X linkage

1
X linkage

• Lecture 4
• http//www.ucl.ac.uk/ucbhjow/index.html

2
objectives

• Describe X inactivation
• Describe dominant and recessive modes of X linked
  inheritance
• Explain the relationship between the mutation
  rate of X linked genes and the incidence of X
  linked lethal conditions
• Estimate from family data the risk of being a
  carrier of an X linked mutation.

3
X inactivation

• All autosomal monosomies are lethal
• But males with only one X chromosome are normal.
• How is this accomplished?
• The answer is by inactivation of one of the two X
  chromosomes in females
• The inactive X chromosome is visible as a dark
  staining "Barr body".

• A very small number of genes on the
  inactivated X escape inactivation.

4
Dominant X linked inheritance

• Sex linked dominant conditions are extremely
  rare, examples include incontinentia pigmenti
  (which is lethal in males) and congenital
  generalized hypertrichosis (wolf man syndrome).
• The pattern of inheritance will be similar to
  autosomal dominant. However, all the daughters
  but none of the sons of affected males will be
  affected.

5
X linked inheritance

• Usually only males affected
• No cases of male to male transmission
• All the affected males can be linked through
  unaffected carrier females

• Males are hemizygous.
• If the mutant gene is lethal (such as Duchenne
  Muscular Dystrophy) then it takes an unusual
  event to produce an affected female.

6
Examples

• There are many well known X linked recessive
  conditions, some of the best known are Duchenne
  muscular dystrophy (DMD), Haemophilia (two types)
  and colour blindness.

7
Mutation rate of X linked genes

• One third of all X chromosomes are present in
  males and hence one third of mutant X chromosomes
  are present in males.
• Consequently, if the condition is lethal, then
  one third of the mutant X chromosomes will be
  lost from the population each generation.
• If the frequency of the disease is not changing
  then the lost mutant chromosomes will have to be
  replaced by new mutation.
• Consequently, the mutation rate of a lethal X
  linked recessive disease is one third of the
  frequency of the disease
• One third of the cases of this disease will be
  caused by newly mutated X chromosomes

8
Risk estimation

• Consider the pedigree on the right in which there
  is no previous history of DMD but not many
  generations are known. What is the chance that
  the sister of the affected boy is a carrier?
• The obvious (wrong) answer is ½. This answer
  assumes that the mother must be a carrier.
• However, because the affected boy may be the
  result of a new mutation, there is only a ?
  chance that his mother is a carrier and therefore
  only a ? chance that his sister is a carrier.
• If however there had been two affected brothers
  or an affected maternal uncle as well as the
  affected brother then we could have been certain
  that the mother was a carrier and the first
  answer would have been correct.