Sex Chromosomes and Aneuploidy

Sex chromosomes determine sex and pose a dosage problem the cell solves by inactivating one X, while errors in chromosome separation produce aneuploidies whose effects depend on which chromosome is involved.

Definition

Aneuploidy is the presence of an abnormal number of individual chromosomes, usually one too many or one too few, while sex chromosomes are the chromosomes that determine sex and are subject to dosage compensation through X inactivation.

Scope

This topic covers chromosomal sex determination and the role of the Y, X-chromosome inactivation as dosage compensation, the mechanism of nondisjunction, the major autosomal aneuploidies such as trisomy 21, and sex-chromosome aneuploidies including Turner and Klinefelter syndromes. It treats abnormalities of chromosome number and the special biology of the sex chromosomes; structural changes are covered in the adjacent topic.

Core questions

• How do sex chromosomes determine sex, and what role does the Y chromosome play?
• How does X-chromosome inactivation equalize gene dosage between the sexes?
• How does nondisjunction produce aneuploid gametes and offspring?
• Why do different aneuploidies have such different viabilities and phenotypes?

Key concepts

• Chromosomal sex determination and the Y chromosome
• X-chromosome inactivation and dosage compensation
• Nondisjunction in meiosis and mitosis
• Autosomal trisomies and monosomies
• Sex-chromosome aneuploidies

Mechanisms

In mammals the Y-linked SRY gene triggers male development, and dosage compensation silences one X in each female cell through the noncoding Xist RNA; aneuploidy arises when chromosomes fail to separate at meiosis or mitosis, and the phenotype reflects the dosage imbalance of the genes on the affected chromosome, which is why most autosomal monosomies and trisomies are lethal.

Clinical relevance

Aneuploidy is the most common chromosomal cause of pregnancy loss and intellectual disability, with trisomy 21 producing Down syndrome and sex-chromosome aneuploidies producing Turner and Klinefelter syndromes; recognizing these patterns guides prenatal screening and counseling, presented here for education rather than clinical direction.

History

Stevens and Wilson identified the X and Y as sex-determining chromosomes in the early 1900s, Lejeune showed in 1959 that Down syndrome results from an extra chromosome 21, and Lyon proposed X-chromosome inactivation in 1961, explaining how females tolerate two X chromosomes.

Key figures

• Mary Lyon
• Nettie Stevens
• Jérôme Lejeune

Seminal works

• lyon1961

Frequently asked questions

What is X-chromosome inactivation?

In mammals, female cells silence one of their two X chromosomes early in development so that both sexes express a similar dose of X-linked genes; which X is inactivated is random in each cell, producing a mosaic of cell populations.

Why is trisomy 21 survivable when most trisomies are not?

Chromosome 21 is one of the smallest and carries relatively few genes, so the dosage imbalance from an extra copy is more tolerable than for larger, gene-rich chromosomes, whose trisomies are usually incompatible with survival.