Sex Determination

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Sex Determination
The Advantages of Sex Are Not Obvious (to Biologists)
Sex is Expensive:
-Energy and risk costs of mating
-Two-fold cost of making males
-Two-fold cost of meiosis (only passing on half your genes at a time)
Even species where both mating types can reproduce pay a price for sex
Hypothesis: Benefit of increased genetic variation overcomes cost of sex
(Weismann, 1904)
BUT, recombination can separate favorable (co-adapted) 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: not easy to generate
Only 74 of approx. 42,300 vertebrate species are asexual
(Vrijenhoek, 1989)
Most existing asexual species have evolved recently from
sexual ancestors
i.e. they are evolutionarily short-lived
Exceptions exist: some asexual species are stable
Asexual Champions: bdelloid rotifers are thought to have been asexual for 100 my
-380 morphological species in 20 genera
-molecular evidence supports the evolution of rotifer species from common
ancestors
Sex is Not Always Binary
Sexual 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
Type II Male
-Mates by courting and
attracting females
Two mating strategies:
Type II Male:
-Small body size
-Only short vocalizations
-No nesting or care of young
Type I Male -Huge testis
Female
Hatchlings
Type II Male
Female:
-Small body size
-Only short vocalizations
-No nesting or care of young
”sneak spawning”--enters nest
of Type I male and fertilizes
eggs
“satellite spawning”--ejaculate
just outside nest and fan sperm
into nest
-Lays eggs in nests of
Type I males
Sex is Not Forever
Naturally occuring sex reversal: e.g. clownfish
-sex is determined by social context (not genetic)
-largest fish becomes fertile female
-next largest becomes fertile male
-others arrested as juveniles
If dominant female removed, fertile male
becomes fertile female
A juvenile matures into fertile male
Female to Male Switching in the wrasse Thalassoma duperrey
Female
Switching
Male
How is Sex Determination Initiated?
What is a Sex Determination Switch?
Karyotype vs. Phenotype in Drosophila
Karyotype
XX
XY
Phenotype
Female
Male
X/A
1.0
0.5
XO
XXY
Male
Female
0.5
1.0
X:A
XXX:AAA
XXXX:AAAA
Female
Female
Female
1.0
1.0
1.0
XX:AAA
Intersex
0.66
Therefore sex is determined by X:A ratio in Drosophila
The Sxl Promoter Interprets the X:A Ratio
Alternative RNA Splicing Controls Sex Determination
Alternative RNA Splicing Controls Sex Determination
Alternative RNA Splicing Controls Sex Determination
Drosophila Sex Determination
XX
XY
Sex lethal
ON
OFF
ON
transformer
OFF
DSXF
tra 2
doublesex
DSXM
(Appearance
and Behavior)
fruitless
(Behavior)
Karyotype vs. Phenotype in Humans
Karyotype
XX
XY
XO
Phenotype
Female
Male
Female (1:2500)
Syndrome, associated phenotypes
wt
wt
Turner’s syndrome
(Short stature, infertile, many spontaneously abort)
XXX
XXXX
XXXXX
XXY
XXXY
XXXXY
Female (1:1000) Pretty normal, extra Barr Body
Female
Pretty normal, extra Barr Bodies
Female
Pretty normal, extra Barr Bodies
(Some mental retardation with extra X chormosomes)
Male (1:700)
Male
Male
Klinefelter’s Syndrome, Barr Body
Klinefelter’s Syndrome, Barr Bodies
Klinefelter’s Syndrome, Barr Bodies
(Mental retardation and hypogonadism/infertility, increases with X chromosome dose, 60% spontaneously abort)
XYY
XYYY
XYYYY
Male
Male
Male
Pretty normal (mental retardation)
Pretty normal (mental retardation)
Few reports
Therefore sex is determined by Y chromosome
Hypothesize a “Testis Determining Factor” (TDF)
Mapping the Testis Determining Factor (TDF)
XY w / Y Deletions
XX w/ Y DNA translocated to autosome
Some Female
Some Male
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+
Koopman et. al. 1991
XX Sry+
Gonad Sexual Dimorphism
WNT4a
FGF9
DMRT’s
Foxl2
Rspondin
WNT4a
Bipotential
Gonad
