SEX DETERMINATION

1. SEXDETERMINATION • from these studies concluded that genes are on • chromosomes and specialized chromosomes • determine sex

2. Modes of Sex Determination • XX/XY (ZZ/ZW) (Lygaeus) • - heteromorphic sex chromosomes • XX/XO (Protenor)

3. heteromorphic chromosomes - a chromosome pair with some homology, but differing in size, shape or stainingproperties heterogametic sex (e.g. XY OR ZW) - the sex with different sex chromosomes; the gametes have different sex chromosomes …..the opposite of homogametic sex

4. Human Males have Heteromorphic Sex Chromosomes

5. XY Method of Sex Determination X Y X Y X A XX XY XY method common in higher organisms Y-chromosome evolved to give X a pairing partner A = autosome, any non sex-chromosome

6. Sex Determination in Humans (X) Primary non-disjunction XXX XXY XO YO

7. Aneuploid Offspring • XXX -- Trisomy-X • XXY -- Klinefelter • XO -- Turner • YO -- Dies • aneuploidy involving the sex chromosomes • is much better tolerated than autosomal • aneuploidy

8. XXX Syndrome 47, XXX female (also see XXXX and XXXXX) 1/1200 female live births Variable phenotype, frequently appear normal, sterile, may show mental retardation. Under-developed secondary sex characteristics

9. 47, XXY male (XXXY, XXXXY, XXYY) 1/500 male live births Male genitalia, testes undeveloped, fail to produce sperm Female secondary-sex characteristics Klinefelter Syndrome

10. 45, XO female 1/2000 female live births Ovaries rudimentary, sterile Short stature, shield-like chest, webbed neck Normal intelligence Many XO fetuses miscarry Turner Syndrome

11. XYY Condition 47, XYY male 1/1000 male live births Above-average height, 2% in maximum security prisons are XYY, personality disorders, subnormal intelligence Fertile Most XYY males socially normal

12. Presence of Y is male-determining Lack of Y is female-determining Y produces testis-determining factor (TDF) Human Sex-Determination Mechanism XY XO XXY XX XYY XXX XXYY XXXX XXXY XXXXX XXXXY CONCLUSION:

13. crossing over between X and Y during • meiosis occurs in pseudoautosomal • region (PAR) • ……necessary for normal disjunction • PAR homologous to region of • X-chromosome • non-recombining region of Y (NRY) • unique to Y chromosome • human Y chromosome contains gene • SRY (sex-determining region Y) • which makes TDF • XY females deleted for SRY region • are observed and XX males with TDF • gene translocated to X chromosome

14. hemizygous gene a gene present in only one copy in a diploid organism e.g. any gene on the X or Y (NRY) chromosome in human males

15. Primary and Secondary Sex-Ratio Primary 1 : 1.20 - 1.60 Secondary 1 : 1.025 - 1.15 Maturity 1 : 1 Old Age 1 : <1 Explanation for primary sex-ratio: Y sperm more able to fertilize egg, or, better survival in reproductive tract Y lacks most genes on X, any subvital/ lethal genes uncovered in hemizygous males, higher lethality

16. Autosomal genes are inherited in equal frequencies by both sexes Aa x Aa 1AA : 2Aa : 1aa (if allele a is recessive equal numbers of females and males should be affected)

17. Y always inherited father to son Gene found only on Y-chromosome Y-Chromosome Linkage in ManHolandric Inheritance Hairy Pinna

18. Inheritance of Sex (X)-Linked Traits Color Blindness colorblind = = cc CY Color-blindness is a sex-linked recessive trait cY cY CC Cc CY Cc Cc CY Cc Cc or CC Cc or CC Cc or CC cY CY • trait more common in males because of hemizygosity

19. Dosage Compensation in Mammals Observation -- Trisomys- XXX, nearly normal XXXY looks fairly normal 21/21/21 Down’s quite abnormal 13/13/13 Severely affected Why can individuals tolerate additional X-chromosomes but not additional autosomes? How is X-chromosome gene expression controlled?

