Human sex determination: The supremacy of the Y

1
Human sex determination The supremacy of the Y

• Genetic analyses established the Y as
  testis-determining
• XO female
• XXY male
• Gonadal sex determination
• early fetal indifferent gonad
• determination as testis or ovary
• exptl evidence for subsequent role of hormones
  (esp. testosterone and Mullerian inhibiting
  hormone, MIS)

2
Review The search for TDF (SRY)

• Experimental paradigm sex-reversed individuals
• XY females (missing critical bit of Y)
• XX males (possessing critical bit of Y)
• Deletion mapping of Y coupled with analysis of
  sex-reversed individuals and chromosome walking
  to get new sequences

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The pivotal male sex-determining gene SRY

• Sequencing revealed a conserved motif that could
  have DNA-binding function
• SRY TDF
• XY sex-reversed females have deletions or
  mutations of SRY
• transgenic mouse model - XX Sry leads to testis
  development
• SRY expressed in gonad, but only transiently, at
  the onset of differentiation

4
Downstream sex-determining genes

• Puzzling XY sex-reversed females without
  detectable mutation in SRY provide evidence for
  additional genes, including
• DAX1 - on X, can suppress testis-formation in a
  dosage-sensitive manner
• SOX9 - on 17q, required with SRY for normal
  testis formation

5
Other genes influence sexual differentiation

• X-linked androgen insensitivity identified the
  androgen receptor gene
• Deficiency for 5a-reductase leads to failure to
  convert T to active form, DHT, and subsequent
  feminization of external genitalia in affected
  males
• Congenital adrenal hyperplasia, e.g., deficiency
  of 21-hydroxylase, leads to excess androgen and
  masculinization of female genitalia