Chromosomal Aberrations (Structural).pptx

Structural Chromosomal Aberrations by Dr. S M MUHALLIL - Postgraduate Scholar.

1. Chromosomal Aberrations (Structural) Presented By : Dr. Muhallil ( Postgraduate Scholar ) Moderator : Dr. Shamima Banoo ( Assistant Professor ) Postgraduate Department Of Anatomy

2. LEARNING OBJECTIVES Introduction to Chromosomes Chromosomal Aberrations Different types of Structural Aberration Related Clinical Syndromes Summary

3. INTRODUCTION

4. Each chromosome has - One Centromere . Two Telomeres . Short arm Long arm

5. Most species have a characteristic number of chromosomes, EACH WITH A DISTINCT SIZE AND STRUCTURE

6. However, variations in number and structure periodically arise. These variations are termed as chromosomal Aberrations and they frequently play an important role in evolution.

7. Types of chromosomal Aberrations Chromosomal Aberration Numerical Structural

8. Structural Aberration in Chromosomes

9. DUPLICATION It is an aberration in which, part of chromosome has been DOUBLED. Original chromosome Duplicated chromosome

10. Types of Duplication

11. Tandem Duplication AB•CDEFG AB•CDEF EF G Chromosome aberration in which a duplicated chromosome segment is adjacent to the original segment.

12. Displaced Duplication AB•CDEFG AB•CDEFG EF Chromosome aberration in which the duplicated segment is some distance from the original segment, either on the same chromosome or on a different one

13. Reverse Duplication AB•CDEFG AB•CDEF FE G Duplication of a chromosome segment in which the sequence of the duplicated segment is inverted relative to the sequence of the original segment.

14. Effect Of Chromosome Duplication An individual with duplication on chromosomes Homozygous for duplication Heterozygous for duplication Duplication has occurred on both homologous chromosomes Duplication has occurred on one chromosome while other chromosome is normal

15. The pairing and synapsis of homologous regions require that one or both chromosomes loop and twist so that these regions are able to line up. Original chromosome Duplicated chromosome Alignment in prophase 1 of meiosis The duplicated region EF must loop out to allow homologous sequences of the chromosomes to align

16. How does chromosome duplication alter the phenotype?

17. ABNORMAL GENE DOSAGE

18. Interaction of gene products Normal chromosome Gene expression Developmental process often require the interaction of many genes. Development may be affected by relative amounts of gene products

19. Interaction of gene products Mutant chromosome Gene expression Duplicated segment of chromosome Development gets affected by extra amount gene product It results due to increase in gene product from one gene while other gene products remain normal

20. Unequal Crossing Over Unequal crossing over is frequently the cause of RED – GREEN colour blindness in humans. Perception of colour is affected by RED and GREEN opsin genes.

21. These Genes Are Found On The X Chromosome And Are 98% Identical In Their DNA Sequence.

22. Red opsin gene Green opsin gene Chromosome do not align properly resulting in unequal crossing over Unequal Crossing over One resulting chromosome has two green opsin genes (duplication) Another chromosome has no green opsin gene (deletion)

23. When a male inherits the chromosome that is missing one of the opsin genes, it results in the RED – GREEN colour blindness

24. IMPORTANCE OF DUPLICATION IN EVOLUTION Chromosome duplications are one way in which New Genes Evolve. In many cases, existing copies of a gene are not free to vary because they encode a product that is essential to development or function. However, after a chromosome undergoes duplication , extra copies of genes within the duplicated region are present.

25. The original copy can provide the essential function , whereas an extra copy from the duplication is free to undergo mutation and change . Over evolutionary time, the extra copy may acquire enough mutations to assume a new function that benefits the organism.

26. “A well studied example of this concept is the evolution of GLOBIN GENE in Humans”

27. Humans possess 13 different genes found on chromosomes 11 and 16 that encode globin like molecules, which take part in oxygen transport.