20. Dosage Compensation Background X-chromosome inactivation in mammals 1. Barr (1949) -- Observed chromatin bodies in the nerve cells of female cats. Somatic cells only. 2. Ohno -- Proposed Barr body is X-chromosome 3. The # of chromatin bodies is one less than the # of X-chromosomes. Restricted to somatic cells. Interphase Cells of Cells of XXX = XY = XXY = XXXX =

21. Dosage Compensation Explained Lyon Hypothesis (1962) (English Mouse Geneticist) 1. The chromatin body is an X-chromosome One X-chromosome is inactivated - visible as a differentially stained Barr body during interphase. Genes inactivated. 3. The inactive X can be either maternal or paternal in origin. Inactive X-chromosome is late-replicating. It lags on the metaphase plate during mitosis. 5. X-inactivation in humans begins about 16 days into development. 6. Once an X-chromosome becomes inactive it will always be inactive in all cells derived from that cell.

22. mosaic / chimera - an individual composed of two or more genetically different cell types

23. Dosage Compensation (cont.) B B b b B B b b B b b b B b B B

24. Dosage Compensation Example Calico Cat Black BB BY Calico Bb ---- Yellow bb bY Exception: XXY Klinefelter male calico cat

25. Bridges Sex-Balance Theory Drosophila melanogaster The white eye gene in Drosophila was the first gene to be located on a chromosome. a) Crossed XW XW (x) X+ Y XW X+ Y XW X+ XW Y Wild Type White (red eye) Exceptional offspring occurred at low frequency 1. White 2. Wild type (sterile) } Primary Exceptions

26. XW XWX+ XW XWY X+ O OY Hypothesis XW XW (x) X+ Y [Primary non-disjunction] XW XW X+ Y Dies Sterile Fertile Metafemale dies

27. = XXAA II + III + IV = XYAA = 1 Set Autosomes (A) Chromosomes of Drosophila centromere II III X IV X II IV III X & Y = Sex-chromosomes Autosomes Autosome = any chromosome that is not a sex-chromosome

28. Mutation of a third chromosome gene, C3G, leads to a high degree of non-disjunction. Non-disjunction shown for X-chromosome and complete sets of autosomes. XXXAAA (X) XYAA Chromosome Segregation during Meiosis X XX X XX XXAA XA XAA XXA AA A A AA

29. CONCLUSIONS: Female and male determining factors on X-chromosome and autosomes Y-chromosome carries male fertility genes X:A ratio determines sex XA XXAA XAA XXA (Triploid ) XXXAAA (Intersex) XXAAA (Meta ) XXXAA XXAA XA (Intersex) XXYAAA (Meta ) XYAAA XXYAA YA XYAA

30. .5 .67 1 Intersex XXAA = 2/2 = 1 = XYAA = 1/2 = .5 = XXXAAA = 3/3 = 1 = XXXAA = 3/2 = 1.5 = Meta XYAAA = 1/3 = .33 = Meta XXYAA = 2/2 = 1 = XXAAA = 2/3 = .67 = Intersex XXYAAA = 2/3 = .67 = Intersex

31. External Environment and Sex Determination Bonellia Worm -- Marine Worm 1. and have same chromosomes. 2. If young worm is raised from an isolated larva it becomes a female. 3. Drop larva in water with females. If larva comes in contact with female then larva turns into male and eventually migrates to female reproductive tract. 4. Possibly a hormone is secreted from the proboscis of female to initiate male sexual differentiation.

32. Sex • Determination • in Turtles • all males • at 25oC • all females • at 30.5oC

33. Sex Determination in Alligators and Crocodiles • Alligators: • all females • at 31oC; • all males • at 33oC; • all females • at 35oC • temperature affects levels of male and female • sex hormones

34. Solving Pedigrees 5 basic types - autosomal recessive - autosomal dominant - sex-linked recessive - sex-linked dominant - Hollandric inheritance 1. Recessive characters often skip generations 2. Dominant characters are usually observed in every generation. 3. Autosomal characters are inherited equally by females and males. 4. Recessive sex-linked characters are inherited at a much higher frequency by males. 5. Y-linked characters are only inherited by males.

35. Hints: - when determining inheritance of a rare mutation - if an individual marries into the family assume that the individual is homozygous for the wild-type allele (non-disease allele) unless there is evidence suggesting otherwise - dominant mutations are usually lethal when homozygous; assume that individuals carrying dominant mutations are heterozygotes - when determining the mode of inheritance in a pedigree be sure to rule out other possibilities

36. Duchenne Muscular Dystrophy : X - linked dominant inheritance

37. Rare autosomal recessive kidney disease What is the probability that individuals 1 and 2 will have an affected child?