Sex Determination and Sex Chromosomes

Harry Ostrer, M.D.Human Genetics ProgramNYU School of MedicineOctober 18, 2006

What causes sex differences?

What are sex chromosomes doing?

Development of the Embryonic Gonad

Hindgut

Cloaca

Genital ridge

Metanephric duct

Mesonephros

Yolk sac

It starts with germ cell migration at 4 weeks

Retinoic acid in germ cell environment influences differentiation

Sertoli cell – gonocytes(Mitotic arrest)

Elsewhere – oogonia(Entry into meiosis)

Spermatozoan

Round spermatid

Spematocyte

Spermatogonia

Peritubularmyoid cells

Vascular endothelial cell

Leydig cells

Sertoli cell

Organization of the Seminiferous Tubule and Ovarian Follicle

Follicular cells

1o Oocyte

MüllerianDucts

WolffianDucts

MüllerianDucts

Mesonephros

Vas deferens

Uterus

Testis

WolffianDucts

+ SRY

+ MIFGonad

Wolffian duct

Urogenital sinus

Ureter

Metanephros

Seminal vesicle

Mullerian duct

Mullerian tubercle

Upper third of vagina

Epididymis

Ovary

Fallopian tube

+ testosterone

Development of male and female internal genitalia

Common Genital Analgen

tubercle

folds

swellings

tubercle

tubercle

folds

swellings

folds

swellings

Development of Male and FemaleExternal Genitalia

+ dihydrotestosterone

Expression Of SRY in the Developing Male Embryo

7 wks

9 wks

10 wks

12 wks

alk phos antisense sense

Aberrant Sex Chromosome Transmission

46,XY

46,XY

47,XYY

47,XXY

69,XXY

48,XXYY

48,XXXY

49,XXXXY

Usual observation

45,X

45,X

46,XX

46,XX

47,XXX

48,XXXX

49,XXXXX

Exceptions

with gonadal dysgenesis

triploidy with gonadal dysgenesis

Recombinational Models for Individuals with Genetic Sex Reversal

46,XX male 46,XY female

Non-homologous Recombination

SRY SRY

Y YX X

Y

SRY

Y

Unequal Recombination

X X

SRY

Genes Involved in Male Sex Determination

WT1

Denys-Drash syndromeFrasier syndromedel(9p)

dup(X)(p21)

campomelicdysplasia

del(10q)

46,XYgonadaldysgenesis

SRY

SOX9

SF1 adrenalfailure

del(2q)

XH2alpha-thalassemiaretardation syndrome

dupWNT4A

DHH

Hawkins, 1992 Jager, 1992

Vilain, 1992SRY I90M binding

SRY F109S - nl binding

SRY V60L binding

Schmitt - Ney, 1995

a b

SRY P125L binding SRY I90M binding

Bilbao, 1996

Hines, 1997

Barbosa, 1995

SRY 97C-T truncated proteindelSRY

SRY 609T-G missense

mosaic

mosaic

mosaic

mosaic

Known Mechanisms of Familial 46,XY Pure Gonadal Dysgenesis

Genetic Sex Reversal46,XX True Hermaphrodite

SRY Immunocytochemistry in Familial True Hermaphroditism

82-3951 - newborn TH 85-941 - newborn TH 97-4155 - 14 year TH

Hypothesis: SRY-Bearing Cell Line is Responsible for Testis Development

46,XX 46,XY

47,XXY47,XXY

Chimerism: product of twozygotes

Mosaicism: non-disjunction withpost-zygotic loss

46,XX 46,XXSRY SRYY-to-X translocation with random

X chromosome inactivation

Organization of Human Sex Chromosomes

Y

X

pseudoautosomalregions

(short arms)

sex-limitedregions

pseudoautosomal regions

(long arms)

Many genes escape inactivation

Xce – X chromosome inactivation center

Length: 153,692,391 bpGene Count: 1228

Length: 50,286,555 bpGene Count: 160

Why is One X Chromosome Inactivated?

