1. CHROMOSOMAL MUTATIONS • Identify several types of mutations and variations in chromosome structure • Discuss the effects on the organism when chromosomes are changed or the number of chromosomes is changed • Describe types of chromosome rearrangements that alter the expression of genes

2. TYPES OF CHROMOSOMAL MUTATIONS • Chromosomal mutations are variations from the wild-type condition in either the number of chromosomes or the chromosome structure • Mutations can occur spontaneously, or they can be induced by chemical or radiation treatment • Usually chromosomal mutations induce APOPTOSIS in the cell (Suicide, Programmed Cell Death)

3. VARIATIONS IN CHROMOSOME STRUCTURE • Deletion • Duplication • Inversion • Translocation

4. VARIATION IN CHROMOSOME NUMBER • Changes in one or a few chromosomes • Changes in complete sets of chromosomes

5. CHROMOSOME REARRANGEMENTS THAT ALTER GENE EXPRESSION • Amplification or deletion of genes • Inversions that alter gene expression • Transpositions that alter gene expression

6. VARIATIONS IN CHROMOSOME STRUCTURE

7. Deletion • A deletion is a chromosomal mutation involving the loss of a chromosomal segment that begins where breaks occur • Deletion mutations cannot revert to wild-type • Deletions can be used to determine the physical location of a gene on a chromosome, by localizing the gene to the deleted segment

8. A deletion of a chromosome segment

9. Deletion • Several human genetic disorders are caused by deletions • Cri-du-chat syndrome: heterozygous deletion in the short arm of chromosome 5 • Prader-Willi syndrome: heterozygous deletion in the long arm of chromosome15

10. A Child with Cri-du-Chat Syndrome

11. Cri-du-Chat Syndrome • Deletion in the short arm of chromosome 5 • Symptoms are seen in heterozygotes • In homozygotes, it is lethal most of the time • Mental retardation, physical abnormalities, cry like a cat

12. Prader-Willi Syndrome • Heterozygosity for a deletion in the long arm of chromosome 15 • Infants are weak, poor sucking reflex (can’t eat) • Then later for unknown reasons they become compulsive eaters  obesity  health problems • If untreated, they can feed themselves to death • Mental retardation, sexual problems

13. Duplication • A duplication is a chromosomal mutation that results in the doubling of a chromosomal segment • Sizes of duplicated segments can vary from small to large • Reverse tandem duplications occur when the order of genes on the duplicated segment is opposite the order of the original

14. Duplication, with a chromosome segment repeated

15. Duplication • Terminal tandem duplications occur when the duplications are arranged tandemly at the end of a chromosome • Duplications have played an important role in the evolution of multigene families such as the genes for hemoglobin in humans

16. Forms of chromosome duplications are tandem, reverse tandem, and terminal tandem duplications

17. Inversion • An inversion is a chromosomal mutation that results when a segment of a chromosome is excised and then reintegrated in an orientation opposite that of the original orientation • A pericentric inversion involves the centromere • A paracentric inversion does not include the centromere

18. Inversions

19. Inversion • Inversions do not result in a loss of genetic material but phenotypic consequences may occur if the inversion disrupts genes or gene regulatory regions • If homozygous inversion: normal meiosis • If heterozygous inversion: abnormal meiosis- crossing-over within inversion heterozygotes has serious genetic problems-formation of inversion loops

20. Cytological effects of meiosis of heterozygosity for a deletion

21. Consequences of crossing-over in a paracentric inversion If no crossing-over → all gametes are viable

22. Meiotic products resulting from a single crossover within a heterozygous, pericentric inversion loop

23. Translocation • A translocation is a chromosomal mutation in which there is a change in the position of particular chromosome segment • No genetic material is lost or gained (in a population of chromosomes) due to translocation • Intrachromosomal translocations involve a change in the position of a chromosome segment within the same chromosome

24. Translocation • Interchromosomal translocations involve more than one chromosome • Interchromosomal translocations that result in a one-way transfer of genetic material from one chromosome to another are called nonreciprocal translocations • If segments are exchanged it is a reciprocal translocation

25. Chromosomal Translocations

26. Translocation • Translocations alter the linkage relationships of genes • Human cancers such as chronic myelogenous leukemia (CML), Burkitt’s lymphoma, and acute promyelocytic leukemia (APL) result from chromosomal translocations

