Class 25 Sex Determination

1
Class 25 Sex Determination
Sex is determined by different factors in
different organisms
In some amphibians and reptiles,temperature
affects sex determination by affecting hormone
levels
2
In most other organisms, sex is determined
by 1. a single sex chromosome XX (female)
vs. XY (male) mammals ZY (female) vs. ZZ
(male) birds 2. the ratio of sex chromosomes
to autosomes
3
Sex determination by XA ratio
4

• From this information, what is the normal
  function of her-1?
• To make the gonad hermaphrodite
• To make the gonad male

5
Two possible pathways are consistent with this
data a. Tra-1 -- her-1 -- hermaphrodite b.
Her-1 -- tra-1 ? hermaphrodite
Double mutant tra-1 (lf) her-1 (lf)
male male
From this data,which pathway is correct, a or b?
6
High X/A ratio inhibits her-1 while Low X/A ratio
activates her-1
High X/A --
Each member of the pathway works by repression
tra-1 acts as the ultimate switch gene (encodes a
transcription factor) Expression causes
hermaphrodite development while repression causes
male development
7
Drosophila sex determination XX Female XY Male

• Based on the information in the table below, what
  determines whether a fly will be a normal male?
• Number of X chromosomes
• One Y chromosome
• An XA ratio of 1
• An XA ratio of less than 1
• An XA ratio of .5

• X chromosomes Y chromosome Autosome Sets
  Sex
• 4 0 4 female
• 2 0 2 female
• 2 0 3 intersex
• 2 1 4 male
• 1 1 2 male
• 1 0 2 male

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numerator proteins encoded by X chromosome that
act as transc. factors
denominator autosomal proteins that block
binding of the numerator proteins
9
Mechanism of switch (for Sxl gene)
Sxl protein then allows transformer transcript to
be spliced, and become functional protein
Alberts
10
Simplified scheme
G, 5.30
11
The rest of the genes in the pathway include
additional products that are alternatively
spliced to render either a nonfunctional product
or a different product for males vs. females
12
Mammalian sex determination
A single chromosome determines male vs.
female XX female XY male XO female XXY male
(The Y chromosome)
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Formation of the gonad The Primordial Germ Cells
(PGCs) migrate into the embryo from
extraembryonic mesoderm these cells ultimately
become sperm or eggs within the gonad
19.7
14
Formation of the gonads arise from intermediate
mesoderm
Bipotenital gonad
17.3
15

Testes development
Mesenchyme cells produce testosterone Epithelial
sex cords produce AMH
16
Ovarian development
Mesenchyme cells Epithelial sex cords Together
these cells make up the follicles, which
nurture the oogonia
17
Primary Sex Determination sex reversals gave
first clue
XX individuals that were male XY
individuals that were female
Had a translocation of part of the Y chromosome
Missing a piece of the Y chromosome
17.5
18
Later, a single gene was found to be responsible
for testes development the SRY gene (Sex
determining Region of the Y chromosome)

• Sry transcripts are present in the genital ridge
  in mice during the
• indifferent gonad stage
• Sry mutations have been found in 25 of human XY
  females
• Sry transgene converts XX female mice into males

19

• Sry encodes an HMG box DNA binding protein
• Probably works by bending the DNA when it binds
  (thus making it easier to transcribe, more
  accessible to transc. factors)
• Interestingly, the Sry sequence is poorly
  conserved among mammals suggesting it arose
  relatively recently (evolutionarily)

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Primary vs. Secondary sex determination
Secondary sex determination (outward sex-specific
physical appearance) is dependent upon hormones
produced by the male- or female-specific ductal
systems
21
At the indifferent gonad stage, both Mullerian
and Wolffian ducts are present
17.4
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Secondary sex determination depends on hormones
released from the gonads
In testes MIS (AMH) induces Mullerian duct to
regress testosterone induces
Wolffian duct to form
17.4
In ovaries estrogen allows full differentiation
of Mullerian duct
23
Examples of sex reversals due to hormonal
problems Androgen (testosterone) Insensitivity
Syndrome individuals with an XY genotype look
externally female DHT-deficiency XY, look
female at birth, then male.

• If an XX individual has a translocation
  containing the SRY gene,
• they will have
• Testes and a Wolffian duct
• Ovaries and a Mullerian duct
• Ovaries and a Wolffian duct
• Testes and a Mullerian duct
• Testes but no ductal system
• Ovaries but no ductal system

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Sry is only part of the story of primary sex
determination
At least two other genes are required
Sox9 for male development Dax-1for female
development
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Sry is only part of the story of primary sex
determination
At least two other genes are required for testes
development
Sox9 transcription factor related to Sry
Expressed at indifferent gonad stage in both
sexes Maintained in testes Evolutionarily
conserved Probably activated by Sry Loss
results in sex reversals
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Sox-9 XX transgenic mice look male
17.7
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Is female development default? Not really At
least two genes are required for ovary
development (or suppression of testes development)

• Dax1
• initially found due to duplications of a region
  of the X chromosome that led to female
  development in
• XY individuals
• transcription factor, initially expressed in
  both sexes
• later only in ovary

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Dax-1 expression maintained only in female gonad
17.10
29

• What does the data below indicate about the role
  of Dax-1 in gonad development?
• Dax-1 is inactive in XY individuals
• Dax-1 only specifies ovary development when
  present in two copies
• Relative levels of Dax and Sry determine ovarian
  or testes development

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A possible model
17.11
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The overall picture
17.2