1. CHROMOSOMAL ABERRATION (STRUCTURAL)
TASMIN WAHAB

2. Chromosomes
The chromosomes have been considered as the physical bases of heredity because they have a special organization, individuality, functions and are capable of self-reproduction. Their main chemical constituent is DNA, an universally accepted genetic or hereditary material, found to carry genetic informations from one generation to next generation.

3. CHROMOSOMES

4. The Global Structure of Chromosome
Nucleotides --> DNA --> Gene --> Chromosome --> Genome
Human DNA is ~ 2 meters long.
Specialized proteins bind to and fold DNA into coils and loops, providing higher level of organization.
The most important function of DNA is to carry genes. The information that specifies all the proteins that make up an organism-including information aobut when, in what types of cells, and in what quantity each protein is to be made.
The complete set of information in an organism’s DNA is called its genome. The genome of eucaryotes are packed into a set of chromosomes. To pack 2 meter DNA into a nucleus is equivalent to packing 40 km of extremely find thread into a tennis ball.

5. Therefore genetic information is found on our chromosomes

6. repetitive (satellite) sequence DNA repetitive sequence (TTAGGG)n
Chromosome
repetitive (satellite) sequence DNA
repetitive sequence (TTAGGG)n
DNA
telomere
short (p-) arm
centromere
chromatid
long (q-) arm
telomere

7. Telomeres of human chromosomes

8. Identifying chromosomes
Chromosomes can be identified by:
Their size
Their shape (the position of the centromere) NB Chromosomes are flexible
Banding patterns produced by specific stains (Giemsa)
Chromosomes are analysed by organising them into a KARYOTYPE
© Biologyreference.com
© 2007 Paul Billiet ODWS

9. Human Chromosomes We have 46 chromosomes, or 23 pairs.
44 of them are called autosomes and are numbered 1 through 22. Chromosome 1 is the longest, 22 is the shortest.
The other 2 chromosomes are the sex chromosomes: the X chromosome and the Y chromosome.
Males have and X and a Y; females have 2 X’s: XY vs. XX.

10. Chromosomal aberrations
A chromosome anomaly, abnormality or aberration reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes.

11. Chromosomal aberrations
Substantial changes in chromosome structure
Typically affect multiple genes (loci)

12. Radiation Induced Chromosomal Aberrations

13. Chromosomal aberration may be divided into two broad categories: 1
Chromosomal aberration may be divided into two broad categories: 1. Structural changes 2. Numerical changes

14. Structural changes

15. Changes in the number of genes
deletions: genes missing
duplications: genes added

16. Changes in the location of genes
inversions: 180o rotation
translocations: exchange

17. DELETIONS

18. DELETIONS
Deletions involve the loss of a chromosome segment Because these mutations are due to the loss of genetic material, they cannot revert to wild type

19. Types of DELETIONS

20. DELETIONS Arise through spontaneous breakage
some chromosomes have fragile spots
radiation, UV, chemicals, viruses may increase breakage

21. x DELETIONS May arise through unequal crossing over A B C D E F G
A B C D E F F G
A B C D E G
Deletion Duplication

22. DELETIONS
The effects of the deletion depend on which genes are deleted And on what alleles of these genes reside on the homologous chromosome

23. DELETIONS

24. DELETIONS Deletion of one allele of a homozygous wild type  normal.
Deletion of heterozygote  normal or mutant (possibly lethal).
Deletion of centromere  typically results in chromosome loss(usually lethal; no known living human has a complete autosome deleted).

25. Deletion Mapping A B C D E F a b c d e f a b c d e f A B E F F1:WT
A B C D E F
a b c d e f X
a b c d e f
deletion
A B E F
F1:
A B C D E F
All WT
50%
a b c d e f
&
A B E F
Mutant phenotype for c and d
(c & d phenotype “uncovered by deletion)
50%
a b c d e f

26. DELETIONS
Any genes in the deleted region are now present in a hemizygous condition on the homologue
If these alleles are recessive, their phenotypes will now be expressed. This phenomenon is called pseudodominance.
pseudodominance -- expression of a recessive allele when placed over
a deletion

27. Several human disorders are due to deletions
Several human disorders are due to deletions. All of these are small deletions - large deletions apparently cannot be tolerated Also, the deletions have their effects in heterozygotes; homozygotes are probably lethal

28. Ring Chromosome

29. X Ring

30. Retinoblastoma Chromosome 13 ring syndrome
A syndrome in which parts of both ends of chromosome 13 have been lost (deletion) and the two broken ends reunited to form a ring-shaped figure.

31. Ring chromosome 18 syndrome
One or both ends of chromosome 18 have been lost .
The ends are joined forming a ring-shaped figure.
Associated with mental retardation, limb deformities and other defects.
No two people with Ring 18 are exactly alike, and share the same symptoms.

