X-inactivation - A CAT STORY

The calico cat has an illustrious role in the formulation of the X-inactivation hypothesis by Mary Lyon almost 60 years ago (Lyon, 1961; Kalantry and Mueller, 2015). Calico cats are almost exclusively females and comprise of two colors of fur on an otherwise white background. Lyon proposed that this coat color pattern arises due to inactivation of one or the other of the two equivalent X-chromosomes in females early during embryogenesis. In the orange patches in the calico cat shown above, the X-chromosome that harbors the brown allele is inactivated. In brown patches, the X-chromosome with the orange allele is inactivated.

[To answer a question about origins of the white coat color: it is due to an autosomal gene that affects migration of melanocytes - pigment-producing cells; the slower the migration, the more the fur is white. Calico cats often have lots of white fur but rather discrete patches of brown and orange colored fur. Cats with very little white fur and which display a brindled pattern with a more intimate mixture of brown and orange lie at the other end of the spectrum and are referred to as tortoiseshell cats - close cousins of calico cats.]

The second key feature - arguably the more important one - of Lyon’s hypothesis is that X-inactivation is a very stable phenomenon and that the discreteness of the coat color patches is due to clonal expansion of early embryonic progenitor cells that had inactivated one or the X-chromosome. The implication being that once inactivated, replicated copies of the inactive X-chromosome are stably maintained as inactive through many rounds of cell division. Like the calico cat coat color, almost all eutherian female mammals are mosaics. Each tissue in females can consist of a mixed population of cells, with some cells inactivating one X-chromosome and other cells the other X-chromosome.

That two identical or nearly-identical X-chromosomes can become transcriptionally divergent and that this difference is stably transmitted across many cell division cycles have made X-inactivation a paragon of epigenetic transcriptional regulation.