28. Gene duplication Gene duplication Multiple duplication Multiple duplication

29. DELETION AB•CD EF G AB•CDG Deletion refers to loss of chromosomal segment resulting in the loss of genes.

30. The break in the chromosomes may be caused by several agents such as CHEMICALS, DRUGS AND RADIATIONS.

31. The BREAKAGE usually occurs at random and either in- both the chromatids of a chromosome – CHROMOSOME BREAK CHROMATID BREAK or only in one chromatid –

32. Segment that is LOST due to Deletion does not survive , because it LACKS the centromere .

33. The portion of the chromosome CARRYING the centromere functions as a genetically deficient chromosome

34. Types Of Deletion Terminal deletion Intercalary or interstitial deletion

35. Terminal Deletion It refers to the loss of a segment from one or the other end of the chromosome. The terminal acentric part of the chromosome is unable to survive and causes terminal deletion. + Origin of terminal deletion

36. Intercalary or Interstitial deletion It involves the loss of an intercalary segment of the chromosome with the reunion of terminal segments. Therefore, the intercalary deletion is caused by two breaks and the reunion of terminal parts + Origin of Intercalary Deletion

37. Behaviour of deletion of chromosome In individuals heterozygous for deletions , the normal chromosome must loop out during the pairing of homologs in prophase I of meiosis to allow the homologous regions of the two chromosomes to align and undergo synapsis. Formation of deletion loop during pairing of homologs in prophase 1 One Normal chromosome One chromosome with Deletion

38. Phenotypic Effects of Deletions These effects depend on TYPE OF GENES that are located in the deleted region.

39. If the deletion includes the centromere , then the chromosome will not segregate

40. Many deletions are lethal in the HOMOZYGOUS state

41. Even individuals HETEROZYGOUS for a deletion may have multiple defects for 3 reasons: - IMBALANCES IN THE AMOUNTS OF GENE PRODUCTS

42. PSEUDODOMINANCE.

43. HAPLO-INSUFFICIENCY

44. CHROMOSOME DELETION IN HUMANS

45. CRI DU CHAT SYNDROME This syndrome results from a deletion on the short arm of chromosome 5. It is also known by other names such as “ 5p Deletion Syndrome” And “ Lejeune’s Syndrome” . Incidence : - 1 in 25,000 live births. Male : Female ratio: - 4:3

46. Clinical Manifestation Cry that is high – pitched and sounds like a cat Low set or abnormally shaped ears MENTAL RETARDATION Microcephaly and Micrognathia

47. Ashley’s Story Ashley Naylor had 5p- syndrome also called CRI-DU-CHAT SYNDROME. Ashley defied her doctors’ expectations . She learned to walk with the aid of a walker and express herself using sign language and a communication device. With early intervention and education, Ashley found the resources and additional encouragement she needed to succeed. SHE DIED SHORTLY BEFORE HER SIXTH BIRTHDAY FROM PNEUMONIA

48. MICRO-DELETIONS In this aberration, there is deletion of few CONTIGUOUS GENES – Hence, known as MICRO-DELETION SYNDROME or CONTIGUOUS GENE SYNDROME . Sites where these deletions occur are called CONTIGUOUS GENE COMPLEXES These complexes are usually identified by Fluorescence in situ hybridization (FISH)

49. Examples Of Micro-deletion Angelman Syndrome Prader – Willi Syndrome

50. Angelman syndrome This syndrome results from the micro – deletion on the long arm of MATERNAL CHROMOSOME 15

51. Intellectual disability Inability to speak Poor motor development Prone to unprovoked and prolonged periods of laughing

52. Prader - Willi syndrome This syndrome results from the micro – deletion on the long arm of PATERNAL CHROMOSOME 15

53. Hypotonia Obesity Intellectual disability Hypogonadism Undescended testes

54. COMPARISON Angelman syndrome Prader – willi syndrome Chromosome 15 Chromosome 15 GENOMIC IMPRINTING Maternal Paternal