SRY
SOX9
FGF9
Ovary
Testis
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
Foxl2
-premature ovarian failure (heterozygous truncations—could be dom neg)
-ovarian tumors
Wnt4
-female to male sex reversal
Various chromosomal regions associated with sex reversal
Primary Sex Determination Switches
Y Chromosome
Mammals
ZZ vs. ZW
Birds
X:A Ratio
Flies and Worms
Temperature
Some reptiles
Temperature-dependent Sex Determination
Temperature is “read out” in the gonads
26°C (Male)
33°C (Female)
Cultured
Gonads
Intact
Embryos
Sox9
Sea Turtle
Lepidochelys olivacia Expression
2001
Sox100B is a Drosophila Sox 9 Homolog Expressed in a
Male-specific Pattern in the Gonad
Male
Sox100B
VASA
Sox100B
VASA
Female
(2003) Developmental Cell, 5;205
StDeFalco
17
DeFalco (2008) Developmental Cell, 14;275
Sox100B is Required for Testis Development
Sox100B gonad phenotype
Testes
Accessory gland
Sox100B-/Wild type adult
In Collaboration with Steven Russell,
University
pharate
adult of Cambridge
Creating Sexual Dimorphism
Mammals
Birds
Flies
Reptiles
Mammals
Birds
Flies
Reptiles
Drosophila Sex Determination
XX
XY
Sex lethal
ON
OFF
ON
transformer
OFF
DSXF
tra 2
doublesex
DSXM
(Appearance
and Behavior)
fruitless
(Behavior)
Evolution of Sex Determination Pathways in Insects
PMID: 20877001
Doublesex/Mab3 Related Transcription Factors (DMRTs)
Conserved Regulators of Sexual Dimorphism
Conserved Mechanisms for Gonad Sexual Dimorphism
Mammals
Birds
Flies
Reptiles
Molecular Mechanisms
Fly
Human
dsx
DMRTs
Sox100B
Sox9
How does a sex determination switch
control sexual dimorphism?
Primary vs. Secondary Sex Determination
Primary sex determination: (cell autonomous)
a cell or tissue directly assesses its sex based on
the sex determination switch
Secondary sex determination: (non-cell autonomous)
a cell or tissue receives information about sexual
identity from another tissue
Cell Autonomous Sex Determination
“Every cell decides for itself”
(In Drosophila) “the chromosomal composition of each somatic
cell determines its sexual development.”
L. Wolpert, Principles of Development, 3rd Edition, 2007
J Szabad
www.insectcompany.com
underwatertimes.com
Mammals Mostly Undergo
Secondary Sex Determination
XX
XY
XY
Gonadectomy
Female
Jost, 1940’s
Female
Male
Non-Autonomous Sex Determination in Mammals
Sry
Sertoli
Cells
Leydig
Cells
Mullerian Duct
Regression
Mesonephric
Cell Migration
Testosterone
Germ
Cells
Early Events in Mouse Gonad Sexual Dimorphism
Non-autonomous Events
Fgf9
Tgf-ß??
Only Sertoli Cells Are
Thought to Autonomously
Require Sry
Dhh?
Brennan and Capel, 2004
Autonomous and Non-Autonomous Sex Determination Are Not
Mutually Exclusive
dsx both autonomously and nonautonomously to
control sexual dimorphism
male
Hub Cells
Pigment Cell Precursors
Nonautonomous Sex
Determination
female
Autonomous Sex
Determination
msSGPs
Nonautonomous Sex
DeFalco, Camara, Le Bras, & Van Doren(2008) Dev Cell 14(2): 275-86 Determination
DSX is expressed in the
SGPs and hub cells
dsx in situ
BDGP
DSXM
Hempel and Oliver(2007) BMC Developmental Biology, 7:113
New Ideas About Creating Sexual Dimorphism in Drosophila
1) Not all cells decide their own sex:
Cell-cell signaing is critical for
regulating sexual dimorphism
2) Not all cells even know their sex:
dsx and fru expression is highly
tissue-specific
Sex is DANGEROUS: Ectopic expression of dsx is lethal
Jursnich and Burtis, 1993
“Knowing” Your Sex Chromosome Constitution
vs. “Knowing” Your Sex
Drosophila
Mouse
# X’s
# X’s
Sxl
Dosage
Compensation
(All Cells)
tra
dsx, fru
Primary Sex
Determination
(Tissue Specific)
Secondary Sex
Determination
(Signaling)
Y
SRY
Dosage
Compensation
Primary Sex
(All Cells)
Determination
(Tissue Specific)
Secondary Sex
Determination
(Signaling)
How does a sex determination switch
control sexual dimorphism?
