006 X-linkage

Question 1

what are the sex chromosomes for typical men and women?

Answer 1

• XX = women
• XY = man

Question 2

what is X inactivation?

Answer 2

• in females (XX) in every cell only one X chromosome gene is functional despite having 2 copies
• so we have the same number of X functional genes as males
• the inactive X chromosome is visible as a dark staining Barr body

Question 3

what is the inactive X chromosome called/ what does it look like?

Answer 3

• Barr body
• dark stained circled/clump

Question 4

what is the method of X chromosome inactivation?

Answer 4

• most genes are silenced due to repressive heterochromatin (very gene poor), a small number of genes escape inactivation
• DNA is very tightly packed and inactivated into facultative heterochromatin by:
  - DNA methylation
  - Low levels of histone acetylation
  - Presence of histone macroH2A: helps to compress DNA even more

Question 5

when does X inactivation occur?

Answer 5

• Irreversible X inactivation occurs in the blastocyst stage of development
• each cell independently and randomly inactivated 1 X chromosome
• all daughter cells will have the same X-chromosome inactivated

Question 6

what is the critical gene involved in sex determination?

Answer 6

SRY
- also know as Testis Determining factor (TDF)

Question 7

how does SRY determine sex?

Answer 7

• the SRY gene product together with SF1 protein, is a transcription factor that upregulates other transcription factors (most importantly SOX-9) and it activates testes promoting genes and represses ovary-promoting genes
• SRY is usually on the Y chromosome
• however XX men can have SRY gene copy translocated to their X chromosome, so XX (women) would develop testes
• and XY women would have a lack of functional SRY gene, XY (men) not develop testes

Question 8

describe the pattern of dominant X-linked inheritance

Answer 8

• very rare
• similar to autosomal dominant inheritance ( only need 1 copy of dominant allele to get disease)
• however, all the daughters but none of the sons of males will be affected
• this is as sons do not inherit their father’s X chromosome

Question 9

give 2 examples of dominant X-linked inheritance

Answer 9

• incontinentia pigmenti (IP2 gene - usually lethal in males) causes blotches of hyperpigmentation
• congenital generalised hypertrichosis (wolf man syndrome)

Question 10

what inheritance does this pedigree show?

Answer 10

• dominant X-linked inheritance

Question 11

describe recessive X-linked inheritance

Answer 11

• usually only males are affected (as females have 2 X chromosomes so would only get if both parents had recessive allele - unless turner syndrome (XO))
• no cases of male to male transmission (don’t pass on X chromosome)
• all affected males can be linked through unaffected carrier females
• males are hemizygous (only 1 X chromosome)
• if the mutant gene is lethal then it would be very rare to produce an affected female ( if lethal dad would be dead, could only be due to something like turner’s syndrome (XO)

Question 12

what inheritance does this pedigree show?

Answer 12

recessive x linked inheritance

Question 13

give some examples of X-linked inherited diseases

Answer 13

• Duchenne muscular dystrophy
• haemophilia A and B
• red/green colour blindness
• Lesch-Nyhan syndrome (HGPRT deficiency)
• glucose-6-phosphate dehydrogenase deficiency

Question 14

what are the child outcomes of an X-linked recessive carrier mother and normal father?

Answer 14

• 25% normal boy
• 25% disease boy
• 25% normal girl
• 25% carrier girl

Question 15

what are the child outcomes of an X-linked recessive father with disease and normal homozygous mother?

Answer 15

• 50% normal boy
• 50% carrier girl

Question 16

why don’t female carriers of X-linked recessive diseases also suffer the disease as they inactivate their X-chromosome?

Answer 16

• sometimes they do (e.g. in Fabry disease most of female carriers show some disease manifestation, sometimes severe)
• sometimes they show milder but related symptoms to those seen in males
• some genes escape X-inactivation (up to 25% in humans)
• preferential inactivation of 1 X chromosome (e.g. the parental X chromosome)

Question 17

what is sex-linked vs sex-limited

Answer 17

• sex-linked = inherited on X chromosome
• sex-limited = only XX or XY will inherit certain traits unless there is an abnormality
  e.g. breast cancer, endometriosis

Question 18

what is imprinting in terms of genes?

Answer 18

• when the parental chromosomes cause different activation/inactivations of a gene due to their evolutionary desires
• these can cause different diseases
• can give a false impression of sex linkage

Question 19

give an example of diseases caused by imprinting

Answer 19

• Angelman syndrome and Prader-Willi syndrome are 2 different conditions, both of which seem to be caused by very similar deletions of a small part of chromosome 15
• the Angelman gene (UBE3A) is inactivated on the parental chromosome
• the Prader-Willi gene is inactivated on the maternal chromosome
  (same deletion, different parental chromosome, different diseases

Question 20

describe the association between X chromosome and the brain

Answer 20

• 3.75% of all genes are on the X chromosome
• 27% of brain disabilities with known genetic cause map to the X chromosome
• more than 333 brain disorders are associated with X chromosome mutations
• women are more protected than men from non/reduced function alleles
• brain-associated disorders are more common in males

Question 21

what effect does Turner’s syndrome have on social skills?

Answer 21

• some women have 1 X chromosome and nothing else
• if they inherited it from their fathers they were shown to have more social skills than if they inherited from their mothers
• men inherit their X chromosome from their mothers
• men suffer more from conditions associated with reduced social skills
  imprinting?

Question 22

describe the mutation rate of X-linked genes if the condition is lethal

Answer 22

• 1/3 of all X chromosomes (XX, XY) are in males, thus 1/3 of mutant X chromosomes are present in males
• if the condition is lethal, then 1/3 of the mutant X chromosomes will be lost from the population each generation
• if the frequency of the disease is constant then the lost mutant chromosomes will have to be replaced by a new mutation
• the mutation rate of a lethal X-linked recessive disease is 1/3 of the frequency of the allele
• 1/3 of the cases will be caused by newly mutated X chromosomes

Question 23

explain how in this pedigree where there is no known history of DMD, how you can use risk estimation to work out the chance the sister of the affected boy is a carrier?

Answer 23

• the obvious wrong answer is 1/2 which assumes the mother must be a carrier
• however because the affected boy may be due to a new mutation with a 1/3 chance, there is only a 2/3 chance that his mother is a carrier (XX) and thus 1/3 chance sister is carrier (1/2 of mum’s X chromosomes)
• so it is 1/3

Question 24

explain the ‘problem of phase’ in sex-linked inheritance

Answer 24

• phase represents original allele combinations that an individual receives from its parents
• imagine you have 2 sites on a chromosome that are variable, site 1 can have C or T and site 2 can have A or G
• if you genotype an individual, they will be heterozygous at both sites
• however you don’t have complete information about which allele belongs to which copy of chromosome
• can find out using statistics, molecular analysis, look at state of those sites in families, see how alleles are coinherited
  (only a problem in women)