Tag Archives: epigenetics

Calico Cats and X inactivation – Embryogenesis Explained Book Excerpt

It has long been a source of frustration to cat breeders that you can’t get the lovely tricolour cat pattern also known as the calico cat, to breed true. Here’s why.1024px-Calico_and_dilute_calico_cats

Two female cats (sisters) illustrating the difference between the calico and dilute calico coats. by Leonardo Boiko

Female mammals have two X chromosomes. (There are a few individual and species exceptions, as always.) Two X chromosomes is one too many and so one has to be shut down in order (presumably) to keep gene dosage at the same level as that in the male. Very early in embryogenesis, when a female mammalian embryo is a small ball of cells, one X chromosome is inactivated in each cell. This inactivated X moves to the outer edge of the nucleus and sits there visible in the light microscope as a Barr body. (Named for Murray Barr who first discovered it.) The timing varies between species so when cats have X inactivation is different in development from when humans have it. Which of the two X chromosomes was silenced in a particular embryonic cell is generally random. Once silenced, that inactivated X is carried on during all future mitoses. There is a gene for coat pigmentation in cats that is also located on the X chromosome. Since females have two X chromosomes they also have two genes for pigmentation. In the female cat, one gene for coat color is shut off when the X is inactivated. If a female cat happens to get an orange gene from one parent and a black gene from the other (she is a heterozygote, i.e. the alleles are different), then during early embryogenesis, the cat will have some cells with only a working orange pigment gene and others cells will have only the black gene working. Both genes, one from the mother and one from the father, are present. Only one is used in each cell because the other is coiled up and sequestered on the inactive X.

The gene for coat pigmentation doesn’t actually “work” until much later in development. Recall the neural crest cells that break free from the boundary zone of the neural ectoderm and the epithelial ectoderm during neural tube closure (Chapter 2). These neural crest cells migrate out and later on some of them form the pigment cells that give us the color we see on the cat. When it is time for the genes to be turned on about half of the calico cat’s cells have only the orange gene turned on and half have the black gene turned on. The pigment cells migrate to their place and then do several rounds of replication to produce patches that are all clones of the first cell to migrate into an area. These patches of cells replicate and expand until they meet cells from another clone. The cat continues developing and the result is the orange and black blotch pattern we see on her coat.

A mutation on a totally separate gene from another chromosome causes the white patches on the calico cat. When this altered gene is active, pigment cell migration is slowed and the cells don’t migrate all the way out to all edges of the cat. They also mix up less than they otherwise would for reasons not really understood. Hence, the white pattern, not associated with the genes on X chromosome, is usually pretty symmetrical on both sides causing the attractive “dipped in milk” look of the classic calico cat. The patches of black and orange are random but larger than on a cat without the white. If the cat has no mutation on the gene, the pigment cell migration is not slowed and she develops into a plainer tortoiseshell cat usually (though not always) with smaller and more blended patches of colour. (Another common allele is an allele called dilute, which makes the colour softer, black to grey and orange to apricot as in the picture.)

The calico cat has one X chromosome inactivated in each cell and the inactivation of that one X is for her entire life. The inactivated state of this X chromosome is transmitted to all copies of that chromosome during subsequent cell divisions and their mitoses. All mechanisms, including DNA methylation, histone modifications and coating by various RNAs such as Xist, that are involved in the transmission of the state of a gene from a cell to its daughter cell at mitosis, are transmitted by bookmarking (Chapter 3). Bookmarking is transmission of a cell’s “memory” to its progeny.

Yet, when a calico cat has kittens she can pass on either the orange gene or the black gene to each of her babies and her kittens will not have the same pattern of inactivation. The male kittens she has will each get one X chromosome from her and one Y chromosome from their father. Because the pigment gene is only on the X chromosome any male kittens will be either orange or black and he will inherit only one of his mother’s coat color genes. What color her female kittens are depends on the both parents’ contribution. If the father is black, he will always contribute one X chromosome with the black gene. The mother can contribute either a black or orange gene. The female kittens will be either black and orange like her or all black, depending on which X they got from their mother. If the father is orange, the reverse happens and the female kittens will be orange or orange and black. The all orange and all black female kittens will undergo their own X inactivation in early development and be just as much mosaics as their prettier calico sisters but the X inactivation pattern will be invisible. X inactivation is “reset” with each generation.

X inactivation was originally discovered by a female scientist Mary Frances Lyon FRS (15 May 1925 – 25 December 2014). Another term for X inactivation is Lyonization.

This post contains excerpts from Chapter 4 of our upcoming book Embyrogenesis Explained.


Figure Caption: The calico cat is a female cat ♀ with white underparts. The gene for color is located on the X chromosome (vertical line with circle under a cat). The female cat has two X chromosomes and therefore two color pigment genes (two vertical lines with orange and black circles). When the cat embryo reaches about 64 cells X inactivation of one X in each cell occurs. (Nowack, R. (1993). Curious X-inactivation facts about calico cats. NIH Res. 5, 60-65.)The result as it grows is patches of yellow and patches of black in the kitten. Male cats ♂ have only one X chromosome and one Y chromosome (short, vertical grey line) and so are either all black or all orange. The gene which creates white, pigmentless patches is inherited independently of the color genes and is not located on the X chromosome. When a calico cat has kittens she can have an all black or an all yellow daughter with probability ¼, but not both. Which solid color daughter she has depends on the color gene on the X chromosome contributed by the father (left: black father, right: orange father). This is why people often say all orange female cats are relatively rare and why there are no normal male calico cats.

