Genetics
In genetic terms calico cats are tortoiseshells in every way, except that in addition they express a white spotting gene. There is however one anomaly: as a rule of thumb the larger the areas of white, the fewer and larger the patches of ginger and dark-or-tabby coat. In contrast a non-white-spotted tortoiseshell usually has small patches of color or even something like a salt-and-pepper sprinkling. This reflects the genetic effects on relative speeds of migration of melanocytes and X-inactivation in the embryo.
Serious study of calico cats seems to have begun about 1948 when Murray Barr and his graduate student E.G. Bertram noticed dark, drumstick-shaped masses inside the nuclei of nerve cells of female cats, but not in male cats. These dark masses became known as Barr bodies. In 1959, Japanese cell biologist Susumu Ohno determined the Barr bodies were X chromosomes. In 1961, Mary Lyon proposed the concept of X-inactivation: one of the two X chromosomes inside a female mammal shuts off. She observed this in the coat color patterns in mice.
Calico cats are almost always female because the X chromosome determines the color of the cat and female cats, much like all female mammals, have two X chromosomes, whereas male mammals, including common male cats, have one X and one Y chromosome. Since the Y chromosome does not have any color genes, there is no chance he could have both orange and non-orange together. One main exception to this is when, in rare cases, a male has XXY chromosomes (see Klinefelter's syndrome), in which case the male could have tortoiseshell or calico markings. Male calico or tortoiseshell cats are sterile due to the abnormality of carrying two X chromosomes. Few of these males can breed (1 in 3,000) and are rejected by breeders for studding purposes and would, in any event, pass on only one of those X chromosomes to any male offspring, producing normal (non-calico) male kittens. "In the case of a calico cat, the feline’s parents passed on different versions of X chromosomes genes related to coat color." The color of calico or tortoiseshell cats is determined by the X chromosome(s). Tortoiseshell and calico cats are almost always female because of X chromosome inactivation.
As Sue Hubble stated in her book Shrinking the Cat: Genetic Engineering before We Knew about Genes,
"The mutation that gives male cats a ginger-colored coat and females ginger, tortoiseshell, or calico coats produced a particularly telling map. The orange mutant gene is found only on the X, or female, chromosome. As with humans, female cats have paired sex chromosomes, XX, and male cats have XY sex chromosomes. The female cat, therefore, can have the orange mutant gene on one X chromosome and the genes for a black or white coat on the other, and those can affect or modify the orange mutant gene. If that is the case, those several genes will be expressed in a blotchy coat of the tortoiseshell or calico kind. But the male, with his single X chromosome, has only one of that particular coat-color gene: he can be not-ginger or he can be ginger (although some modifier genes can add a bit of white here and there), but unless he has a chromosomal abnormality he cannot be a calico cat."
It is currently impossible to reproduce the fur patterns of calico cats by cloning. "This is due to an effect called x-linked inactivation which involves the random inactivation of one of the X chromosomes. Since all female mammals have two X chromosomes, one might wonder if this phenomenon could have a more widespread impact on cloning in the future."
Calico cats may have already provided findings relating to physiological differences between male and female mammals. This insight may be one day broadened to the fields of psychology, psychiatry, sociology, biology and medicine as more information becomes available regarding the complete effect of random X-inactivation in female mammal.
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