In mammals, biological sex is determined by sex chromosomes. Females typically possess two X chromosomes (XX), while males have one X and one Y chromosome (XY). The X chromosome is much larger and contains hundreds of genes vital for various bodily functions, not solely related to sex. This difference in chromosome number presents a unique challenge: females have two copies of every X-linked gene, whereas males have only one. If left unaddressed, this imbalance could lead to an excessive production of X-linked gene products in females compared to males.
X-Chromosome Inactivation: The Basics
To resolve potential gene dosage imbalance, X-chromosome inactivation (XCI) occurs. This mechanism ensures females, despite having two X chromosomes, express X-linked genes at levels comparable to males. Early in female embryo development, one of the two X chromosomes in each somatic cell is randomly silenced. This process, known as dosage compensation, equalizes the genetic “dose” of X-linked genes across sexes.
Geneticist Mary Lyon discovered X-chromosome inactivation, proposing the concept in 1961 as the Lyon hypothesis. This hypothesis explained how one X chromosome becomes condensed and functionally inactive, forming a Barr body within the cell nucleus. This inactivation is a stable epigenetic modification, altering gene expression without changing the underlying DNA sequence. It prevents an overdose of X-linked gene products.
The Replication Process of the Inactive X
Despite its inactive state, the inactive X chromosome still undergoes replication during the cell cycle, just like all other chromosomes. For the inactive X, this replication occurs during the S-phase, when DNA synthesis takes place.
The inactive X chromosome’s replication is distinguished by its timing. Unlike the active X chromosome and most other active, gene-rich regions of the genome (euchromatin), the inactive X typically replicates later. This late replication usually occurs in the late S-phase. This timing is a hallmark feature of heterochromatin, which is densely packed, transcriptionally inactive chromatin. The inactive X maintains its condensed, compact structure throughout the replication process, reflecting its silenced state.
Maintaining Inactivation Through Cell Division
The faithful inheritance of the inactive state of the X chromosome through successive cell divisions is important for maintaining proper gene dosage. After DNA replication, the cell must ensure that newly synthesized DNA strands also carry the epigenetic marks that define the inactive X. This maintenance involves the precise copying and re-establishment of these modifications.
Specific epigenetic marks, such as DNA methylation and various histone modifications, are crucial for this process. DNA methylation, often occurring at CpG sites, involves the addition of a methyl group to DNA bases, which leads to gene silencing. Similarly, histone modifications, like specific patterns of histone acetylation and methylation, alter how DNA is wrapped around histone proteins, influencing gene accessibility. These marks are propagated to the daughter DNA strands following replication, ensuring that the inactive X chromosome in each new cell retains its silenced status.
Implications of X-Inactivation
X-chromosome inactivation has significant biological consequences, leading to mosaicism in females. Because inactivation of either the paternal or maternal X chromosome occurs randomly in different cells early in development, adult females are a mosaic of two cell populations. Each cell population expresses genes from only one of the two X chromosomes. This cellular mosaicism means that different cells within the same female individual may have distinct functional X chromosomes.
Calico cats, almost exclusively female, are a classic example of this mosaicism. Their distinctive patches of black, orange, and white fur arise because coat color genes are on the X chromosome, and different X chromosomes are active in various skin regions. X-inactivation can also influence the presentation of X-linked genetic conditions in females. While males with a single affected X chromosome exhibit the full condition, females, due to mosaicism, can experience variable expressivity or reduced severity, such as in color blindness or Rett syndrome.