CausesXist (X-inactive specific transcript) expressed from and binds to inactive X chromosome

Methylation of specific cytidine residues

Late replication

EffectsDosage compensation between the sexes

mCpG

X-Linked Inheritance

Unaffected parent Carrier parent

possible germ cells(egg or sperm)

possible gametes

offspring statusCarrierdaughter

YX XX

Normaldaughter

25% 25%25%25%

Normalson

Affectedson

Examples:Color blindnessHemophiliaDuchenne muscular dystrophyHypophosphatemic rickets

Girl with Duchenne Muscular Dystrophy

Delays in sitting and standing Waddling gait Difficulty climbing Rapidly progressive Wheelchair bound by 12 yearsCardiomyopathy after age 18 Survival up to third decade

DMD dystrophin stainingDystrophin staining

Factors Influencing Expression of X-Linked Phenotypes in Females

45,X chromosomalconstitution

Homozygosity for mutant allele

Skewed X chromosome inactivation

Selection againstcells expressing wild-type gene

M

M MM M

MWT MWT

MWT WT M

Aberrant Sex Chromosome Transmission

46,XY

46,XY

47,XYY

47,XXY

69,XXY

48,XXYY

48,XXXY

49,XXXXY

Usual observation

45,X

45,X

46,XX

46,XX

47,XXX

48,XXXX

49,XXXXX

Exceptions

with gonadal dysgenesis

triploidy with gonadal dysgenesis

Turner syndrome

Most commonly 45,XShort statureWebbed neckShield chestGonadal dysgenesisCoarctation of the aortaKidney malformationHypothyroidismSensorineural hearing loss

Important Structural Abnormalities of the X Chromosome

Isodicentric Xq chromosome --> Turner syndrome

ring(X) with deletion Xce --> mental retardationand other phenotypic features*

dup(X)(p21) --> overexpression of DSS and gonadal dysgenesis in 46,XY individuals*

*no X chromosome inactivation

Aberrant Sex Chromosome Transmission

46,XY

46,XY

47,XYY

47,XXY

69,XXY

48,XXYY

48,XXXY

49,XXXXY

Usual observation

45,X

45,X

46,XX

46,XX

47,XXX

48,XXXX

49,XXXXX

Exceptions

with gonadal dysgenesis

triploidy with gonadal dysgenesis

Klinefelter syndrome

Most commonly 47,XXY with random X inactivation

Hypogonadism (small testes, azoospermia/oligospermia)

Hyalinization of seminiferous tubules

Gynecomastia at late puberty

Psychosocial problems

Triploidy syndrome

69,XXY or 69,XXX

Dysmorphic

Prematurity

Partial mole of the placenta

Gonadal dysgnesis, if XXY

Die in the early neonatal period

Y Chromosome

p11.3

p11.2

p11.1

q11.1

q11.21

q11.22

q11.23

q12 Map of the Human Y Chromosome

0 kb pseudoautosomal boundary

SRY

10

20

30

sex-limited region

XG

pseudoautosomal region

Boundary of XX males

Genes Genetic Functions

RBM2

SMCYRBMRBM1, RBM2DAZSPGYRBM

GCY2

TS

GBYTS

GCY1AZFa

AZFb

AZFc

CSF2RAIL3RAANT3ASMTXE7MIC2RMIC2XG

SRYZFYRPS4YRBM1TSPY (major)AMELYTSPY (minor)

XGPYRBMKALRBM1RBM2STSp

Disorders SRY gonadal dysgenesis DAZ azospermia

Sex Chromosome Expression in Germ Cells

SpermX and Y inactive during meiosisSome genes reactivated following meiosis

OocytesX chromosome reactivation during oogenesisDeletion of specific regions --> gonadaldysgenesis

Sex Determination and Sex ChromosomesConclusions

Sex chromosomes play an important role in sex determination

Gene dosage is important with both overexpression and underexpression leading to abnormalities

Both sex chromosomes may be subject to inactivation during the course of their life cycle X Y