The Germ Cells
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.
Karyotype vs. Phenotype in Humans
Karyotype
XX
XY
Phenotype
Female
Male
Syndrome, associated phenotypes
wt
wt
XO
Female (1:2500) Turner’s syndrome
(Short stature, infertile, many spontaneously abort)
XXX
XXXX
XXXXX
Female (1:1000) Pretty normal, extra Barr Body
Female
Pretty normal, extra Barr Bodies
Female
Pretty normal, extra Barr Bodies
(Some mental retardation with extra X chormosomes)
XXY
XXXY
XXXXY
Male (1:700)
Male
Male
Klinefelter’s Syndrome, Barr Body
Klinefelter’s Syndrome, Barr Bodies
Klinefelter’s Syndrome, Barr Bodies
(Mental retardation and hypogonadism/infertility, increases with X chromosome dose, 60% spontaneously abort)
Turner’s Females and Klinefelter’s Males May Be Infertile Due to a
Sexual Incompatibility Between Soma and Germline
Contol of Germline Sexual Behavior by Retinoic Acid
Cyp26b1 is expressed in male but not female somatic gonad
RA levels are higher in female gonad
Loss of Cyp26b1 leads to induction of
meiotic markers in male gonads
Could JH play a similar role in Drosophila?
F
M
JH epoxide hydrolase 2
Somatic Signals and Germ Cell Autonomous Cues Also
Regulate Germline Sex Determination in Drosophila
How does a sex determination switch
control sexual dimorphism?
Other reproductive structures
The Mouse Internal Reproductive Tract Develops
From Either the Mullerian or Wolffian Ducts
Anti-Mullerian Hormone
(AMH, MIS)
Testosterone
epididymis
vas deferens
Estrogen
Regulated by non-cell
autonomous signals
oviducts, uterus,
cervix, upper vagina
The External Genitalia Develops From a Common Bipotential Tissue
Dihydrotestosterone
(DHT)
Regulated by non-cell
autonomous signals
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
Gonad Sexual Dimorphism
WNT4a
FGF9
DMRT’s
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?
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
Sex and
the Brain
swashtara.50g.com/ Brains.html
Drosophila Sex-specific Courtship Behavior
Male
Orienting
Following
Tapping
Singing
Licking
Copulation
Female
Running away
Kicking
Wing flicking
Slows down
Lowers wings
Drosophila Sex Determination
XX
XY
Sex lethal
ON
OFF
ON
transformer
OFF
DSXF
tra 2
doublesex
DSXM
(Appearance
and Behavior)
fruitless
(Behavior)
Generating Male- or Female-Specific Alleles of fru
Dickson Lab, Baker Lab
Male Splicing of Fru is
Required for Males to
Court Females
And is Sufficient to Induce
Females to Behave as Males
and Court Females
Males (XY)
Females (XX)
Dickson Lab, Baker Lab
Sex-specific Behavior in Zebra Finch
Males Sing
Females Don’t
Gonadal hormones thought to be key trigger
in sex-specific behavior and CNS morphology
Gynandromorphic Zebra finch
Gonads
Left: Ovary but no oviduct
Right: Mature but dysmorphic testis
Plumage
Left: Female
Right: Male
Agate et al, PNAS 2003
Brain Genotype is
half male, half female
ZZ (Male)
ZW (Female)
Reproductive Behavior= male
Sing to, court and mate with females
(Females lay and incubate infertile eggs)
Fight with males
HVc and RA on “female” side are masculinized
Therefore, hormonal influence
BUT
HVc still bigger on male side than on female
Therefore, contribution from brain genotype,
since both sides receive same hormonal input
Sex and the brain

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