32. Cri-du-chat Syndrome
chromosome 5p deletion

33. Cri-du-chat Syndrome Mental retardation Slow motor skill development
Low birth weight and slow growth
Small head (microcephaly)
Partial webbing of fingers or toes
Wide-set eyes (hypertelorism)
High-pitched cry

34. Cystic Fibrosis
Mucous in the airways cannot be easily cleared from the lungs

35. Cystic Fibrosis
Colon
Feeding problems because of difficulty swallowing and sucking.
Low birth weight and poor growth.
Severe cognitive, speech, and motor delays.
Behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements.
Unusual facial features which may change over time.
Excessive drooling.
Constipation.
Strong salt taste on dry skin
Sticky mucus
secretion
Pancreas
Ducts are filled with sticky mucus. Scaring of tissue

36. DUPLICATIONS A segment of chromosome is doubled A good example of duplication is seen in the Bar mutants of Drosophila

37. Duplications
A chromosomal duplication is usually caused by abnormal events during recombination
Figure 8.5

38. Duplication
Tandem, reverse tandem, and tandem terminal duplications are three types of chromosome duplications.
Duplications result in un-paired loops visible cytologically.
Fig. 16.5

39. Duplication
Duplication type
Phenotypic consequences of duplications correlated to size & genes involved
Duplications tend to be less detrimental

40. Duplication
Phenotypic consequences of duplications correlated to size & genes involved
Duplications tend to be less detrimental

41. Fig. 16.6, Drosophila Bar and double-Bar results from duplications caused by unequal crossing-over (Bridges & Müller 1930s).

42. Unequal crossing-over produces Bar mutants in Drosophila.

43. Bar-eye Phenotype due to Duplication
Figure: 07-12a
Caption:
(a) Genotypes & phenotypes.

44. Duplications Generate Gene Families
Genes derived from a single ancestral gene
Figure 8.9

45. Gene Families Well-studied example is the globin gene family
Genes encode proteins that bind oxygen
Globin gene family
14 homologous genes derived from a single ancestral gene
Accumulation of mutations in the members of generated
Globin genes expressed during different stages of development
Globin proteins specialized in their function

46. Beckwith-Wiedemann syndrome
Duplications of chromosome region 11p15
Patient with Beckwith-Wiedemann syndrome. The face shows the enlarged tongue (macroglossia), the ear the typical earlobe creases - Marcel Mannens

47. INVERSIONS

48. An inversion results when a segment of a chromosome gets reoriented 180o from normal This requires two breaks in the chromosome

49. 180o reversal of chromosome segment
Inversions
180o reversal of chromosome segment
A B C D E F G H I J K
A B C H G F E D I J K
180O

50. INVERSIONS May change phenotype through “position effects”
No loss of genetic information
Many inversions have no phenotypic consequences
May change phenotype through “position effects”
move active genes to sites generally inactive; lose gene function
move inactive genes to sites generally active; gain gene function

51. INVERSIONS Homozygous: ADCBEFGH  no developmental problems ADCBEFGH
Heterozygote: ABCDEFGH  unequal-crossing
Gamete formation differs, depending on whether it is a paracentric inversion or a pericentric inversion.

52. Inversion Heterozygotes
Individuals with one copy of a normal chromosome and one copy of an inverted chromosome
Usually phenotypically normal
Have a high probability of producing gametes that are abnormal in genetic content
Abnormality due to crossing-over within the inversion interval
During meiosis I, homologous chromosomes synapse with each other
For the normal and inversion chromosome to synapse properly, an inversion loop must form
If a cross-over occurs within the inversion loop, highly abnormal chromosomes are produced

53. The homologous chromosomes attempt to align similar regions next to each other as well as they can.

54. The chromosomes assume this characteristic loop configuration

55. This causes no problem, unless crossing over occurs within the inverted region

56. Inversions and Crossing-Over
Inversions cause complicated synapsis at meiosis for heterozygotes
Chromatids involved in crossing over do not allow development of functional gametes
Only parental type chromosomes passed on

57. Crossing-over in paracentric inversion:
(inversion does not include the centromere)
Results:
1 normal chromosome
2 deletion chromosomes
(inviable)
1 inversion chromosome
(all genes present; viable)

58. Crossing-over in paracentric inversion:
(inversion does not include the centromere)
Results:
1 normal chromosome
2 deletion chromosomes
(inviable)
1 inversion chromosome
(all genes present; viable)

59. Crossing-over in paracentric inversion:
(inversion does not include the centromere)
Results:
1 normal chromosome
2 deletion chromosomes
(inviable)
1 inversion chromosome
(all genes present; viable)