55. GENOMIC IMPRINTING EPIGENETIC PROCESS MECHANISM : Trisomic Conceptus resulting in a “RESCUED CELL”

56. INVERSION AB•CD EF G AB•CD FE G It is a chromosomal aberration in which a chromosome segment is inverted

57. For an INVERSION to take place, the chromosome must break in two places

58. Types of inversion PARA-CENTRIC INVERSIONS Inversions that do not include the centromere PERI-CENTRIC INVERSIONS Inversions that include the centromere

59. Phenotypic Effects of Inversion Individual organism with inversions have neither lost nor gained any genetic material; only the DNA sequence has been altered .

60. An inversion may break a gene into two parts , with one part moving to a new location and destroying the function. Even when the chromosome breaks lie between genes , phenotypic effects may arise from the INVERTED GENE DISORDER. POSITION EFFECT

61. Inversion In Meiosis When an individual is homozygous for a particular inversion, no special problems arise in meiosis, and the two homologous chromosomes can pair and separate normally

62. When an individual is heterozygous for an inversion. The gene order of the two homologs differs, and the homologous sequences can align and pair only. If the two chromosomes form an INVERSION LOOP The heterozygotes has one normal chromosome One chromosome with an inverted segment In prophase I of meiosis, the chromosomes form an inversion loop Formation of inversion loop

63. Formation of INVERSION LOOP allows the homologous sequences to ALIGN

64. Importance Of Inversion In Evolution G-banding patterns reveal that several human chromosomes differ from those of CHIMPANZEES by only a peri -centric inversion Peri -centric inversion

65. Madison’s Story Madison and Grant were excited about getting the results of the AMNIOCENTESIS because Madison had never carried a pregnancy this far before. Then the doctor’s office called and asked them to come in for the results. Expecting bad news, the couple was surprised and confused to learn that the foetus had an inverted chromosome . Some of the bands that normally appear on Chromosome 11 were flipped. Before the GENETIC COUNSELLOR would describe which genes might be affected, she advised that the parents to-be have their chromosomes checked. Karyotyping revealed that Madison had the same inversion as the foetus . Because Madison was healthy, the unusual chromosome would likely not harm their daughter. When she was older, however, she might, like her mother, experience pregnancy loss.

66. TRANSLOCATIONS A translocation entails the MOVEMENT OF GENETIC MATERIAL between NON- HOMOLOGOUS chromosome or within the same chromosome.

67. Translocation should not be confused with CROSSING OVER, in which there is an exchange of genetic material between HOMOLOGOUS chromosomes.

68. Types of Translocation Non-reciprocal translocation Reciprocal Translocation

69. Non – Reciprocal Translocation AB•CD EF G MN•OPQRS AB•CDG MN•OP EF QRS In this translocation, genetic material moves from one chromosome to another without any reciprocal exchange.

70. Reciprocal Translocation In this type of translocation, there is a two-way exchange of segments between the chromosomes AB•CD EFG MN•OP QRS AB•CD QRS MN•OP EFG

71. EFFECTS OF TRANSLOCATION Translocations can affect a phenotype in several ways.

72. First , they can physically link genes that were formerly located on different chromosomes . These new linkage relations may affect gene expression A POSITION EFFECT

73. Second , the chromosome breaks that bring about translocations may take place within a gene and disrupt its function.

74. Molecular geneticists have used these types of effects to map human genes

75. A WELL STUDIED EXAMPLE TO THE MAPPING OF HUMAN GENES IS “ NEUROFIBROMATOSIS”

76. Linkage studies first placed the locus that, when mutated, causes neurofibromatosis on CHROMOSOME 17 Neurofibromatosis results from an autosomal dominant mutation. But its precise location was unknown.

