X-Inactivation (Lyonization)

X-inactivation, often called Lyonization after its discoverer Mary Lyon, is the developmental process by which one of the two X chromosomes in each cell of a female mammal is transcriptionally silenced. Because the choice of which X to inactivate is usually random and is then clonally inherited, female mammals become functional mosaics of two cell populations, and X-linked gene dosage is balanced against that of XY males.

Definition

X-inactivation (Lyonization) is the process whereby one X chromosome in each somatic cell of a female mammal is stably silenced early in development, so that each cell expresses X-linked genes from a single X and dosage is compensated relative to males.

Scope

This topic covers the dosage-compensation rationale for X-inactivation, the random versus imprinted choice of the inactive X, the developmental timing of silencing, the clonal maintenance and resulting mosaicism, and the concept of skewing. The detailed XIST and chromatin machinery is treated in the companion topic on X-silencing mechanisms; here the focus is the principle and its consequences.

Core questions

• Why do female mammals need to inactivate one X chromosome?
• How is the choice of which X to silence made, and when?
• How is the inactive state maintained through subsequent cell divisions?
• What is X-inactivation skewing and why does it matter?

Key concepts

• Dosage compensation
• Random vs imprinted X-inactivation
• Counting and choice
• Clonal maintenance of the inactive state
• Functional mosaicism
• Skewed X-inactivation
• Barr body (condensed inactive X)

Key theories

Lyon hypothesis

Lyon proposed that early in female development one X chromosome is inactivated at random, that the choice is fixed and clonally propagated, and that females are therefore mosaics in which some cells express the maternal and others the paternal X.

Mechanisms

Early in female embryogenesis cells count their X chromosomes relative to autosomes and select one X to remain active and the other to be silenced. In most somatic tissues the choice is random, generating a mosaic of cells expressing either the maternal or the paternal X; in some tissues, such as the extra-embryonic lineages of certain mammals, the paternal X is preferentially inactivated (imprinted X-inactivation). Once chosen, the inactive X is condensed into a heterochromatic Barr body and the silenced state is faithfully copied to all descendant cells. Departures from a 50:50 ratio, termed skewing, arise by chance or by selection for cells expressing a particular X and can influence the manifestation of X-linked traits in females.

Clinical relevance

Because X-inactivation makes females cellular mosaics, the clinical expression of X-linked conditions in females depends on the proportion of cells in which the mutant X remains active; markedly skewed inactivation can make a carrier symptomatic or, conversely, protect her. This topic explains why parent of origin and chance both shape female phenotypes; it is descriptive and not a guide to individual testing or care.

Epidemiology

X-inactivation is a universal feature of female mammalian somatic cells rather than a disease state. Skewing of the inactivation ratio is common to a mild degree in the general female population and increases in frequency with age and in carriers of certain X-linked mutations.

History

Mary Lyon advanced the single-active-X hypothesis in 1961 to reconcile coat-colour mosaicism in female mice with the cytological observation of the Barr body and with dosage compensation. Over the following decades the random-choice, clonal-maintenance, and skewing aspects were confirmed across mammals, and reviews in the late 1990s and 2010s integrated the principle with the underlying molecular machinery.

Key figures

• Mary F. Lyon
• Edith Heard
• Philip Avner
• Stanley Gartler

Seminal works

• lyon-1961
• heard-1997
• galupa-heard-2018

Frequently asked questions

Does X-inactivation silence the entire X chromosome?

Most of the inactive X is silenced, but a subset of genes escapes inactivation and continues to be expressed from both X chromosomes, which is part of why X-linked dosage differences are not absolute.

What is skewed X-inactivation?

Skewing is a departure from the expected roughly equal mix of cells using each X. It can occur by chance or because cells expressing one X are favoured, and it can influence whether a female carrier of an X-linked mutation shows features of the condition.