Genetics of Color Vision

Alan and Noah

Picture by Ann Marquez

One of the great things about being both a geneticist and a grandmother is I get to see how genes get transferred around. That shuffling of genes at meiosis produces some really fascinating results. This week I spent time with my youngest grandchild. He is two. He is in that delightful stage when the whole world is a wonder and a joy. His particular fascination now is colors and flowers. While dropping his big brother off at school, we walked past some flower beds of petunias and the little guy was completely taken with flowers.

“Flower, yellow!” (Except it sounded like lellow)

“Flower, Red!”(Pronounced wed)

We wanted some quality time so since the kid was so taken with flowers we decided to visit the Assiniboine Park’s Old English Garden in Winnipeg. This really is an old fashioned English garden with more varieties and colors of flowers in one spot than I have ever seen anywhere else. My grandson was positively in heaven.


This picture is from the Assiniboine Park website.

“Flower, blue!”

“Flower, lellow!”

And we saw some giant trumpet shaped pink blossoms.

“Flower, pink, BIG!”

He had a wonderful time. In fact we wore him out. All the extra stimulation of the color varieties in the English Garden meant he fell asleep on the drive home and took a longer nap than usual as his developing brain processed all that input.

Watching the little guy it seemed to me that he was seeing a lot more color in these flowers than I was. He is much more fascinated by color than either his sibling or any of his cousins. From testing, I know that I can’t see shades of red as well as I can see shades of blue. I inherited my father’s X chromosome complete with his gene for red/green colour blindness. Fortunately due to X inactivation I am not red/green color blind. My color vision cells are a blend with some cells having the X chromosome I inherited from my father inactivated and in the rest it is my mother’s X chromosome that is inactivated. The result is that I do have an ability to distinguish reds and greens because of the mosaic pattern in my eye but I do have some near color deficits. Due to random meiotic shuffling, none of my sons inherited the red/green color blindness. My sons see color just fine. My brother, on the other hand, was tested in the military and his color vision far exceeds normal. He has such excellent color vision that after he left the military he actually made his living as a color matcher for a kitchen cabinet making company. Being male, he didn’t get an X chromosome from our father. Instead he got our mother’s X and likely something more.

The evolution of color vision in mammals is not a simple progression. Each vertebrate has up to 5 functional visual photopigment opsin genes that clump into two gene families that can be traced back up to 540 million years ago. Four of these genes are expressed in the cone cells in the retina. The other is expressed in the rod cells, which are generally associated with black and white vision but in low light can also have a role in color vision. Mammals started 200 million years ago with one opsin gene on the X chromosome, which itself originated from our tetrapod ancestors about 300 million years ago. For the past 35 million years the catarrhine primates, which include humans, have had two cone opsin genes side by side on the X chromosome, probably as a result of a gene duplication followed by evolutionary divergence. Another opsin gene is located on chromosome 7. With two X chromosomes, human females have two pairs of genes for color vision on them. Males have only one pair. Color blindness is therefore much more common among human males than among human females, my father and I being an excellent example of this when it comes to red.

One of the opsin genes on the X chromosome is called OPN1LW and it codes for protein pigment used by cone cells that respond to the yellow/orange part of the visible spectrum (longer-wavelengths of light). The other gene on the X chromosome is called OPN1MW and it codes for a protein pigment used to detect light at middle wavelengths (yellow/green light). The gene on chromosome 7 that codes for the third opsin gene type is called OPN1SW and it codes for a protein pigment that is used to see the blue/violet part of the visible spectrum (short-wavelength light) Thus there are three different kinds of cone cells, heavily concentrated in the foveal region of the retina, yet each individual cell expresses only one of the three possible opsins. Somehow, there is regulation that ensures one opsin gene, and only one opsin gene, is expressed. These cells are arranged in a patchy manner, including some large patches of one type or another.

With the combination of the three cone cell types we humans have trichromatic vision. A few people have tetrachromatic vision meaning we have four different types of cones and that gives those individuals even more ability to distinguish color. Males can have tetrachromatic vision only if they have two different variations (alleles) of the gene on chromosome 7. They can express one of the two genes on their single X in each cone cell and the two different alleles they have on chromosome 7. I suspect my brother, with his superior color perception has tetrachromatic vision. Females can have tetrachromatic vision in two ways. They can have two alleles on chromosome 7 and they can also have tetrachromatic vision if they have a mosaic pattern in their retina due to X inactivation. In theory, a rare women could even have hexachromatic vision but there is no evidence of that having ever occurred because we simply don’t test beyond tetrachromacy. It would seem that the X inactivation patches are usually too big for tetrachromacy for except perhaps one woman found in an investigated group of 24 women. Even so, it is well established that on average, women have much better color vision than men.

It’s far too soon to tell for certain but I suspect my color obsessed youngest grandchild also has tetrachromatic vision. If that is true, then his visual apparatus is very finely attuned to see all the wonderful colors in the Old English Garden. He will go through life seeing far more beauty than I ever will. And he will wince more often as the less gifted among us wear what appears to his eye as bizarro and clashing combinations.

My husband has green/brown color deficits. He was fascinated by the idea of prosthetic color vision glasses so he could see the world the way we did. He had an undergraduate student, Andrea Wsiaki, who did an undergraduate thesis on “Design of a computer graphics viewer for colour deficiency correction” in 2000. Others have brought this line of research to practical fruition. You can see one of the results here:

A young man gets color compensating glasses and sees purple for the first time in his life.

This young man’s reaction was very similar to watching my grandson in the English Garden

“That’s purple?!! Oh my God!!!”

(This post is based, in part, on material in the epigenetics chapter of our upcoming book, Embryogenesis Explained.)