Sex-linked and Non-Standard Inheritance Flashcards
What are the typical sex chromosomes associated with males and females?
Males are XY
Females are XX
Describe the Lyon hypothesis.
Define Barr body.
What are the rules of inactivation?
Females have twice as many X chromosomes as males. Lyon hypothesis is an attempt to explain “dosage compensation” which is to say how females don’t use one of our X’s so men don’t feel left out.
Lyon hypothesis states that one X chromosome in each cell is inactive, pushed to the side of the nucleus and seen as a Barr body.
Rules of inactivation: inactivation is random, fixed, and incomplete.
How do X-inactivation patterns present?
Because each cell has a random X that is inactivated, two cell types can emerge and may express different alleles.
This results in mosaics, which every female is. This is visible in calico cats, where splotches of the cats are expressing different X chromosomes resulting in random color patterns.
Describe the X-inactivation center. How does this work? What are two mechanisms that may be involved?
The X-inactivation center is a specific region located on the inactivated X. It contains at least one gene, XIST. This transcribes one 17 kB RNA that coats the inactive X to maintain deactivation.
Methylation and histone deacetylation may be involved.
How do X-linked recessive disorders affect females?
Frequency of affected females is very low.
Requires an affected father or a new mutation.
Half of their cells would express the mutation, but the other half of normal cells can compensate.
What are pedigree clues that you are looking at an X-linked recessive disorder?
- NO father-son transmission
- Passage through females with “skipped” generations
- Affected father and normal mother will have NO affected children
Name X-linked recessive disorders.
- Hemophilia A (factor VIII)
- Duchenne Muscular Dystrophy
- Color Blindness
Describe Hemophilia A.
What mutation causes this?
What are the symptoms?
What is the current therapy?
Defect in Factor VIII gene on X chromosome - very large gene - nonsense, deletions, inversions result in severe disease - missense mutations usually mild
Varies in severity (half have severe form with less than 1% normal factor VIII, moderate has 1-5%, mild has 5-25% normal activity)
Prolonged/severe bleeding from wounds, hemorrhages in joints and muscles, hearth roses is common, intracranial bleeding
Current therapy is Factor VIII infusions
Describe Duchenne Muscular Dystrophy.
What gene is affected?
What is a milder form of this disease?
Severe, progressive muscle atrophy
Usually shows by age 5, and wheelchair bound by age 11. Typically death by 25.
Early diagnostic indicator is creating kinase released by muscle
Dystrophin gene, largest known gene, binds F-actin and dystroglycan - typically absent entirely in DMD
Becker MD is milder with altered dystrophin
Describe color-blindness.
Which type of color blindness is X-linked?
Normal vision is trichromatic, not seeing one color is dichromatic.
Red-green color blindness is x-linked. Red and green ops is are adjacent on X and share 98% sequence identity. Usually one red followed by one or more green. Unequal crossing over leads to variations - no green(deuteranopia) or disrupted red(protagonist)
Which is more common X-linked dominant or recessive?
Who is more likely to be affected by X-linked dominant disorders?
X-linked recessive is more common.
Females are twice as likely. But heterozygous may be less affected.
Name 3 X-linked dominant disorders and their symptoms.
- Hypophophatemic rickets - kidneys can’t absorb phosphate, abnormal ossification, bent bones
- Incontinentia pigmenti - abnormal skin pigmentation and teeth, neuro and ocular abnormalities - males lost in utero
- Rhett syndrome - autism, ataxia, cognitive delay - some males survive to term
What are some X-linked dominant pedigree clues?
- More females affected
- In EVERY generation
- NO father-son transmission
- Males show more severe phenotype
Describe Y-chromosome inheritance.
What is the technical name for this?
What is the common function of genes on the Y chromosome?
Special region
“Holandric inheritance”
Occurs strictly from father to son
Most genes involved with sex determination, spermatogenesis, and testicular function
There is a special region that are not related to that above. These have homologs on the X chromosome, and escape inactivation
X-Y crossover can occur in this region
Describe Fragile X syndrome.
What is the Sherman paradox?
What is the cause of this syndrome?
Occurs when the end of the long arm of X breaks off when cultured in low folic acid.
Most common form of INHERITED developmental delay
Odd inheritance pattern - “Sherman paradox”
Sisters of normal transmitting males are less likely to be affected than granddaughters of normal transmitting males
daughter of NTMs are never effected by grandchildren may be
CGG repeats in the 5’ UTR of FMR1 gene. Typically these repeats exist as 6-50 copies. Transmitting males have 50-230 copies. Over 230 copies have the syndrome. These repeats expand only in female meiosis so offspring of NTMs have same as him
