Genetic determination of the sex

Marie Černá

Lecture No 504-V

Meiosis – reconstruction of genetic material

• Rearrangement of chromosomes on the basis of crossing-over

• Chance segregation of maternal and paternal chromosomes into gametes

– combination number 223 (8 388 608)

Meiosis

Prophase of Meiosis I

1. Leptotene – chromosome condensation

2. Zygotene – chromosome synapse → bivalent

3. Pachytene – chromatid tetrad, crossing-over

4. Diplotene – chiasmata

5. Diakinesis – chromosome segregation

Gamete maturation

Male meiosis - spermatogenesis

• is initiated during puberty by androgens• takes about 64 days• includes spermiogenesis

conversion of spermatids into functional spermatozoa:

- formation of the acrosome

- nucleus condensation and cytoplasm shedding

- formation of the neck, midpiece and tail

Female meiosis - oogenesis

• dictyotene state – in the fetus at 12 – 20 weeksdivision of the primary oocytes stops

at diplotene of prophase of Meiosis I• ovulation - from puberty to menopause

the secondary oocyte is shed into the uterine tube →division of the secondary oocytes stops

at metaphase of Meiosis II • fertilization - entry of a sperm the ovum

the end of Meiosis II

Spermatogenesis Oogenesis

spermatogonia↓

primary spermatocytes↓

secondary spermatocytes↓

spermatids↓

spermatozoa

oogonia↓

primary oocytes↓

secondary oocytes↓

fertilized egg (zygote)

mitosis

meiosis I

meiosis II

Barr body

Sex determination

• in mammals (humans),

some insects (fruit flies)

• in some insects

(grasshoppers, crickets, roaches)

• in birds, some fishes,

some insects (butterflies, moths)

• in bees and ants

The sex is estimated:

• Genetic determination →

GONADS → hormones

• Hormonal differentiation →

genital ducts, external genital + brain

• Psychological differentiation →

self-determination

Early developmentpaired indifferent gonad

• in the 5th week of pregnancy• up to 2 000 primordial germ cells from

the endoderm of the yolk sac infiltrate

the primitive sex cords within

the mesodermal genital ridges, which are developments of the coelomic epithelium

Further development without presence of the Y chromosome

• the primitive sex cords break down• proliferation of the epithelial cortical cords• oestrogens, from the maternal system,

placenta and fetal ovaries, →the paramesonephric Műllerian ducts develop

→ the uterine tubes and uterusthe mesonephric Wolffian ducts regressdifferentiation of the external genitalia

The SRY gene on the Y chromosome• in the 7th week „zinc finger protein“ is activated• leads to proliferation in the testis cords:

- Leydig cells from mesenchyme →androgens (testosterone) →the mesonephric Wolffian ducts develop

→ vas deferens and epididymis- Sertoli cells from epithelium, in the 4th month

→ Műllerian inhibiting substance (MIS) → the paramesonephric Műllerian ducts regress

The SRY gene on the Y chromosome

• production of androgens (testosterone) →• in the 8th – 18th week (until the 4th month)

differentiation of the external genitalia

testosterone under action of local 5-α-reductase

converts to dihydrotestosterone• in the 7th month of pregnancy

contraction of the gubernaculum

– descent of the testis into the scrotum

Puberty is triggered by

hormones secreted by the pituitary gland:

• Adrenal glands → androgens (androsterone) →

pubic and axillary hair in girls

• Ovaries → oestrogens → breast growth,

menstruation, uterus matur., pelvis broadening

• Testes → enlargement of the testes

→ androgens (testosterone) →

penis and larynx growth, spermatogenesis

Traits Sex-limited Sex-influenced

expressed in only one sex -

secondary sexual characteristics

level of their expression is different in different sex - early baldness

as an autosomal dominant trait in men

both are encoded by genes on autosomes

Turner syndrome

Turner syndrome

Turner syndrome

Klinefelter syndrome

Klinefelter syndrome

Klinefelter syndrome

Chromosome Y

• Pseudoautosomal homologous regions at the distal ends of short (Xp and Yp) and long (Xq and Yq) arms of sex chromosomes → homologous recombination in meiosis I

• SRY gene on short arm Yp,

determines male sex (gonads - testes)

• AZF regions on long arm Yq, determine

development of male gametes (sperms)

Disorders of Sex Determinationdue to Mutation of SRY Gene

Male phenotype with karyotype 46,XX can be caused by abnormal presence of SRY gene:

• SRY gene is transferred to X chromosome during abnormal crossing-over out of homologous regions of X and Y chromosomes

• SRY gene is transferred to autosome by translocation

Disorders of Sex Determinationdue to Mutation of SRY Gene

Female phenotype with karyotype 46,XY can be caused by missing of SRY gene:

• SRY gene is deleted

• SRY gene is mutated

Disorders of Gonadal and Sexual Development

• hermaphroditism – presence of

both ovarian and testicular tissue

→ the genitalia are ambiguous• pseudohermaphroditism – presence of

gonadal tissue of only one sex

but with ambiguous or opposite

external genitalia

Female pseudohermaphroditism

46,XX karyotypes → normal ovaries, but

male external genitalia

Congenital adrenal hyperplasia

- autosomal recessive disorder

- deficiency of 21-hydroxylase

of the adrenal cortex

- ↓ cortisol + aldosteron, ↑ androgens

Congenital adrenal hyperplasia

Male pseudohermaphroditism

46,XY karyotypes → normal testes, but

female external genitalia

Deficiency of the steroid 5-α-reductase

- autosomal recessive disorder

Androgen insensitivity syndrome

- X-linked syndrome of testicular feminization

- mutations of the androgen receptor gene

DNA is the most stable molecule of our body

secret room in the tomb of Amenhotepa II

in Kings’ valley in Luxor

queen Nefertiti

1381 – 1344 B.C.

LiteratureGenetics in Medicine, sixth edition, revised reprintThompson & ThompsonSaunders, 2004

Chapter 2: Chromosomal Basis of HeredityHuman Gametogenesis and Fertilizationpages 12 – 16

Chapter 10: Clinical CytogeneticsThe Sex Chromosomes and Their Abnormalitiespages 165 – 179

Clinical Case Studies: 27, 32

Literature

Medical Genetics at a Glance, second edition,Dorian J. Pritchard & Bruce R. KorfBlackwell Publishing, 2008

Part 1: Developmental biology 10,(11,12),13Part 2: Medical genetics 23, 25pages 28 – 35, 59 – 61, 64 – 65