Sex Determination

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Sex Determination
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The Advantages of Sex Are Not Obvious
Sex is Expensive Two-fold Cost of Making
Males Even species where both mating types can
reproduce pay a price for sex
Assumption Benefit of increased genetic
variation overcomes cost of sex (Weismann,
1904) BUT, recombination can separate favorable
allele combinations just as easily as it can
assemble favorable combinations
Is sex (exchange of genetic material)
advantageous? Evidence from Nature Asexual
species are few in number and, though constantly
arising, appear short-lived Experimental Data
Very little
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Sex is Not Always BinarySexual Phenotypes in
Plainfin Midshipman Fish(Porichthys notatus)
Type I Male -Large body size -Vocalize (hum)
to attract mate and defend territory -Excavate
and defend nest -Cares for eggs and hatchlings
-Mates by courting and attracting females
Two mating strategies sneak spawning--enters
nest of Type I male and fertilizes
eggs satellite spawning--ejaculate just outside
nest and fan sperm into nest
Type II Male -Small body size -Only short
vocalizations -No nesting or care of young -Huge
testis
Female -Small body size -Only short
vocalizations -No nesting or care of young
-Lays eggs in nests of Type I males
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Sex Determination is Not ForeverFinding Nemo
The Disney Version
A clownfish father and son make their atypical
family unit work after the mom is tragically lost
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Sex Determination is Not ForeverFinding Nemo
The Real Story
Once Nemos mother is lost, Nemos father
undergoes sex reversal to become a fertile
female. Nemo, being the next largest fish in the
social group, rapidly progresses to male sexual
maturity and begins mating with his, now female,
father.
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How is Sex Determination Initiated?What is a Sex
Determination Switch?
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Karyotype vs. Phenotype in Drosophila
Karyotype Phenotype X/A XX Female 1.0 XY Male
0.5 XO Male 0.5 XXY Female 1.0 XXXAAA Fem
ale 1.0 XXXXAAAA Female 1.0 XXAAA Intersex 0
.66
Therefore sex is determined by XA ratio in
Drosophila
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Karyotype vs. Phenotype in Humans
Karyotype Phenotype Syndrome, associated
phenotypes XX Female wt XY Male wt
XO Female (12500) Turners syndrome
(Short stature, infertile,
many spontaneously abort) XXX Female
(11000) Pretty normal, extra Barr
Body XXXX Female Pretty normal, extra Barr
Bodies XXXXX Female Pretty normal, extra Barr
Bodies (Some mental retardation with extra X
chormosomes)
XXY Male (1700) Klinefelters Syndrome, Barr
Body XXXY Male Klinefelters Syndrome, Barr
Bodies XXXXY Male Klinefelters Syndrome, Barr
Bodies (Mental retardation and hypogonadism/infert
ility, increases with X chromosome dose, 60
spontaneously abort) XYY Male Pretty normal
(mental retardation) XYYY Male Pretty normal
(mental retardation) XYYYY Male Few reports
Therefore sex is determined by Y
chromosome Hypothesize a Testis Determining
Factor (TDF)
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Primary Sex Determination Switches
Y Chromosome Mammals
XA Ratio Flies and Worms
Temperature Some reptiles
ZZ vs. ZW Birds
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Temperature-dependent Sex Determination
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Primary Sex Determination Switches
Y Chromosome Mammals
XA Ratio Flies and Worms
Temperature Some reptiles
ZZ vs. ZW Birds
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The Sxl Promoter Interprets the XA Ratio
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Alternative RNA Splicing Controls Sex
Determination
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Alternative RNA Splicing Controls Sex
Determination
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Alternative RNA Splicing Controls Sex
Determination
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Drosophila Sex Determination
XX
XY
ON
OFF
Sex lethal
ON
OFF
transformer
tra 2
doublesex (Appearance)
DSXF
DSXM
fruitless (Behavior)
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Primary Sex Determination Switches
Y Chromosome Mammals
XA Ratio Flies and Worms
Temperature Some reptiles
ZZ vs. ZW Birds
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Mapping the Testis Determining Factor (TDF)
