Sex Chromosomes and Nondisjunction Diseases

1. Sex Chromosomes and Nondisjunction Diseases A. P. Biology Chapter 15 Mr. Knowles Liberty Senior High School

2. Human Chromosomes 46 Total (23 pair) 22 pair are perfectly matched-autosomes. Remaining pair- sex chromosomes. Human: XX normal female XY normal male Y chromosome highly condensed with a few dozen genes.

3. Chromosomal Basis of Sex Two similar X’s = human female Two dissimilar X and Y = human male NOT true for all diploid organisms. Both sex chromosomes behave like homologues during meiosis in the testes and ovary. They may cross-over at Pro I. Each gamete receives one sex chromo.

4. Spermatogenesis Oogenesis

5. Chromosomal Basis of Sex Each ovum contains one X chromosome. Sperm have either X OR the Y chromosome.

6. What determines sex in humans? Before two months, all fetuses are anatomically the same. The gonads are generic and can become either ovaries or testes. Depends upon hormone levels in the embryo. Trigger is the SRY gene on the Y.

7. Y Chromo. Encodes Few Genes

8. SRY on the Y Chromosome

9. The Human Y Chromosome Encodes a protein called SRY- the “sex-determining region of Y”. SRY is a regulator for other genes on other chromosomes. Responsible for development of testes. Without SRY, the gonads develop into ovaries. Female is default sex in humans.

10. SRY Protein Binding to DNA (Gene Regulation)

11. Sex-linked Genes Have a Unique Pattern of Inheritance In 1910, Thomas Hunt Morgan saw a remarkable mutation in Drosophila. Saw a mutant male with white eyes! Followed Mendel’s techniques- F1 showed that the white phenotype was recessive to wild-type red eye color. F2 - 3:1 red : white but all white eyes were MALE!

13. Explanation to Morgan’s Dilemma The gene that causes the white eye phenotype is on the X chromosome and not found on the Y. Proved that inheritable traits do reside on the chromosomes. Any trait or gene found on the X chromosome- sex linked.

14. Mapping the First Chromosome In 1913, A. H. Sturtevant located the relative positions of 5 recessive genes on the X chromosome of Drosophila by estimating their frequency of recombination due to X-over. This was a linkage map.

16. Genetic Maps Cross-over occurs more frequently between two genes farther apart. Use x-over rates in progeny to plot relative position of genes on chromosomes- Linkage Map. Distance is measured in frequency of recombination between two genes. Genes very close are linked- they do not x-over.

17. Genetic Map A linear sequence of genetic loci on a particular chromosome. Linkage Maps are based on frequency of recombination between two loci. What about genes very far apart? Linkage maps are NOT a picture of chromosomes. NOT physical map of genes.

18. Cytological Maps of Chromosomes Locate genes with respect to chromosomal features such as banding patterns. G-banding (Giemsa staining) stains C-banding (Centromere staining) stains heterochomatin of the centromere.

19. Cytological Mapping of Chromosome 15

20. Human Genome Project Physical sequencing of the DNA on each chromosome. Shows the distance between loci in DNA nucleotides. Finished Human Genome Project in Spring 2000. Identified 30,000 genes in humans in Winter 2001. Other genomes sequenced: C. elegans, D. melongaster, many prokaryotes.

21. Finished Human Chromosome 22

22. X -linked Traits If a sex-linked trait is recessive, female will be heterozygous; one X comes from the mother and the other X from the father. Seldom will be homozygous for the genes on the X chromosome. Males only inherit X from the mother- called hemizygous. More likely to be affected by X-linked diseases.

23. >60 X-linked Human Diseases Colorblindness Duchenne and Becker Muscular Dystrophies Albinism-Deafness Syndrome Two proteins (Factor 8 and 9) for blood clotting. Mutations here cause Hemophilia, Hemophilia A and B. SCID (Boy in the Bubble, Johnny T.)

24. SCID David Vetter- lacked cytokines for the immune system. Died at age 12.

25. X Chromosome Genetic Map

26. Some Diseases Mapped to X

30. Duchenne’s Muscular Dystrophy On the X chromosome, the gene for dystrophin- a protein found attached to the inner surface of the sarcolemma in normal muscle fibers (cells). Dystrophin regulates Ca+ ion channels- mutations keep the channels open too long. Candidate for gene therapy-successful in rats.

