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 Leptotene – chromosome condensation Zygotene – chromosome synapse → bivalent Pachytene – chromatid tetrad, crossing-over Diplotene – chiasmata 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 weeks division 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 development paired 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 uterus the mesonephric Wolffian ducts regress differentiation 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 both are encoded by genes on autosomes 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

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 Determination due 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 Determination due 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 queen Nefertiti 1381 – 1344 B.C. secret room in the tomb of Amenhotepa II in Kings’ valley in Luxor

Literature Genetics in Medicine, sixth edition, revised reprint Thompson & Thompson Saunders, 2004 Chapter 2: Chromosomal Basis of Heredity Human Gametogenesis and Fertilization pages 12 – 16 Chapter 10: Clinical Cytogenetics The Sex Chromosomes and Their Abnormalities pages 165 – 179 Clinical Case Studies: 27, 32

Literature Medical Genetics at a Glance, second edition, Dorian J. Pritchard & Bruce R. Korf Blackwell Publishing, 2008 Part 1: Developmental biology 10,(11,12),13 Part 2: Medical genetics 23, 25 pages 28 – 35, 59 – 61, 64 – 65