XY w / Y Deletions Some Female XX w/ Y DNA
translocated to autosome Some Male
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SRY is TDF
SRY (Sex-determining region of the Y) -Contained
within Y chromosome critical region -HMG box
containing transcription factor -Expressed in
primitive gonad -Sry transgene can transform XX
mouse into male
XY Sry
XX Sry
XY Sry
XX Sry
Koopman et. al. 1991
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Genetics of Primary Sex Determination in Humans
SRY thought to account for only 20 of human XY
sex reversal Sox9 -Sox9-/ Campomelic
Dysplasia 75 of XY individuals phenotypically
female -Duplication including Sox9 XX individual
phenotypically male (no SRY present) -Sox9
expression sufficient for testis development in
XX mouse
Deletion 9p -DMRT 1 and 2 deleted in 9p human XY
sex reversals -Related to fly doublesex and worm
mab-3
Various chromosomal regions associated with sex
reversal
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Gonad Sexual Dimorphism
WNT4a
FGF9
DMRTs
WNT4a
Ovary
Bipotential Gonad
SRY
SOX9
Testis
FGF9
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Creating Sexual Dimorphism
Mammals
Flies
Birds
Reptiles
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Sox100B is Expressed in a Male-specific Pattern
in the Drosophila Gonad
Male
Sox100B VASA
Female
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Sox100B is Required for Testis Development
Sox100B gonad phenotype
Testes
Accessory gland
Sox100B-/- pharate adult
Wild type adult
In Collaboration with Steven Russell, University
of Cambridge
In Collaboration with Steven Russell, University
of Cambridge
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Conserved Mechanisms for Gonad Sexual Dimorphism
Mammals
Flies
Birds
Reptiles
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How does a sex determination switch control
sexual dimorphism?
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Primary vs. Secondary Sex Determination

• Primary sex determination a tissue or cell
  directly assesses its sex (cell autonomous)
• Secondary sex determination a tissue or cell
  receives information about sexual identity from
  another tissue (non-cell autonomous)

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Most Drosophila Cells Undergo Primary Sex
Determination(or so we used to think)
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Mammals Mostly Undergo Secondary Sex Determination
XX
XY
Female
Male
Jost, 1940s
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Secondary Sex Determination Non-Cell
Autonomous Thought to be the predominant
mechanism in mammals
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A Gynandromorphic Zebra Finch
Female
Male
Agate et al, PNAS 2003
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How does a sex determination switch control
sexual dimorphism?Example 1 The somatic gonad
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Does every cell decide for itself in Drosophila?
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Sexual Dimorphism in the Embryonic Gonad
Male
Sox100B VASA
Female
St 15
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dsx is Only Expressed in the SGPs
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Non-autonomous Sex Determination in the
Drosophila Somatic Gonad
tra
dsx
Germ cells
Somatic Gonad msSGPs
Survival Signal
Pigment Cells
Male-specific SGPs
msSGPs survive and join male gonad
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Gonad Sexual Dimorphism
WNT4a
FGF9
DMRTs
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Early Events in Mouse Gonad Sexual Dimorphism
Only Sertoli Cells Are Thought to
Autonomously Require Sry
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Male-specific cell migration into the developing
gonad Janet Martineau, Katarina Nordqvist,
Christopher Tilmann, Robin Lovell-Badge, Blanche
Capel Current Biology 11 November 1997,
7958-968.
gonad
mesonephros
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How does a sex determination switch control
sexual dimorphism?Example 2 The germ cells
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Germline Sex Determination in the Mouse
Germ Cell Somatic Gonad Germ Cell Behavior
XX XX Enter Meiosis XY
XY Mitotic Arrest
XY XX Enter Meiosis XX
XY Mitotic Arrest
Therefore, the sex of the soma determines the
initial sex of the germline.
However, an XX germ cell cannot form sperm in a
testis and XY germ cells form few oocytes in an
ovary. Therefore, BOTH somatic signals and germ
cell autonomous factors regulate germline sexual
development.
