Chromosomes and Human Genetics

1. Chromosomes andHuman Genetics Chapter 15

2. Chromosomes & Cancer • Some genes on chromosomes control cell growth and division • If something affects chromosome structure at or near these loci, cell division may spiral out of control • This can lead to cancer

3. Philadelphia Chromosome • First abnormal chromosome to be associated with a cancer • Associated with a chronic leukemia • Overproduction of white blood cells

4. A Reciprocal Translocation 1 2 Chromosome 9 and chromosome 22 exchanged pieces 6 13 15 19 20

5. An Altered Gene • When the reciprocal translocation occurred, a gene at the end of chromosome 9 fused with a gene from chromosome 22 • This hybrid gene encodes an abnormal protein that stimulates uncontrolled division of white blood cells

6. Understanding Chromosomes • 1882 - Walter Fleming • 1887 - August Weismann • 1900 - Rediscovery of Mendel’s work

7. Genes • Units of information about heritable traits • In eukaryotes, distributed among chromosomes • Each has a particular locus • Location on a chromosome

8. Homologous Chromosomes • Homologous autosomes are identical in length, size, shape, and gene sequence • Sex chromosomes are nonidentical but still homologous • Homologous chromosomes interact, then segregate from one another during meiosis

9. Alleles • Different molecular forms of a gene • Arise through mutation • Diploid cell has a pair of alleles at each locus • Alleles on homologous chromosomes may be same or different

10. Sex Chromosomes • Discovered in late 1800s • Mammals, fruit flies • XX is female, XY is male • In other groups XX is male, XY female • Human X and Y chromosomes function as homologues during meiosis

11. Karyotype Preparation - Stopping the Cycle • Cultured cells are arrested at metaphase by adding colchicine • This is when cells are most condensed and easiest to identify

12. Karyotype Preparation • Arrested cells are broken open • Metaphase chromosomes are fixed and stained • Chromosomes are photographed through microscope • Photograph of chromosomes is cut up and arranged to form karyotype diagram

13. Human Karyotype 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 XX (or XY)

14. X X X Y Y X X X XX XX XY XY Sex Determination eggs sperm Female germ cell Male germ cell sex chromosome combinations possible in new individual

15. The Y Chromosome • Fewer than two dozen genes identified • One is the master gene for male sex determination • SRY gene (Sex-determining region of Y) • SRY present, testes form • SRY absent, ovaries form

16. appearance of structures that will give rise to external genitalia appearance of “uncommitted” duct system of embryo at 7 weeks Effect of YChromosome 7 weeks Y present Y absent Y present Y absent testes ovaries 10 weeks ovary testis birth approaching

17. The X Chromosome • Carries more than 2,300 genes • Most genes deal with nonsexual traits • Genes on X chromosome can be expressed in both males and females

18. X X X Y Discovering Linkage One cross homozygous dominant female recessive male x Gametes: heterozygous female heterozygous male All F1 offspring have red eyes

19. Discovering Linkage Reciprocal cross homozygous recessive female dominant male x Gametes: X X X Y heterozygous females recessive males F1 offspring Half are red-eyed females, half are white-eyed males

20. Discovering Linkage • Morgan’s crosses showed relationship between sex and eye color • Females can have white eyes • Morgan concluded gene must be on the X chromosome

21. Linkage Groups • Genes on one type of chromosome • Fruit flies • 4 homologous chromosomes • 4 linkage groups • Indian corn • 10 homologous chromosomes • 10 linkage groups

22. A A a B B b A a B b a b Full Linkage AB ab Parents: x F1 offspring: All AaBb meiosis, gamete formation 50%AB 50%ab With no crossovers, half of the gametes have one parental genotype and half have the other

23. A a a c c C A C Incomplete Linkage AC ac x Parents: F1 offspring All AaCc meiosis, gamete formation Unequal ratios of four types of gametes: a a A A C c C c Most gametes have parental genotypes A smaller number have recombinant genotypes

24. Crossover Frequency Proportional to the distance that separates genes A B C D Crossing over will disrupt linkage between A and B more often than C and D

25. Linkage Mapping in Humans • Linkage maps based on pedigree analysis through generations • Color blindness and hemophilia are very closely linked on X chromosome • Recombination frequency is 0.167%

