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Human sex determination: The
supremacy of the Y


Genetic analyses established the Y as “testisdetermining”
– XO = female
– XXY = male
Gonadal sex determination
– early fetal “indifferent” gonad
– determination as testis or ovary
– expt’l evidence for subsequent role of
hormones (esp. testosterone and Mullerian
inhibiting hormone, MIS)
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
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
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
Other genes influence sexual
differentiation


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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