27. Balanced Chromosomal Translocations

28. CML • Fatal cancer • Uncontrolled growth of WBC stem cells • 90% have Philadelphia chromosome • Activated oncogene c-abl (protein tyrosine kinase)

29. Origin of the Philadelphia chromosome in chronic myelogenous leukemia (CML) by a reciprocal translocation involving chromosomes 9 and 22

30. FISH Analysis of Ph Chromosome • Probes for abl and bcr genes tagged with fluorescent markers • abl gene fluoresces red or pink • bcr gene fluoresces green • Ph- cells show evidence of 2 markers of each color • Cells with bcr-abl fusion gene (Ph+) show 1 normal marker of each color and 1 fused marker (often appears yellow)

31. Burkitt’s lymphoma • Virus induced cancer • B-cells are affected • c-myc oncogene is translocated

32. APL • Acute leukemia: cancer of the blood cells (leukemia) that characteristically comes on abruptly and (if not treated) progresses rapidly • Differentiation is blocked at the promyeloid (precursors of macrophages and granulocytes) cell stage • Formation of PML/RARalpha fusion protein • Nonfunctional RAR and PML

33. Acute Promyelocytic Leukemia (APL) is due to a reciprocal translocation involving chromosomes 15 and 17

34. Acute Promyelocytic Leukemia (APL) is due to a reciprocal translocation involving chromosomes 15 and 17

35. Acute Promyelocytic Leukemia (APL) is due to a reciprocal translocation involving chromosomes 15 and 17

36. Position Effect • Position effect is a change in the phenotypic expression of one or more genes as a result of a change in the gene’s position in the genome • Euchromatin versus heterochromatin

37. Fragile Sites and Fragile X Syndrome • Some chromosomes develop narrowings or gaps which are called fragile sites, where the chromosome is prone to breakage • The human condition fragile X syndrome is caused by a fragile site on the long arm of the X chromosome

38. Diagram of a human X chromosome showing the location of the fragile site responsible for fragile X syndrome

39. Fragile Sites and Fragile X Syndrome • The fragile X trait is inherited as a Mendelian trait • The fragile X site was localized to a particular region on the X chromosome using cytogenetics, linkage analysis, and somatic cell hybridization techniques

40. Fragile Sites and Fragile X Syndrome • CGG repeats at fragile X site: • Normal: X = 29 • Carrier: 55-200 copies • Fragile X syndrome: 200-1300 copies • Affected males: mental retardation in 80% of individuals • Heterozygote females: milder symptoms, 30% mental retardation

41. VARIATIONS IN CHROMOSOME NUMBER • Euploid organisms have a complete set of chromosomes or an exact multiple • For example, diploid organisms such as humans that have two sets of chromosomes are euploid • Aneuploid organisms do not have a complete set of chromosomes or an exact multiple • This includes chromosomes with duplications or deletions

42. Changes in One or Few Chromosomes • In aneuploidy, one or several chromosomes are lost from or added to the normal set of chromosomes • In animals, aneuploidy is generally lethal (with exceptions) • Aneuploidy in diploid organisms usually occurs in one of four ways

43. Changes in One or Few Chromosomes • Nullisomy (the cell is 2N - 2) • Monosomy (the cell is 2N - 1) • Trisomy (the cell is 2N + 1) • Tetrasomy (the cell is 2N + 2)

44. Normal (theoretical) set of metaphase chromosomes in a diploid (2N) organism (top) and examples of aneuploidy (bottom)

45. Changes in One or Few Chromosomes • In humans, autosomal aneuploidy occurs only rarely, and more commonly with the sex chromosomes • Down’s syndrome results from a trisomy of chromosome 21

46. A child with Down’s Syndrome

47. Changes in Complete Sets of Chromosomes • Monoploidy (one set of chromosomes) and polyploidy (several sets of chromosomes) are euploid states that are lethal to animal species but exist in plants

48. Variations in number of complete chromosome sets

49. Number and type of chromosomal abnormalities among spontaneous abortions and live births in 100,000 pregnancies Klinefelter Syndrome: XXY XXXY XXYY Klinefelter syndrome (male) Turner syndrome (female) Triple X (female)

50. Turner Syndrome • 1/10,000 females are affected • Female • Sterile • 99% of all 45,X embryos die before birth • No major effects until puberty  fail to develop secondary sexual characteristics • Poorly developed breasts and immature internal sexual organs • Shorter than average  2 X chromosomes are needed for normal development in females