X- and Y-Linked Inheritance, Dosage Compensation, and the Lyon Hypothesis

Patterns of Single-Gene Inheritance: X- & Y-Linked Inheritance

Introduction

This section introduces the genetic principles underlying the inheritance of genes located on the sex chromosomes (X and Y), with a focus on dosage compensation and the Lyon hypothesis. These concepts are fundamental to understanding sex-linked genetic disorders and the mechanisms that balance gene expression between males and females.

X and Y Chromosomes

Structure and Function

• Males have one X and one Y chromosome (XY).

• Females have two X chromosomes (XX).

• The X chromosome is larger, containing approximately 155 megabases (Mb) of DNA and about 1,000 genes.

• The Y chromosome is smaller, with about 60 Mb of DNA and roughly 60 genes.

• The Y chromosome contains genes involved in sex determination and other protein-coding genes.

Dosage Compensation

Definition and Importance

• Dosage compensation is the process by which organisms equalize the expression of genes between individuals with different numbers of sex chromosomes.

• Although females have two X chromosomes and males have one, gene expression from the X chromosome is balanced so that both sexes have similar levels of X-linked gene products.

• In females, only one X chromosome is transcriptionally active in each cell; the other is inactivated.

Mechanisms and Evidence

• Evidence for dosage compensation comes from biochemical studies and cytological studies (e.g., observation of Barr bodies).

• Genes from only one of the female's two X chromosomes are transcribed into RNA in each cell.

Enzymes Coded for by X Chromosome Genes

Isozyme Expression

• Females heterozygous for X-linked genes (e.g., G6PD or PGK) express only one isozyme in each cell.

• This demonstrates that only one X chromosome is active per cell, supporting the concept of X inactivation.

Barr Body

Definition and Characteristics

• A Barr body is a small, dense chromatin body found in the nuclei of normal female cells but not in normal male cells.

• It consists of the inactivated X chromosome, which is condensed and heterochromatic.

• The Barr body replicates later during the DNA synthesis phase of the cell cycle than other chromosomes.

• RNA is not transcribed from the Barr body.

Barr Body Counting

# of Barr Bodies	# of X Chromosomes
0	1 (XY)
1	2 (XX, XXY)
2	3 (XXX)

The number of Barr bodies in a female's cells is always one less than the total number of X chromosomes.

Lyon Hypothesis

Historical Background and Explanation

• Proposed by Mary F. Lyon in 1962, the Lyon hypothesis explains the mechanism of dosage compensation in mammals.

• It states that in female mammals, one of the two X chromosomes in each cell is randomly inactivated during early embryonic development.

• This inactivation is permanent in all descendants of that cell, leading to a mosaic pattern of X-linked gene expression in females.

Key Points of the Lyon Hypothesis

• X inactivation is random with respect to the maternal or paternal origin of the X chromosome.

• Once an X chromosome is inactivated in a cell, all daughter cells will have the same X chromosome inactivated.

• The inactivated X chromosome forms the Barr body.

Example: Calico Cats

• Calico cats are a classic example of X inactivation, where different patches of fur color result from the random inactivation of X chromosomes carrying different color alleles.

Summary Table: X Chromosome Inactivation

Sex Chromosome Complement	# of Barr Bodies	Phenotype
XY	0	Normal male
XX	1	Normal female
XXY	1	Klinefelter syndrome
XXX	2	Triple X female

Key Terms

• Dosage Compensation: Mechanism that equalizes X-linked gene expression between males and females.

• Barr Body: Inactivated X chromosome visible as a dense chromatin mass in female cells.

• Lyon Hypothesis: Theory that one X chromosome in each female cell is randomly inactivated.

• X Inactivation: The process by which one X chromosome is silenced to achieve dosage compensation.

Equations and Genetic Principles

• Number of Barr Bodies:

$\text{Number of Barr Bodies} = \text{Number of X Chromosomes} - 1$

Applications and Clinical Relevance

• X inactivation explains why females who are heterozygous for X-linked mutations can be mosaics for the expression of those traits.

• Abnormalities in X inactivation can lead to clinical syndromes such as Turner syndrome (XO), Klinefelter syndrome (XXY), and Triple X syndrome (XXX).