77. Geneticists later narrowed down the location when they identified two patients with neurofibromatosis who possessed a translocation affecting CHROMOSOME 17

78. Deletions frequently accompany translocations Example to this concept is ROBERTSONIAN TRANSLOCATION

79. ROBERTSONIAN TRANSLOCATION Translocation in which the long arms of two acrocentric chromosomes become joined to a common centromere , resulting in a chromosome with two long arms and usually another chromosome with two short arms The short arm of one acrocentric chromosome Is exchanged with long arm of another ch. Creating a large metacentric chromosome And a fragment that often fails to segregate and is lost Robertsonian translocation

80. Rhiannon’s Story When Rhiannon P. was born, while her parents marveled at her beauty, the obstetrician was disturbed by her facial features : the broad, tilted eyes and sunken nose looked like the face of a child with Down syndrome . The doctor might not have noticed, except that he knew that the mother, Felicia, had had two spontaneous ABORTIONS, a family history suggesting a CHROMOSOME PROBLEM . So the doctor looked for the tell-tale single crease in the palms of people with Down syndrome, and found it. Gently, he told Felicia and her husband Matt that he’d like to do a CHROMOSOME CHECK . Two days later, the new parents learned that their daughter has an unusual form of Down syndrome that she inherited from one of them, rather than the more common “extra chromosome” form.

81. Since Matt’s mother and sister also had several miscarriages , the exchanged chromosomes likely came from his side. KARYOTYPES OF MATT AND FELICIA CONFIRMED THIS: Matt was a translocation carrier . One of his CHROMOSOME 14S had attached to one of his CHROMOSOME 21S , and distribution of the unusual chromosome in meiosis had led to various imbalances. Rhiannon has VERY MILD DOWN SYNDROME . She has none of the physical problems associated with the condition, and she does well in school with the help of a special education teacher. Matt and Felicia chose to see the bright side—each conception will have a one-in-three chance of having balanced chromosomes. SOME DAY THEY HOPE TO GIVE RHIANNON A BROTHER OR SISTER

82. Fragile sites Fragile sites are chromosomal regions susceptible to breakage under certain conditions

83. Fragile sites Common fragile sites Rare fragile sites

84. These are often the locations of chromosome breakage and rearrangements in cancer cells, leading to – chromosome deletions, translocations, and other chromosome rearrangements. Common fragile sites

85. These are often associated with genetic disorders, such as intellectual disability. Rare fragile sites

86. One of the most intensively studied Rare fragile sites is located on the human X chromosome and is associated with FRAGILE – X SYNDROME

87. FRAGILE – X SYNDROME It is the SECOND MOST commonly inherited cause of moderate intellectual disability after Down syndrome. Incidence : - 1 in 4000 male births

88. An 8-year-old mentally deficient boy has a – Relatively Normal Appearance With A Long Face And Prominent Ears. His 6-year-old sister , who also has this syndrome Siblings with Fragile X Syndrome.

89. ISOCHROMOSOME It is a chromosome that has identical arms. Formation: - When the centromeres part in the wrong plane. Isochromosomes are known for chromosomes 12 and 21 and for the long arms of the X and the Y. Normal

90. Ring chromosome They arise when TELOMERES ARE LOST , leaving sticky ends that adhere. Most ring chromosomes consist of DNA repeats and do not affect health. Broken ends Broken ends

91. Summary There are mainly 4 types of Structural chromosomal aberrations Duplication is a mutation in which, part of chromosome has been DOUBLED. Deletion refers to loss of chromosomal segment resulting in the loss of genes. Micro-deletion is deletion of few CONTIGUOUS GENES Angelman and Prader willi syndrome occur due to Genomic Imprinting Inversion is a chromosomal aberration in which a chromosome segment is inverted Translocation is MOVEMENT OF GENETIC MATERIAL between NON- HOMOLOGOUS chromosome Isochromosome is a chromosome that has identical arms. Ring chromosome arise when TELOMERES ARE LOST , leaving sticky ends that adhere.

92. THANK YOU