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Karyotype vs. Phenotype in Humans
Karyotype Phenotype Syndrome, associated
phenotypes XX Female wt XY Male wt XO Female
(12500) Turners syndrome
(Short stature, infertile, many
spontaneously abort) XXX Female (11000) Pretty
normal, extra Barr Body XXXX Female Pretty
normal, extra Barr Bodies XXXXX Female Pretty
normal, extra Barr Bodies (Some mental
retardation with extra X chormosomes) XXY Male
(1700) Klinefelters Syndrome, Barr
Body XXXY Male Klinefelters Syndrome, Barr
Bodies XXXXY Male Klinefelters Syndrome, Barr
Bodies (Mental retardation and hypogonadism/infert
ility, increases with X chromosome dose, 60
spontaneously abort)
Turners Females and Klinefelters Males May Be
Infertile Due to a Sexual Incompatibility Between
Soma and Germline
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Contol of Germline Sexual Behavior by Retinoic
Acid
Cyp26b1 is expressed in male but not female
somatic gonad
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Somatic Signals and Germ Cell Autonomous Cues
Also Regulate Germline Sex Determination in
Drosophila
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Conserved Mechanisms for Gonad Sexual Dimorphism
Mammals
Flies
Birds
Reptiles
-Non-autonomous Sex Determination -Sex-specific
Cell Recruitment -Soma Control of Germ Cell
Sex Determination
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How does a sex determination switch control
sexual dimorphism?Example 3 Other
reproductive structures
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The Mouse Internal Reproductive Tract
Develops From Either the Mullerian or Wolffian
Ducts
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Regulated by non-cell autonomous signals
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The External Genitalia Develops From a Common
Bipotential Tissue
Dihydrotestosterone (DHT)
Regulated by non-cell autonomous signals
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Development of the Genital Disc in Drosophila
Female genital primordium only develops in
females to make female internal and external
structures (analogous to Mullerian Duct) Male
genital primordium only develops in males to make
male internal and external structures (analogous
to Wolffian Duct) Anal primordium develops along
male or female pathway to make external
structures (analogous to mammalian external
genitalia)
Not hormonally controled, but some non-cell
autonomous signals involved
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Gonad Sexual Dimorphism
WNT4a
FGF9
DMRTs
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Androgen Insensitivity Syndrome (AIS)
Mutation in androgen (testosterone) receptor
blocks secondary sex determination dependent on
testosterone
-XY genotype with normal Y and SRY -Testes form
normally -AMH produced and Mullerian ducts
regress -Wolfian ducts also regress -Female
external genitalia -Female gender image
Jamie Lee Curtis XY with AIS?
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Secondary Sex Determination
5-alpha ketosteroid reductase -Enzyme that
converts testosterone to more potent DHT -DHT
important for male external genitalia development
during embryogenesis -Not required for internal
structures
Mutations in 5-alpha ketosteroid reductase -XY
testis and internal structures fully
male -Infants and young children externally
female -Raised as girls -Puberty Increased
testosterone and second form of enzyme initiate
male external genital development -Young girl
metamorphoses into sexually mature young man
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Example 4 Sex and the Brain
swashtara.50g.com/ Brains.html
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Drosophila Sex-specific Courtship Behavior
Male
Female
Orienting Following Tapping
Running away Kicking Wing flicking
Singing Licking
Slows down Lowers wings
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Genes Controlling Sexual Behavior
Phenotype Gene Female Male fruitless w
t Courts males
dissatisfation rejects males Courts males and
females
XY TraF Courted by other males
hes not interested Dont court
spinster Dont court
Quick to court Court females more
aggressively Also court males
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Drosophila Sex Determination
XX
XY
ON
OFF
Sex lethal
ON
OFF
transformer
tra 2
doublesex (Appearance)
DSXF
DSXM
fruitless (Behavior)
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Generating Male- or Female-Specific Alleles of fru
Dickson and colleagues, Cell 2005
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Male Splicing of Fru is Required for Males to
Court Females
Males (XY)
Dickson and colleagues, Cell 2005
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Sex-specific Behavior in Zebra Finch
Males Sing Females Dont Gonadal hormones
thought to be key trigger in sex-specific
behavior and CNS morphology
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Gynandromorphic Zebra finch
Gonads Left Ovary but no oviduct Right Mature
but dysmorphic testis Plumage Left
Female Right Male
Agate et al, PNAS 2003
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Brain Genotype is half male, half female
ZZ (Male)
ZW (Female)
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Sex and the brain