Sex-linked Inheritance

Question 1

Compare X and Y Chromosomes

Answer 1

X chromosome

• >1,500 genes
• homolog to Y chromosome in males
• females = Homogametic sex (XX)

Y chromosome

• small # of genes
• DNA segments = palindromes & destabilize the chromosome
• transmitted male to male ONLY
• males = Heterogametic sex (XY)

Pseudoautosomal Inheritance

• Genes on Y shared w/ X chromosome = pseudoautosomal region
  
  • PAR1 & PAR2
    
    • opposite ends of Y chromosome
  • can recombine w/ homologous X-chromosome sequences
• Male specific (MSY) region
  
  • includes SRY gene
    
    • important for determining male sex
  • does NOT recombo w/ X-chromosome

Question 2

Pedigree of a Y-chromosome linked marker

Answer 2

Transmission from father to son ONLY

Question 3

What is X‐inactivation? How does it lead to mosaicism?

Answer 3

X‐inactivation aka Lyon Hypothesis; “Lyonization”

• Basics:
  
  • Inactive X’s = heterochromatic
    
    • most genes NOT transcribed
  • Xist gene = encodes RNA that binds & inactivates X chromosome
    
    • inactive X = Barr Body in the nucleus
      
      • (XXXXY = 3 barr bodies) = all but 1 inactivate
• Why does this happen?
  
  • dosage compensation btw males/females
    
    • both now have 1 active X
• Mosaicism
  
  • Random X-inactivation = phenotypic variation in females
    
    • causes variation, including identical twins
      
      • not genetically identical
  • Non-Random inactivation (Ratio not always 1:1)
    
    • predominant activation of 1 of the 2 Xs
      
      • selection against cells
    • ​deleterious mutation of essential gene on 1 X may cause cell w/ that X to die
      
      • makes other X more present

Question 4

How can females develop X-linked disease?

Answer 4

• Non-random X inactivation
  
  • phenotype = milder than males b/c of mosaicism
    
    • 2 genetically different cell populations in 1 individual
  • Highly biased inactivation (or Turners Syndrome)
    
    • allows development of full phenotype
  • Rare true non-random inactivation = results from mutations that affect the X-inactivation system

Question 5

Monoallilic vs Bialielic gene expression in ‘Non‐Random’ X inactivation

Answer 5

A. Monoallelic gene expression

• X inactivation works properly w/ XIC gene
  
  • Xist ncRNA

B. Bialielic gene expression

• No X inactivation
  
  • abnormal X w/ absent XIC gene

Question 6

What is Turner Syndrome?

Answer 6

Turner Syndrome (45,X)

• Basics:
  
  • most common aneuploidy
  • 99% of Turner conceptions = spontaneously abort
• Caused by:
  
  • Absence of all or part of one X chromosome
    
    • absense of Y chromosome
    • leads to FEMALE development
  • Non-disjunction
    
    • sole X is usually maternal
• Symptoms:
  
  • Newborns = nuchal skin (webbed neck)
  • Childhood = short stature
  • Adolescence = primary amenorrhea (no ovulation)
  • Normal intelligence
    
    • Deficiency in spatial perception
  • Normal verbal skills

Question 7

What is Klinefelter Syndrome?

Answer 7

Klinefelter Syndrome (47, XXY)

• Basics:
  
  • Extra copy of X-linked gene
• Phenotypes include:
  
  • incomplete sexual development
  • rubimentary testes & prostate
  • long limbs, large hands & feet
  • some breast tissue development
    
    • Not diagnosed until fertility problems arise
• Mental features:
  
  • not intellectually disabled
  • poor pyschosocial adjustment
  • delayed speech
  • poor motor skills
• **Opposite of Turners…ish**

Question 8

What is 47?

Answer 8

47 XYY

• Basics:
  
  • ​96% phenotypically normal
  • Normal intelligence & fertility
• Phenotypes:
  
  • greater height
  • acne
  • minor speech defects
  • reading/spelling disabilities
• Caused by:
  
  • Paternal Non-Disjunction at meiosis II
    
    • produces YY sperm

Question 9

What is Trisomy X?

Answer 9

Trisomy X (47 XXX)

• Basics:
  
  • ​Normal phenotype
  • Fertility = normal
  • Learning difficulty , but able to function
  • Pubertal development = normal
    
    • exhibits tallness
• Caused by:
  
  • maternal meiosis 1 error
    
    • _​_shows 2 barr bodies (1 active)

Question 10

What is XXYY Syndrome?

Answer 10

XXYY Syndrome

• Basics:
  
  • arises due to unusual oocyte + sperm
    
    • closely related to Klinefelter’s syndrome
• Phenotype:
  
  • tall
  • obese
  • gynocomastic
  • skin ulcers
  • ADD , OCD, learning disabilities, infertile
• Treatment:
  
  • Testosterone

Question 11

What is X‐linked recessive inheritance?

Answer 11

Males:

• affected more than females = due to single X
  
  • hemizygous
  • recessive alleles are expressed

Females

• both chromosomes must harbor defective mutation for disease to occur = due to 2 Xs
  
  • father would ALWAYS express mutation
• plus, X-inactivation

Frequency:

If frequency of defective alleles = 0.01

• 0.01 = 1% of males affected.
• (0.01)^2 = 0.01% of females affected.

Pedigree:

• Skips every generation
  
  • maintained by carrier females only
  • no affected males pass the mutation

Example:

• Hemophilia

Question 12

X‐linked recessive inheritance
affected male and normal female

Answer 12

• Daughters = carrier heterozygotes

Question 13

X‐linked recessive inheritance
Carrier female and normal male

Answer 13

Sons:

• 50% normal
• 50% affected

Daughters:

• 50% normal
• 50% carrier

Question 14

X‐linked recessive inheritance
Carrier female and affected male

Answer 14

Carrier female

• transmit defective allele to 1/2 sons & 1/2 daughters

Affected father

• transmits Y to ALL sons
  
  • 50% of affected
  • 50% normal
• transmits defective allele to ALL daughters
  
  • 50% affected
  • 50% carrier

Question 15

X‐linked Dominant Inheritance

Answer 15

X‐linked Dominant Inheritance (rare)

• Allele may be lethal to male embryos
  
  • male sparing
  • male lethal
• Father passes to ALL daughters (X)
  
  • No father –> son transmission (b/c Y)
  • Disease in female = milder