Y Chromosome and X-inactivation

Special Features of the Y Chromosome

• The evolutionary divergence of the X and Y chromosomes began approximately 200 million years ago.
• The Y chromosome contains the SRY gene, which triggers male development.
• The Sox3 gene on the X chromosome has a similar function but does not determine male sex.
• Some regions of the X chromosome containing the SRI gene became redundant and degraded over time.

X Chromosome Inactivation

• Females have two X chromosomes, but only one is active in each cell to prevent gene dosage effects.
• X inactivation is the mechanism where genes on one of the two X chromosomes are silenced.
• X inactivation occurs randomly early in development where one X chromosome is turned off in each cell.
• Males do not require X inactivation due to having only one X chromosome.
• The inactivated X chromosome is randomly selected in each cell and remains inactive throughout the individual's life.
• X-linked disorders may present differently in females due to the potential compensation from the other X chromosome.

Summary of Chromosomal Differences

• Females have two X chromosomes, and males have one X and one Y chromosome.
• The presence of the SRY gene on the Y chromosome is pivotal for male development.
• The X chromosome is larger than the Y chromosome, containing about 900-1000 genes.
• The Y chromosome is smaller, with only 45-55 unique genes, mainly for male-specific functions.
• Most parts of the X and Y chromosomes are non-homologous, except for two pseudoautosomal regions (PARs).
• Homologous chromosomes are pairs of chromosomes that are similar in size, shape, and genetic content.

Pseudoautosomal Regions (PAR)

• PAR1 and PAR2 allow homologous recombination (crossing over) during meiosis.
• PARs are located at the distal ends of the short arms (PAR1) and long arms (PAR2) of both chromosomes.
• Crossing over in males helps maintain genetic diversity within these regions.
• Homologous recombination is essential during meiosis to promote proper chromosome pairing and segregation in gametes. Failure to properly recombine results in failure to segregate which leads to issues such as aneuploidy.

Y Chromosome Characteristics

• The Y chromosome is roughly 1/3 the size of the X chromosome with an essential function in male development.
• The Y chromosome contains both coding and non-coding regions, including repetitive sequences and PARs.
• Repetitive sequences are present on the Y chromosome that may play roles in structural integrity and gene regulation.

Functional and Non-functional Genes on the Y Chromosome

• Functional genes on the Y chromosome are involved in sexual differentiation, development of sexual characteristics, and spermatogenesis.
• Key genes include SRY, DAZ, and others related to male reproductive structures.
• Non-functional genes may be vestigial or have unexplored functions.

Sexual Differentiation and the Y Chromosome

• Embryo sex is genetically determined at fertilization (XX for female, XY for male).
• Morphological sexual characteristics develop around the seventh week after conception.
• The presence of the Y chromosome initiates male development, while its absence leads to female development.

Testis Determining Factor (TDF) and the SRY Gene

• The SRY gene, located on the Y chromosome, is the primary determinant for male development.
• SRY encodes a DNA-binding protein that acts as a transcription factor, activating genes for male-specific structures.
• The SRY gene triggers the differentiation of the gonads into testes.

Summary of SRY Gene Function

• SRY encodes a protein that binds DNA and acts as a transcription factor, regulating genes critical for male sexual differentiation.
• SRY presence induces male development, while its absence results in female development.
• The gene is expressed in the genital ridges during embryonic development, just before testes differentiation.
• SRY initiates a genetic cascade that leads to the formation of the male reproductive system.

Recognition of the X Chromosome and Its Function

• Genes are essential for development and cellular function
• Recognizing the Lyon Hypothesis
• To identify the relevant mechanisms leading to X chromosome inactivation

The X Chromosome and Its Inactivation

• The X chromosome is submetacentric where the centromere is slightly off-center
• It encodes approximately 1,000 genes
• Females (XX) inherit one X chromosome from each parent. Males (XY) inherit only one X chromosome from their mother
• Dosage compensation is required to equalize gene expression between males and females.

The Lyon Hypothesis (1961)

• Proposed by geneticist Mary Lyon
• In each female cell, only one X chromosome remains transcriptionally active
• X inactivation occurs randomly during early embryogenesis
• Once an X chromosome is inactivated, all descendant cells will maintain the same inactivation pattern.

Timing of X Inactivation

• X inactivation begins shortly after fertilization
• Ensures dosage compensation is established before major organ development
• Prevents overexpression of X-linked genes

Random Nature of X Inactivation

• X inactivation is random and independent in each cell
• Once inactivation occurs, all daughter cells will inherit the same inactive X chromosome
• This random nature results in genetic mosaicism in females.

Mosaicism in Females

• Means that females have a mix of cells, some with an active maternal X and others with an active paternal X
• If a female carries an X-linked mutation, the severity of symptoms depends on which X is inactivated in more cells
• This can explain variability in X-linked disorders in females
• Some female carriers show mild symptoms due to skewed X inactivation.

Detection of Inactivated X Chromosomes

• The inactivated X chromosome can be visualized under a microscope as a Barr body during interphase.
• Barr bodies are dense, compacted heterochromatin, located at the edge of the nucleus.
• The inactivated X chromosome replicates late during S phase, helping to maintain its silent state.

Mechanism of X Chromosome Inactivation

• Key mechanisms involved are DNA methylation of CpG dinucleotides
• Histone modifications
• RNA-based silencing, where a non-coding RNA (XIST) coats the X chromosome to trigger inactivation.

Key Gene Involved in X Inactivation: XIST

• X-inactive specific transcript (XIST) is a long non-coding RNA (lncRNA) that plays a critical role in silencing one X chromosome.
• The XIST gene is found on the X chromosome (Xq13.2).
• XIST RNA coats the X chromosome that is destined for inactivation.

Statistical Distribution of X Inactivation

• The expected maternal-to-paternal X inactivation ratio is 1:1.
• Approximately 10–15% of individuals show an unequal distribution, where one X chromosome is preferentially inactivated.

1. Expected X Inactivation Ratio is 1:1 in theory
2. Most females will have a roughly even split, but some will have more cells expressing one X than the other
3. This happens because some cells may later divide more successfully, leading to an uneven number of cells expressing one X over time.

Clinical Relevance of Skewed X Inactivation

• Some genes escape X inactivation, leading to medical implications
• Example: If a female carrier of hemophilia has skewed inactivation favoring the mutated X, she may show bleeding symptoms.

Scenarios Where Skewed X Inactivation is Clinically Significant

• If the normal X chromosome is inactivated, it can lead to severe symptoms.
• If X inactivation were complete, individuals with Turner syndrome (45,X) or Klinefelter syndrome (47,XXY) would have no clinical phenotype.

Summary of X Inactivation

• In a healthy female, all X chromosomes except one are inactivated to balance gene dosage.

1. Exceptions in Polyploidy (Extra X Chromosomes)

• the usual "one active X per cell" rule changes