26. Pedigree • Chart that shows genetic connections among individuals • Standardized symbols • Knowledge of probability and Mendelian patterns used to suggest basis of a trait • Conclusions most accurate when drawn from large number of pedigrees

27. I II III IV V *Gene not expressed in this carrier. Pedigree for Polydactly female male 5,5 6,6 * 5,5 6,6 6,6 5,5 6,6 5,5 6 7 5,5 6,6 5,5 6,6 5,5 6,6 5,5 6,6 5,6 6,7 12 6,6 6,6

28. Genetic Abnormality • A rare, uncommon version of a trait • Polydactyly • Unusual number of toes or fingers • Does not cause any health problems • View of trait as disfiguring is subjective

29. Genetic Disorder • Inherited conditions that cause mild to severe medical problems • Why don’t they disappear? • Mutation introduces new rare alleles • In heterozygotes, harmful allele is masked, so it can still be passed on to offspring

30. Autosomal Recessive Inheritance Patterns • If parents are both heterozygous, child will have a 25% chance of being affected

31. Galactosemia • Caused by autosomal recessive allele • Gene specifies a mutant enzyme in the pathway that breaks down lactose enzyme 1 enzyme 2 enzyme 3 GALACTOSE-1- PHOSOPHATE GALACTOSE-1- PHOSOPHATE LACTOSE GALACTOSE +glucose intermediate in glycolysis

32. Autosomal Dominant Inheritance Trait typically appears in every generation

33. Huntington Disorder • Autosomal dominant allele • Causes involuntary movements, nervous system deterioration, death • Symptoms don’t usually show up until person is past age 30 • People often pass allele on before they know they have it

34. Acondroplasia • Autosomal dominant allele • In homozygous form usually leads to stillbirth • Heterozygotes display a type of dwarfism • Have short arms and legs relative to other body parts

35. X-Linked Recessive Inheritance • Males show disorder more than females • Son cannot inherit disorder from his father

36. Examples of X-Linked Traits • Color blindness • Inability to distinguish among some of all colors • Hemophilia • Blood-clotting disorder • 1/7,000 males has allele for hemophilia A • Was common in European royal families

37. Fragile X Syndrome • An X-linked recessive disorder • Causes mental retardation • Mutant allele for gene that specifies a protein required for brain development • Allele has repeated segments of DNA

38. Hutchinson-Guilford Progeria • Mutation causes accelerated aging • No evidence of it running in families • Appears to be dominant • Seems to arise as spontaneous mutation • Usually causes death in early teens

39. Duplication • Gene sequence that is repeated several to hundreds of times • Duplications occur in normal chromosomes • May have adaptive advantage • Useful mutations may occur in copy

40. Duplication normal chromosome one segment repeated three repeats

41. Inversion A linear stretch of DNA is reversed within the chromosome

42. Translocation • A piece of one chromosome becomes attached to another nonhomologous chromosome • Most are reciprocal • Philadelphia chromosome arose from a reciprocal translocation between chromosomes 9 and 22

43. Translocation chromosome nonhomologous chromosome reciprocal translocation

44. Deletion • Loss of some segment of a chromosome • Most are lethal or cause serious disorder

45. Aneuploidy • Individuals have one extra or less chromosome • (2n + 1 or 2n - 1) • Major cause of human reproductive failure • Most human miscarriages are aneuploids

46. Polyploidy • Individuals have three or more of each type of chromosome (3n, 4n) • Common in flowering plants • Lethal for humans • 99% die before birth • Newborns die soon after birth

47. Nondisjunction n + 1 n + 1 n - 1 n - 1 chromosome alignments at metaphase I nondisjunction at anaphase I alignments at metaphase II anaphase II

48. Down Syndrome • Trisomy of chromosome 21 • Mental impairment and a variety of additional defects • Can be detected before birth • Risk of Down syndrome increases dramatically in mothers over age 35

49. Turner Syndrome • Inheritance of only one X (XO) • 98% spontaneously aborted • Survivors are short, infertile females • No functional ovaries • Secondary sexual traits reduced • May be treated with hormones, surgery

50. Klinefelter Syndrome • XXY condition • Results mainly from nondisjunction in mother (67%) • Phenotype is tall males • Sterile or nearly so • Feminized traits (sparse facial hair, somewhat enlarged breasts) • Treated with testosterone injections