CELS191 Lecture 17: X-Inactivation

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Lecturer Profile

• Name: Hamish Spencer
• Position: Sesquicentennial Distinguished Professor, Department of Zoology
• Research Interests: Population-genetic theory, genomic imprinting, phylogenetics, phenotypic plasticity, NZ molluscs, history of eugenics.
• Contact: hamish.spencer@otago.ac.nz
• Profile Link: otago.ac.nz

Lecture 17: X-Inactivation Overview

• Objectives:
  • Outline the Lyon Hypothesis and Barr bodies.
  • Understand the concept and consequences of X-inactivation.

Human Sex Determination

• Genes on sex chromosomes (X & Y) determine individual sex.
• The Y chromosome is smaller and has fewer genes than the X.
• Males (XY) have one X chromosome, while females (XX) have two.

Chromosomes and Gender

• Autosomes: Chromosomes 1-22 are present in equal numbers in both sexes.
• Sex Chromosomes: Present in unequal numbers between males and females.
• Importance of understanding the genetic dosage of X-linked genes across sexes.

X Inactivation: The Lyon Hypothesis

• Concept:
  • Random inactivation of one X chromosome in females early in development.
  • Inactive X chromosomes form Barr bodies.
  • Results in mosaic cell patterns in females with two X chromosomes.
  • Essential for balancing X-linked gene expression between sexes.
• Mary Lyon (1925–2014) is the key figure associated with this hypothesis.

Barr Bodies

• Inactive X condenses into a Barr body, located against the nuclear envelope.
• Most genes on the inactivated X chromosome are not expressed.
• The number of Barr bodies equals the number of X chromosomes minus one (N-1).

Evidence of Lyon Hypothesis

• Observations from sex aneuploid conditions provide evidence:
  • In both male and female karyotypes, excess X chromosomes are inactivated as Barr bodies.
• Examples of Aneuploids:
  • Klinefelter Syndrome: XXY male shows one active X, one Barr body.
  • Turner Syndrome: XO female has no Barr bodies due to having only one X.

Mosaicism and X Inactivation

• Calico Cats:
  • Exhibit patchy coloration due to X-inactivation patterns related to fur color gene.
  • All calico cats are female, males typically exhibit solid colors.
• Human Example:
  • Anhidrotic ectodermal dysplasia in heterozygous females leads to mosaic patterns showing sweat gland loss in blue patches.

Genetic Diseases and Gender

• Many X-linked diseases are more common in males due to the presence of a single X chromosome.
• Often lack a mosaic effect in females as gene products can circulate throughout the body (e.g., clotting factor in Hemophilia).

Dosage Compensation Strategies

• In marsupials, the paternal X chromosome is selectively inactivated.
• In Drosophila, male X chromosome gene expression is upregulated to balance dosage.

Practice Questions

1. An XXY human will:

   • (A) exhibit Turner syndrome.
   • (B) have a Barr body in each nucleus.
   • (C) be an abnormal female.
   • (D) be monosomic.

2. A female is color blind in one eye only; her father is color blind in both:

   • Could be due to (A) X-inactivation in a heterozygote, (B) a somatic mutation, (C) damage to one eye, (D) any of the above.

Key Takeaways from Lecture 17

• X-linked dosage compensation happens via X-inactivation, making effective doses equal between sexes.
• One X chromosome is inactivated in female cells creating a Barr body, leading to diverse gene expression profiles.
• Importance of understanding X-inactivation's role in genetic conditions and mosaic patterns in females.

Objectives Recap

• Understand why X-inactivation occurs and the concept of Barr bodies.
• Discuss the random inactivation leading to mosaic patterns, along with examples.
• Outline why most genetic diseases do not show mosaic effects in carrier females.