Y chromosome. Since female felines have XX chromosomes, a female cat will easily express the mixed color pattern of both black and orange with a higher percentage of X chromosomes in their genome compared to male cats.  This results in a more apparent or visible mottled effect due to the higher "concentration" of X chromosomes in females.  Whereas, male felines with an XY chromosome, can only have a black or orange coat; unless they have a genetic abnormality that is known to increase the number of X chromosomes. Typically described as Klinefelter syndrome, a syndrome that can be observed in both humans and animals, where a male has three sex chromosomes, XXY. This XXY combination could be a result of the incomplete separation of the paternal chromosome pair during the time of fertilization. This XXY combination, likewise in humans, results in malformed sexual organs, typically resulting in male calico and tortoiseshell cats being sterile. 

    Male calico/tortoiseshell felines, meaning cats with Klinefelter syndrome, have been found to have a higher risk of developing health problems, potentially decreasing their life span when compared to the average tomcat. Some of these health problems are as listed: increased body fat, leading to diabetes, joint pain, heart disease, kidney disease, hypertension, and even certain types of cancer. 

   I chose this article topic because I have a female calico kitten, and as mentioned above, I was aware that, typically, calicos and tortoiseshell cats are females. Females can display both colors in a calico or tortoiseshell pattern since they have two X chromosomes (multiple colors/patterns of black, orange, and white, or grey, cream, and white). However, males, with only one X chromosome, do not express this mottled color pattern described above as noticeably. While I am aware that some multicolored tomcats exist, I did not realize how this was possible with the involvement of the X chromosome. Although this article does not go into the research that was conducted to support these findings, I find the information interesting, especially when I look at my female dilute calico kitty.

p.s. *from the article* Apparently, in many cultures, calico and tortoiseshell cats are coined with the nickname "money cats," as they are believed to bring money, wealth, and good luck to any families who adopt them! Which is something I have never known before!

Why are calico cat predominantly female?

It is a well known fact that calico cats are mostly female; male calico cats do exist, but this can only happen if the cat has Klinefelter Syndrome, which will be explained later. The reason why only female calico cats is because of a concept called Sex-Linked Genes, a concept that certain traits are determined by the sex chromosomes of an organism.

This diagram shows the X and Y
chromosome relationship with fur
color. 

Fur color in cats is determined by the X chromosome, so in most cases, the genotype of the mother cat will determine what kind of fur color the offspring will have. Since male cats have one X chromosome and one Y chromosome, the male cat's color will be determined by the one X chromosome. For example, if the mother has a X chromosome that expresses orange fur, the son will have orange fur. If the mother has black fur, the son will have black fur.

This idea is more complex in daughter cats. If a daughter has two X chromosomes that express the same fur color, a process called Lyonization will occur. Lyonization is a process that occurs during the blastula stage of embryonic development, and arises randomly in each cell. In each cell, one of the X chromosomes is coiled into a Barr Body, leaving the remaining X chromosome of express the trait. For example, if a daughter has two X chromosomes that express black fur, then one of those chromosomes will become a Barr Body, and the other chromosome will express the black fur in the phenotype. Once again, this is only at the cellular level

Calico cats have two different kinds of X chromosomes- one that expresses black fur and one for orange fur. The cats will not express both of these traits in the same cell; instead, each cell will express only black fur or only orange fur. In Lyonization, both X chromosomes will be separated, and be accompanied by their own Barr Body. Afterwards, each cell will arise from either the X chromosome that expresses from orange fur, or from the X chromosome that expresses black fur. This results in various patches that occur throughout the body called a tortoiseshell coloration.

Male calico cats are the result of Kilnefelter Syndrome, which is when a cat has two X chromosomes and one Y chromosome. The two X chromosomes will be one that expresses orange fur and one that expresses black fur. The only problem with this process is that the male calico cats become unfertile.

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