31. X-Section of Duchenne MD

32. Muscle X-Section of Duchenne MDNormal Duchenne MD

33. Anti-Dystrophin Antibody StainingNormal Duchenne MD

34. Female Mammals are like Floor Tile! Males and females have the same amount of proteins encoded by the X-linked genes! HOW? One X chromosome in each female cell becomes inactive during embryonic development- X -inactivation. Males = Female X-linked gene activity.

37. X - Inactivation The inactive X chromo. Becomes condensed and attaches to the inside of the nuclear envelope- Barr Body. Most genes are NOT expressed. Barr Body Chromosomes are reactivated in ovary cells--> ova.

38. X - Inactivation Mary Lyon - showed that the selection of which X will become the Barr body is random and independent in each embryonic cell present at the time of X-inactivation. After the X is inactive in a particular cell, all the mitotic descendents of that cell have the same X inactivated.

39. Females are Protein Mosaics! Mosaics- half of her cells have the active X derived from the mother, half of her cells have the active X from the father. If heterozygous, the same tissue will express one allele from one X chromosome and another allele from the other X chromosome

40. Calico Cats- An Example of Mosaicism

41. What would a carrier with X-linked disease look like? Diseased Phenotype? Normal?

42. Anti-Dystrophin Antibody LabelingNormal Carrier

43. Mechanism of X-Inactivation Attachment of CH3 groups to cytosines. A gene is active only on the Barr body chromosome-XIST (X-inactive specific transcript)- encodes an RNA. These RNA molecules bind to the chromosome from which they were made. But which X will have an active XIST gene? Unknown!

44. Alteration of Chromosome Numbers Primary Nondisjunction- members of a pair of homologous chromosomes do not move apart properly during anaphase of meiosis I. Unequal distribution of chromosomes in the daughter gametes.

45. Nondisjunction Leads to Abnormal Chromo. # in Zygote If the aberrant gamete units with a normal gamete, the offspring will have an abnormal # of chromosomes- aneuploid. Aneuploid: 2n + 1 = Trisomy 2n - 1 = Monosomy

46. Monosomics Organisms which have lost one copy of a chromosome. Do Not Survive Development! Lethal Error!

47. Trisomics Most do not survive either. Some trisomies do survive for a time: Trisomy 13, 15, 18-severe developmental defects, die within a few months. Trisomy 21- Down Syndrome. Trisomy 22- mentally retarded.

48. Trisomy 13 Facies- Bilateral Cleft Lip

49. Trisomy 18 Syndrome

50. Trisomy 21 Karyotype

51. Chromosome 21 Genetic Map

52. Mapping of Chromosome 21

53. Diseases Mapped to Chr. 21

54. Tiffany with Down’s- Trisomy 21

56. Trisomy 21 Phenoytpe Slower skeletal development- short stature. Below normal I.Q. 11 X more likely for leukemia. Cancer gene located on 21. Often have Alzheimer-like dimentia. Alzheimer gene located on 21. Usually die prematurely. Caused by a nondisjunction event during oogenesis.

58. Nondisjunction of the Sex Chromosomes Two Types: Nondisjunction of the X Chromosome. Nondisjunction of the Y Chromosome.

60. Nondisjunction of the X “Super Females” XXX- Female with one functional X and two Barr bodies; sterile but appears normal. XXY- Klinefelter Syndrome- sterile male with female characteristics, some mental retardation; underdeveloped male characteristics; occurs in 1/ 500 male births.

61. Klinefelter Syndrome (XXY)

62. Without an X Chromosome! OY- zygote is inviable; all humans require at least one copy of the X chromosome. XO - Turner Syndrome- sterile female, short stature, webbed neck, and immature sex organs, lower I.Q.; occurs in 1/ 5,000 female births.

63. Turner Fetus with Cystic Hygroma

64. Amber (age 4) with Turner’s Syndrome

65. Nondisjunction Also Occurs in Males! “Super Males” XYY- fertile males of normal appearance; occurs in 1/ 1,000 male births. Historically thought to be 20 X higher in institutionalized males. Not true.