One geneticist's hypothesis explains why almost every calico cat is female

In 1961, Mary Lyon proposed that female mammals randomly switch off one of their two X chromosomes in each cell, a process now called X-inactivation. Because cat coat-color genes sit on the X chromosome, this explains why calico and tortoiseshell patterns show up almost only in females — each patch marks which X chromosome that patch of cells silenced. A male calico cat is rare enough that it usually means an extra X chromosome.

— Mary F. Lyon, Gene Action in the X-chromosome of the Mouse (Mus musculus L.) — Nature, 1961