60. Crossing-over in pericentric inversion:
(inversion includes the centromere)
Results:
1 normal chromosome
2 deletion/duplication chromosomes
(inviable)
1 inversion chromosome
(all genes present; viable)

61. Since the only viable offspring are those that result from gametes which did not have crossovers within the inverted region, it appears that crossing over in the inversion has been suppressed So this is referred to as crossover suppression

62. Keep in mind that crossing over actually does occur in this region We just can’t observe the result in the progeny The genetic result is very tight linkage of genes in an inverted segment

63. A Dicentric Recombinant 9 Derived from a Paracentric Inversion:
A 4-year-old girl has been shown to have a karyotype of 46,XX,-9,+rec(9),dup pinv(9) (q22.1q34.3)mat, with duplication 9pter-q22.1 and deficiency 9q34.3-qter.
The recombinant was derived by two crossovers, one within the inversion loop and a second outside the inversion loop, between 9q21 and the beginning of the mieotic inversion at 9q22.1.

64. Elucidation of the centromere involvement in an inversion (13) by fluorescent in situ hybridisation.
A newborn infant with phenotypic features of trisomy for distal 13q was found to have recombinant inversion duplication involving the (13)(q22-->qter) region.
Parental karyotypes showed that the mother had a normal 46,XX complement and the father had an apparently balanced pericentric inversion of a chromosome

65. TRANSLOCATIONS

66. A translocation is a chromosomal mutation in which a segment of a chromosome changes position

67. Translocation

68. As with inversions, translocations usually involve no net gain or loss of genetic material

69. Because of this, there are usually no phenotypic consequences for being heterozygous. Like other chromosome rearrangements, if breakpoints occur within genes, can result in mutation of that gene. The most frequent and important type of translocation is the reciprocal translocation.

70. Homologues can pair properly, and crossing over poses no problems

71. But meiosis is a problem in heterozygotes
But meiosis is a problem in heterozygotes. Homologues assume a characteristic cross-shape (cruciform) arrangement at metaphase Disjunction can occur in 3 ways, 2 of which produce abnormal gametes

72. Meiosis in a balanced translocation heterozygote, with no crossing over
Rare event

73. Figure 8.15
8-42

74. How translocation affects the products of meiotic segregation:
Gamete formation differs for homozygotes and heterozygotes:
Homozygotes: translocations lead to altered gene linkage.
If duplications/deletions are unbalanced, offspring may be inviable.
Homozygous reciprocal translocations  “normal” gametes.
Heterozygotes: must pair normal chromosomes (N) with translocated chromosomes (T); heterozygotes are “semi-sterile”.
Segregation occurs in three different ways (if the effects of crossing-over are ignored):
Alternate segregation, ~50%: 4 complete chromosomes, each cell possesses each chromosome with all the genes (viable).
Adjacent 1 segregation, ~50%: each cell possesses one chromosome with a duplication and deletion (usually inviable).
Adjacent 2 segregation, rare: each cell possesses one chromosome with a duplication and deletion (usually inviable).

75. Translocations and Fertility
Only 1/3 of the segregations will lead to usable gametes
Fertility is reduced by 2/3

76. Translocations can sometimes be harmful
Translocations can sometimes be harmful. Even though there is no gain or loss of genetic material, the change in location of a segment may alter the regulation of a gene in the segment

77. This is especially apparent if the gene is involved in the regulation of cell division. Lack of proper regulation of such a gene can result in cancer. In which case, the gene becomes known as an oncogene

78. Translocations and Human Cancers
All these involve oncogenes
oncogenes: genes involved in cell proliferation
normally active only at specific times
embryonic/fetal development, etc.
shut off under normal conditions

79. An example is the translocation between chromosomes 9 and 22, creating the “Philadelphia chromosome” This causes about 90% of the cases of chronic myelogenous leukemia

80. Myelogenous leukemia
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the blood and bone marrow

81. Myelogenous leukemia

82. Fig Origin of the Philadelphia chromosome in chronic myelogenous leukemia (CML) by a reciprocal translocation involving chromosomes 9 and 22
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

83. Burkitt’s lymphoma

84. Burkitt’s Lymphoma
Translocations between chr. 8 and one of three others:
8 & 2 or 8 & or & 22
Chr. 8 has an oncogene
Chr. 2, 14, 22 have genes coding for antibody production and their enhancer genes
Oncogene becomes highly active under control of enhancers!

85. Burkitt’s lymphoma is usually (90%) caused by a translocation (8 and 14)

86. Burkitt’s lymphoma
A reciprocal translocation has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancers of the antibody heavy chain genes on chromosome 14.

87. These are examples of the phenomenon called position effect The phenotype seen depends not just on the allele of a particular gene, but also the position of the gene in a particular chromosome

88. THANKYOU